Clinical Neurology and Neurosurgery

Transcalvarial brain herniation volume as a predictor of posttraumatic hydrocephalus after decompressive craniectomy Publication date: July 2019 Source: Clinical Neurology and Neurosurgery, Volume 182 Author(s): Angelo R. Silva Neto, Marcelo M. Valença Abstract Objectives In patients undergoing decompressive craniectomy for traumatic brain injury(TBI) there has been reported an incidence of hydrocephalus between 0–45%. There are several radiological and clinical features described in association with development of hydrocephalus. For study the influence of these factors we conducted a retrospective observational single-center cohort study in a tertiary care center with special attention to the transcalvarial herniation(TCH) volume after decompressive craniectomy. Patients and methods: We selected 50 patients that underwent decompressive craniectomy after closed head injury between january 2014 and January 2015. Hydrocephalus was defined as a modified frontal horn index greater than 33%, presence of Gudeman CT scan criteria or insertion of ventriculoperitoneal Shunt. Variables analyzed were: age, post-resuscitation Glasgow coma scale (GCS) score, pupil reactivity, Zunkeller index, presence of hygroma, TCH volume, craniectomy diameter and distance of craniectomy from midline. Logistic regression was used with hydrocephalus as the primary outcome measure. Results 17 patients developed hydrocephalus (34%). TCH volume after decompression(p < 0.01), subdural hygroma (p < 0.01), lower admission Glasgow Coma Scale score (p = 0.015), unilateral pupil reactivity(p = 0.042) and higher Zumkeller index(p = 0.044) were significant risk factors for hydrocephalus. Logistic regression analysis showed that factors independently associated with the development of hydrocephalus was the TCH volume (odds ratio 11.08; 95%CI 2.10, 58.4; p = 0.0046), and presence of hygroma (odds ratio 49.59; 95%IC 4.1, 459; p = 0.002). Conclusions There was a clear association between severity of TBI, TCH volume and subdural hygroma with the development of hydrocephalus. Clinicians should follow closely patients with those findings in order to avoid late deterioration.

Cervical carotid pseudoaneurysm eroding the skin with impending blowout Publication date: July 2019 Source: Clinical Neurology and Neurosurgery, Volume 182 Author(s): Abdelaziz Amllay, Ahmad Sweid, Stavropoula Tjoumakaris, Michael R. Gooch, Robert H. Rosenwasser, Pascal M. Jabbour

Two sisters with anti-MuSK-positive myasthenia gravis Publication date: July 2019 Source: Clinical Neurology and Neurosurgery, Volume 182 Author(s): Erdal Kurt, Can Ebru Bekircan-Kurt, Bahadır Konuşkan, İrem Erkent, Ersin Tan, Banu Anlar

Predictability of vascular conflict by MRI in trigeminal neuralgia Publication date: July 2019 Source: Clinical Neurology and Neurosurgery, Volume 182 Author(s): Patrick W. Hitchon, Girish Bathla, Toshio Moritani, Marshall T. Holland, Jennifer Noeller, Kirill V. Nourski Abstract Objective: Magnetic resonance imaging (MRI) has been investigated extensively in its success or failure to identify preoperative vascular compression in patients with trigeminal neuralgia (TN). To this end, we reviewed our case load to evaluate the concordance or discordance between preoperative MRI and intraoperative findings. Patients and Methods: Sixty-nine patients with Type 1 TN and retrievable MRI images, operative reports, and intraoperative photographs were retrospectively reviewed. Results: Our review shows that MRI predicted conflict (arterial or venous) in 58 cases that was confirmed at surgery in 55 cases. MRI predicted no conflict in 11 cases, whereas surgery revealed no conflict in a total of 6 cases. Thus, in predicting conflict at surgery, MRI had a sensitivity of 87%, and specificity of 50%, respectively. Conversely, MRI accurately predicted intraoperative conflict (positive predictive value) in 95% of cases, and the absence of conflict (negative predictive value) in 27%. These results reveal that MRI is more accurate in predicting conflict than the absence of conflict at surgery. Conclusion: Our results support the reliance on the clinical diagnosis of Type 1 TN to recommend microvascular decompression (MVD). The presence of vascular compression by MRI should encourage the surgeon to persevere in search of the offending vessel when it proves elusive. MRI positive and negative predictive values for conflict are expected to increase with better resolution imaging. The absence of neurovascular conflict on high-resolution MRI should not negate MVD in the treatment of a patient with classic TN.

Cost of hospitalization for aneurysmal subarachnoid hemorrhage in the United States Publication date: July 2019 Source: Clinical Neurology and Neurosurgery, Volume 182 Author(s): Sumul Modi, Kavit Shah, Lonni Schultz, Rizwan Tahir, Muhammad Affan, Panayiotis Varelas Abstract Objective Recent large-scale studies describing hospitalization cost trends secondary to aneurysmal subarachnoid hemorrhage (aSAH) in the United States are lacking. We sought to discover the impact of aSAH-related factors upon its hospitalization cost. Patients and methods Patients with a primary diagnosis of aSAH were selected utilizing the National Inpatient Sample. Regression analyses were used to evaluate the impact of aSAH-related factors on hospitalization costs. Results From 2002–2014, 22,831 cases of aSAH were identified. The inflation-adjusted mean cost of hospitalization was $82,514 (standard deviation ± $54,983). The proportion of males was lower (31%), but a higher cost of $3385 (± $685; p < .001) remained compared to females. Median length of hospitalization was 16 days (interquartile range 11–23) and each day increase in hospitalization was associated with a cost increase of $3228 (± $19; p < .001). There was no difference in cost between patients undergoing aneurysmal coiling or clipping. When compared to patients < 40 years old, the increase in cost for patients 40–59 years old was $3829 (± $914; p < .001), and $4573 (± $1033; p < .001) for patients 60–79 years old; however, for patients ≥ 80 years old, there was a decrease in cost of $8124 (± $1722; p < .001). Several central nervous system complications were also associated with increased cost. Conclusion aSAH is a significant financial burden on the United States healthcare system. We were able to identify many important factors associated with higher costs, and these results may help us understand resource utilization and develop future cost-reduction strategies.

Nosocomial Infections among Patients with Intracranial Hemorrhage: A Retrospective Data Analysis of Predictors and Outcomes Publication date: July 2019 Source: Clinical Neurology and Neurosurgery, Volume 182 Author(s): Roa'a W. Jaradat, Amro B. Lahlouh, Osama Y. Alshogran, Belal A. Aldabbour, Abedallah AK. Balusha Abstract Objective Intracranial hemorrhage is a critical medical emergency. Nosocomial infections may promote worse outcomes in these vulnerable patients. This study investigated microbial features, predictors, and clinical outcomes of nosocomial infections among patients with multiple subtypes of intracranial hemorrhage. Patients and methods We conducted a retrospective cohort study of patients that were hospitalized with intracranial hemorrhage between January 2015 and October 2018, and divided them into two groups based on the development of nosocomial infection. Within the cohort of patients with nosocomial infections, microbiology and resistance patterns were established across multiple sites of infection. Moreover, consequences of nosocomial infection such as mortality and length of hospital stay were determined. Results A total of 233 cases were identified that met our inclusion and exclusion criteria out of which were 94 cases of nosocomial infection (40.3%) versus 139 cases with no nosocomial infection (59.7%). The most common infections were pneumonia, urinary tract infections, and bacteremia. Resistance accounted for 70.2% of cultures. Multivariable analysis revealed significant association of nosocomial infections with hypertension (OR: 2.62, 95% CI: 1.11–6.16, p = 0.027), hospital LOS (OR: 1.08, 95% CI: 1.05–1.12, p < 0.001), levetiracetam (OR: 3.6, 95% CI: 1.41–0.922, p = 0.007), and GCS category (OR: 5.42, 95% CI: 1.67–17.55, p = 0.005 and OR: 7.63, 95% CI: 2.44–23.87, p < 0.001 for moderate and severe, respectively). Patients with nosocomial infections witnessed a significant increase in the length of hospital stay (23 versus 8 hospital days, p < 0.001). This finding was significant across most types of brain hemorrhage. Mortality was significantly associated with GCS category (OR: 10.1, 95% CI: 4–25.7, p < 0.001) and percutaneous endoscopic gastrostomy tube insertion (OR: 19.6, 95% CI: 4.1–91, p < 0.001). Conclusions Collectively, these findings suggest that nosocomial infections are common among patients with intracranial hemorrhage and can be predictable by considering certain risk factors. Future studies are warranted to evaluate the efficacy of implementing infection control strategies or protocols on these patients to achieve better therapeutic outcomes.

Cefazolin versus vancomycin for neurosurgical operative prophylaxis – A single institution retrospective cohort study Publication date: July 2019 Source: Clinical Neurology and Neurosurgery, Volume 182 Author(s): Anthony V. Nguyen, William S. Coggins, Rishabh R. Jain, Daniel W. Branch, Randall Z. Allison, Ken Maynard, Brian Oliver, Rishi R. Lall Abstract Objectives Cefazolin and vancomycin are common choices for neurosurgical antimicrobial prophylaxis. Cefazolin is typically first-line due to its lower toxicity profile and specificity for gram-positives such as skin commensals, while vancomycin is often reserved for patients with cephalosporin or penicillin allergies. However, one randomized clinical trial demonstrated superiority of vancomycin for cerebrospinal fluid (CSF) shunt insertions at a hospital with a high prevalence of methicillin-resistance Staphylococcus aureus (MRSA). We aimed to evaluate the association of prophylaxis choice and incidence of surgical site infection (SSI) at our own institution. Patients and methods This was a retrospective cohort study of patients who underwent a neurosurgical operation from January 2013 to April 2016 at one particular hospital belonging to our institution. We included patients who received either only cefazolin or only vancomycin as their pre-incisional prophylaxis. Vancomycin was substituted for cefazolin in patients with known penicillin or cephalosporin allergy. Procedures requiring multiple attending surgeons were excluded. We defined a SSI as a confirmed culture isolated from the wound, implant (if pertinent), or CSF (if pertinent) within a year of surgery. Multivariable logistic regression was performed with consideration of antibiotic, operation performed, wound class, and procedure length. Results A total of 859 operations met study criteria; 664 patients received Cefazolin, and 195 received Vancomycin. We identified 22 SSIs, with 14 in the cefazolin (2.2%) and 8 in the vancomycin (4.1%) group. Upon logistic regression, there was no significant association of vancomycin substitution with incidence of SSIs between the two groups (odds ratio, 1.59; 95% CI, 0.42–6.00, p = .49). In the cefazolin group, 8/14 cultures were positive for S. aureus compared to 1/8 of the vancomycin group. Conclusions There was no significant difference in neurosurgical site infection incidence when vancomycin prophylaxis was substituted for cefazolin. S. aureus was isolated from patients who received cefazolin at a higher rate although this was not statistically significant. At our institution, S. aureus makes up 36% of isolated organisms from inpatient and intensive care units. Institutions should consider their own investigations into local antibiograms, SSI rates, and choice of prophylaxis.

Neuronavigation-assisted surgical treatments for medically refractory epilepsy: Single-hospital experience with 4 surgical approaches Publication date: July 2019 Source: Clinical Neurology and Neurosurgery, Volume 182 Author(s): Jia-Sheng Pei, Peng-Fan Yang, Qiao Lin, Yan-Zeng Jia, Hui-Jian Zhang, Ming-Chao Shang, Zhong-Hui Zhong, Shou-Sen Wang Abstract Objective Surgical treatment should be considered for patients with medically refractory epilepsy, and neuronavigation may benefit and reduce the technical difficulties during surgery. In this study, we aimed to report our single-hospital experience of incorporating neuronavigation for treating patients with medically refractory epilepsy using 4 types of surgery. Patients and methods Patients who were diagnosed as medically refractory epilepsy and received neuronavigation-assisted surgery were included in this retrospective analysis. The type of surgery was decided by the surgery committee after careful evaluation and discussion, including temporo-parietal-occipital (TPO) disconnection, anterior subtotal callosal section, functional hemispherectomy and resection of the epileptogenic zone(s). Postoperative seizure outcome at the last visit was evaluated using Engel classification. Results A total of 173 patients with medically refractory epilepsy who were treated surgically under the assistance of neuronavigation were included. The majority type of surgery was resection of epileptic zone, n = 104 (60.12%). An excellent seizure outcome, Engel Class I was found in 50.86% of the patients, followed by 23.12% patients with a good outcome of Engel Class II. Conclusion Overall more than half of the patients could have excellent seizure outcome of Engel Class I, the postoperative complications were manageable. These results indicated that the applicability of neuronavigation, and the use of neuronavigation provides good efficacy and safety for all kinds of surgical procedures for patients with medically refractory epilepsy.

Predicting Functional Impairment in patients with chronic subdural hematoma treated with burr hole Trepanation—The FIT-score Publication date: July 2019 Source: Clinical Neurology and Neurosurgery, Volume 182 Author(s): Nicolai Maldaner, Marketa Sosnova, Johannes Sarnthein, Oliver Bozinov, Luca Regli, Martin N. Stienen Abstract Objective It remains difficult to estimate prolonged functional impairment in patients with chronic subdural hematoma (cSDH) treated with burr hole trepanation. We aim to establish a score that reliably predicts postoperative functional impairment. Patients and methods Retrospectively analysis of a prospective institutional database. cSDH patients operated in 2013–2016 were identified. Clinical outcome was dichotomized into presence (modified-Rankin-Scale (mRS) ≥ 2) or absence of functional impairment (mRS 0–1) at discharge and last follow-up. A score was developed, based on the effect sizes of a set of outcome predictors. Its accuracy was tested using Area Under the Receiver-Operating Characteristic (AUROC) curve analysis. The 2017 cohort served for internal validation. Results A cohort of 253 patients (mean age 75 years, 75% male) was analyzed, of which 77 patients (30%) remained functionally impaired. In multivariate analysis, severe motor deficits at admission (OR 5.84, 95% CI 2.71–12.59, p < 0.001), age (≥85 years: 5.53, 2.14–14.32, p < 0.0001) and disorientation at admission (2.65, 11.39–5.05, p = 0.003) were associated with persistent functional impairment. Based on those variables, we created the "Functional Impairment after burr hole Trepanation" (FIT-score), which showed an AUROC of 0.77 (95% CI 0.70–0.83) for impairment at discharge and 0.76 (0.70–0.82) for impairment at follow-up. Internal validation confirmed the model with an AUROC of 0.79 (0.68–0.91) at discharge and 0.77 (0.64–91) at follow-up. Conclusions The FIT-score is likely to assist the physician when counseling patients and relatives pertaining to the need for postoperative rehabilitation and mid- to long-term supportive home care.

Blister aneurysms of the internal carotid artery: Surgical treatment and management outcome from a single center experience Publication date: July 2019 Source: Clinical Neurology and Neurosurgery, Volume 182 Author(s): Auricelio B. Cezar-Junior, Ubiratan Alves da Silva Viturino, Eduardo Vieira de Carvalho, Igor Vilela Faquini, Nivaldo S. Almeida, Hildo Rocha Cirne Azevedo-Filho Abstract Objective Blood-blister aneurysms (BBAs) of the internal carotid artery (ICA) are rare entities, but clinically important cause of subarachnoid hemorrhage (SAH). Several surgical and endovascular strategies have been attempted for these heterogeneous lesions. In this study, the authors analyzed the treatment strategy and outcomes in a series of cases of ICA blister aneurysms treated microsurgically. Patients and methods We retrospectively reviewed 15 consecutive cases of patients harboring ruptured BBAs, microsurgically treated at our institution between 2014 and 2018. We performed an analysis of the clinical and surgical aspects, as well as post-operative angiograms and outcomes. Results Fifteen patients were identified; 9 (60%) were female. The mean age of presentation was 43,8 years. Most patients presented in good clinical conditions (Hunt-Hess 1–3 = 86%). The most common Fisher grade at presentation was 3 (60% of cases). All patients underwent digital subtraction angiography (DSA), revealing broad-based aneurysms at non-branching sites on the dorsal wall of the ICA. Intraoperatively, BBAs were confirmed in all cases. The lesions were approached through pterional (11–73%) or lateral supraorbital (4–27%) craniotomy. Direct clipping was performed in all but one lesion, in which case the clip-wrapping technique was used. Final angiographic control revealed complete occlusion in 14 cases. One patient required reoperation due to residual aneurysm filling. At discharge, a good outcome (Glasgow Outcome Scale [GOS] 4 or 5) was observed in 12 (80%) patients. Three patients were discharged with a GOS of 3. Conclusion Blood-blister-type aneurysms are rare and challenging lesions. Preoperative knowledge and careful surgical planning can prevent poor clinical outcomes. Surgical treatment remains an effective and safe option in this context.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

DNA Repair

The Escherichia coli colibactin resistance protein ClbS is a novel DNA binding protein that protects DNA from nucleolytic degradation Publication date: July 2019 Source: DNA Repair, Volume 79 Author(s): Katja Molan, Zdravko Podlesek, Vesna Hodnik, Matej Butala, Eric Oswald, Darja Žgur Bertok Abstract Cells employ specific and nonspecific mechanisms to protect their genome integrity against exogenous and endogenous factors. The clbS gene is part of the polyketide synthase machinery (pks genomic island) encoding colibactin, a genotoxin implicated in promoting colorectal cancer. The pks is found among the Enterobacteriaceae, in particular Escherichia coli strains of the B2 phylogenetic group. Several resistance mechanisms protect toxin producers against toxicity of their products. ClbS, a cyclopropane hydrolase, was shown to confer colibactin resistance by opening its electrophilic cyclopropane ring. Here we report that ClbS sustained viability and enabled growth also of E. coli expressing another genotoxin, the Usp nuclease. The recA::gfp reporter system showed that ClbS protects against Usp induced DNA damage. To elucidate the mechanism of ClbS mediated protection, we studied the DNA binding ability of the ClbS protein. We show that ClbS directly interacts with single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), whereas ssDNA seems to be the preferred substrate. Thus, the ClbS DNA-binding characteristics may serve bacteria to protect their genomes against DNA degradation.

Acetylation of Werner protein at K1127 and K1117 is important for nuclear trafficking and DNA repair Publication date: July 2019 Source: DNA Repair, Volume 79 Author(s): Deblina Ghosh, Vilhelm A. Bohr, Parimal Karmakar Abstract Werner syndrome is a rare autosomal recessive disorder where Werner (WRN) gene is mutated. Being a nucleolar protein, during DNA damage, WRN translocates at the damage site where its catalytic function is required in DNA repair. Several studies have indicated that WRN acetylation may modulate WRN trafficking and catalytic function (Blander et al., 2002; Lozada et al., 2014). Among the six acetylation sites in WRN protein identified by mass-spectrometry analysis (Li et al., 2010) we here explore the role of acetylation sites in C-terminal of WRN (K1127, K1117, K1389, K1413) because the C- terminal domain is the hub for protein- protein interaction and DNA binding activity (Brosh et al. [4]; Muftuoglu et al., 2008; Huang et al., 2006). To explore their functional activity, we created mutations in these sites by changing the acetylation residue lysine (K) to a non-acetylation residue arginine (R) and expressed them in WRN mutant cell lines. We observed that K1127R and K1117R mutants are sensitive to the DNA damaging agents etoposide and mitomycin C and display deficient DNA repair. Importantly, deacetylation of WRN by SIRT1 (Mammalian Sir2) is necessary for restoration of WRN localization at nucleoli after completion of DNA repair. Among all putative acetylation sites, K1127R, K1117R and the double mutant K1127R/K1117R showed significantly delayed re-entry to the nucleolus after damage recovery, even when SIRT1 is overexpressed. These mutants showed partial interaction with SIRT1 compared to WT WRN. Thus, our results suggest that K1127 and K1117 are the major sites of acetylation, necessary for DNA repair. These results elucidate the mechanism by which SIRT1 regulates WRN trafficking via these acetylation sites during DNA damage. Graphical abstract

Regulation of GLI1 by cis DNA elements and epigenetic marks Publication date: July 2019 Source: DNA Repair, Volume 79 Author(s): Robert Taylor, Jun Long, Joon Won Yoon, Ronnie Childs, Kathrine B. Sylvestersen, Michael L. Nielsen, King-Fu Leong, Stephen Iannaccone, David O. Walterhouse, David J. Robbins, Philip Iannaccone Abstract GLI1 is one of three transcription factors (GLI1, GLI2 and GLI3) that mediate the Hedgehog signal transduction pathway and play important roles in normal development. GLI1 and GLI2 form a positive-feedback loop and function as human oncogenes. The mouse and human GLI1 genes have untranslated 5′ exons and large introns 5′ of the translational start. Here we show that Sonic Hedgehog (SHH) stimulates occupancy in the introns by H3K27ac, H3K4me3 and the histone reader protein BRD4. H3K27ac and H3K4me3 occupancy is not significantly changed by removing BRD4 from the human intron and transcription start site (TSS) region. We identified six GLI binding sites (GBS) in the first intron of the human GLI1 gene that are in regions of high sequence conservation among mammals. GLI1 and GLI2 bind all of the GBS in vitro. Elimination of GBS1 and 4 attenuates transcriptional activation by GLI1. Elimination of GBS1, 2, and 4 attenuates transcriptional activation by GLI2. Eliminating all sites essentially eliminates reporter gene activation. Further, GLI1 binds the histone variant H2A.Z. These results suggest that GLI1 and GLI2 can regulate GLI1 expression through protein-protein interactions involving complexes of transcription factors, histone variants, and reader proteins in the regulatory intron of the GLI1 gene. GLI1 acting in trans on the GLI1 intron provides a mechanism for GLI1 positive feedback and auto-regulation. Understanding the combinatorial protein landscape in this locus will be important to interrupting the GLI positive feedback loop and providing new therapeutic approaches to cancers associated with GLI1 overexpression. Graphical abstract

DNA-PKc deficiency drives pre-malignant transformation by reducing DNA repair capacity in concert with reprogramming the epigenome in human bronchial epithelial cells Publication date: July 2019 Source: DNA Repair, Volume 79 Author(s): Ivo Teneng, Maria A. Picchi, Shuguang Leng, Christopher P. Dagucon, Suresh Ramalingam, Carmen S. Tellez, Steven A. Belinsky Abstract The expression of DNA-dependent protein kinase catalytic subunit (DNA-PKc) is highly variable in smokers and reduced enzyme activity has been associated with risk for lung cancer. An in vitro model of lung pre-malignancy was used to evaluate the role of double-strand break DNA repair capacity in transformation of hTERT/CDK4 immortalized human bronchial epithelial cells (HBECs) and reprograming of the epigenome. Here we show that knockdown of DNA-PKc to levels simulating haploinsufficiency dramatically reduced DNA repair capacity following challenge with bleomycin and significantly increased transformation efficiency of HBEC lines exposed weekly for 12 weeks to this radiomimetic. Transformed HBEC lines with wild type or knockdown of DNA-PKc showed altered expression of more than 1,000 genes linked to major cell regulatory pathways involved in lung cancer. While lung cancer driver mutations were not detected in transformed clones, more than 300 genes that showed reduced expression associated with promoter methylation in transformed clones or predictive for methylation in malignant tumors were identified. These studies support reduced DNA repair capacity as a key factor in the initiation and clonal expansion of pre-neoplastic cells and double-strand break DNA damage as causal for epigenetic mediated silencing of many lung cancer-associated genes. The fact that DNA damage, repair, and epigenetic silencing of genes are causal for many other cancers that include colon and prostate extends the generalizability and impact of these findings.

Transcriptional responses to DNA damage Publication date: July 2019 Source: DNA Repair, Volume 79 Author(s): Erica Silva, Trey Ideker Abstract In response to the threat of DNA damage, cells exhibit a dramatic and multi-factorial response spanning from transcriptional changes to protein modifications, collectively known as the DNA damage response (DDR). Here, we review the literature surrounding the transcriptional response to DNA damage. We review differences in observed transcriptional responses as a function of cell cycle stage and emphasize the importance of experimental design in these transcriptional response studies. We additionally consider topics including structural challenges in the transcriptional response to DNA damage as well as the connection between transcription and protein abundance.

Characterization of rare NEIL1 variants found in East Asian populations Publication date: July 2019 Source: DNA Repair, Volume 79 Author(s): Irina G. Minko, Vladimir L. Vartanian, Naoto N. Tozaki, Oskar K. Linde, Pawel Jaruga, Sanem Hosbas Coskun, Erdem Coskun, Chunfeng Qu, Huan He, Chungui Xu, Taoyang Chen, Qianqian Song, Yuchen Jiao, Michael P. Stone, Martin Egli, Miral Dizdaroglu, Amanda K. McCullough, R. Stephen Lloyd Abstract The combination of chronic dietary exposure to the fungal toxin, aflatoxin B1 (AFB1), and hepatitis B viral (HBV) infection is associated with an increased risk for early onset hepatocellular carcinomas (HCCs). An in-depth knowledge of the mechanisms driving carcinogenesis is critical for the identification of genetic risk factors affecting the susceptibility of individuals who are HBV infected and AFB1 exposed. AFB1-induced mutagenesis is characterized by G to T transversions. Hence, the DNA repair pathways that function on AFB1-induced DNA adducts or base damage from HBV-induced inflammation are anticipated to have a strong role in limiting carcinogenesis. These pathways define the mutagenic burden in the target tissues and ultimately limit cellular progression to cancer. Murine data have demonstrated that NEIL1 in the DNA base excision repair pathway was significantly more important than nucleotide excision repair relative to elevated risk for induction of HCCs. These data suggest that deficiencies in NEIL1 could contribute to the initiation of HCCs in humans. To investigate this hypothesis, publicly-available data on variant alleles of NEIL1 were analyzed and compared with genome sequencing data from HCC tissues derived from individuals residing in Qidong County (China). Three variant alleles were identified and the corresponding A51V, P68H, and G245R enzymes were characterized for glycosylase activity on genomic DNA containing a spectrum of oxidatively-induced base damage and an oligodeoxynucleotide containing a site-specific AFB1-formamidopyrimidine guanine adduct. Although the efficiency of the P68H variant was modestly decreased, the A51V and G245R variants showed nearly wild-type activities. Consistent with biochemical findings, molecular modeling of these variants demonstrated only slight local structural alterations. However, A51V was highly temperature sensitive suggesting that its biological activity would be greatly reduced. Overall, these studies have direct human health relevance pertaining to genetic risk factors and biochemical pathways previously not recognized as germane to induction of HCCs.

DNA repair in personalized brain cancer therapy with temozolomide and nitrosoureas Publication date: June 2019 Source: DNA Repair, Volume 78 Author(s): Bernd Kaina, Markus Christmann Abstract Alkylating agents have been used since the 60ties in brain cancer chemotherapy. Their target is the DNA and, although the DNA of normal and cancer cells is damaged unselectively, they exert tumor-specific killing effects because of downregulation of some DNA repair activities in cancer cells. Agents exhibiting methylating properties (temozolomide, procarbazine, dacarbazine, streptozotocine) induce at least 12 different DNA lesions. These are repaired by damage reversal mechanisms involving the alkyltransferase MGMT and the alkB homologous protein ALKBH2, and through base excision repair (BER). There is a strong correlation between the MGMT expression level and therapeutic response in high-grade malignant glioma, supporting the notion that O6-methylguanine and, for nitrosoureas, O6-chloroethylguanine are the most relevant toxic damages at therapeutically relevant doses. Since MGMT has a significant impact on the outcome of anti-cancer therapy, it is a predictive marker of the effectiveness of methylating anticancer drugs, and clinical trials are underway aimed at assessing the influence of MGMT inhibition on the therapeutic success. Other DNA repair factors involved in methylating drug resistance are mismatch repair, DNA double-strand break (DSB) repair by homologous recombination (HR) and DSB signaling. Base excision repair and ALKBH2 might also contribute to alkylating drug resistance and their downregulation may have an impact on drug sensitivity notably in cells expressing a high amount of MGMT and at high doses of temozolomide, but the importance in a therapeutic setting remains to be shown. MGMT is frequently downregulated in cancer cells (up to 40% in glioblastomas), which is due to CpG promoter methylation. Astrocytoma (grade III) are frequently mutated in isocitrate dehydrogenase (IDH1). These tumors show a surprisingly good therapeutic response. IDH1 mutation has an impact on ALKBH2 activity thus influencing DNA repair. A master switch between survival and death is p53, which often retains transactivation activity (wildtype) in malignant glioma. The role of p53 in regulating survival via DNA repair and the routes of death are discussed and conclusions as to cancer therapeutic options were drawn.

The mismatch repair-dependent DNA damage response: Mechanisms and implications Publication date: June 2019 Source: DNA Repair, Volume 78 Author(s): Dipika Gupta, Christopher D. Heinen Abstract An important role for the DNA mismatch repair (MMR) pathway in maintaining genomic stability is embodied in its conservation through evolution and the link between loss of MMR function and tumorigenesis. The latter is evident as inheritance of mutations within the major MMR genes give rise to the cancer predisposition condition, Lynch syndrome. Nonetheless, how MMR loss contributes to tumorigenesis is not completely understood. In addition to preventing the accumulation of mutations, MMR also directs cellular responses, such as cell cycle checkpoint or apoptosis activation, to different forms of DNA damage. Understanding this MMR-dependent DNA damage response may provide insight into the full tumor suppressing capabilities of the MMR pathway. Here, we delve into the proposed mechanisms for the MMR-dependent response to DNA damaging agents. We discuss how these pre-clinical findings extend to the clinical treatment of cancers, emphasizing MMR status as a crucial variable in selection of chemotherapeutic regimens. Also, we discuss how loss of the MMR-dependent damage response could promote tumorigenesis via the establishment of a survival advantage to endogenous levels of stress in MMR-deficient cells.

Role of Y-family translesion DNA polymerases in replication stress: Implications for new cancer therapeutic targets Publication date: June 2019 Source: DNA Repair, Volume 78 Author(s): Peter Tonzi, Tony T. Huang Abstract DNA replication stress, defined as the slowing or stalling of replication forks, is considered an emerging hallmark of cancer and a major contributor to genomic instability associated with tumorigenesis (Macheret and Halazonetis, 2015). Recent advances have been made in attempting to target DNA repair factors involved in alleviating replication stress to potentiate genotoxic treatments. Various inhibitors of ATR and Chk1, the two major kinases involved in the intra-S-phase checkpoint, are currently in Phase I and II clinical trials [2]. In addition, currently approved inhibitors of Poly-ADP Ribose Polymerase (PARP) show synthetic lethality in cells that lack double-strand break repair such as in BRCA1/2 deficient tumors [3]. These drugs have also been shown to exacerbate replication stress by creating a DNA-protein crosslink, termed PARP 'trapping', and this is now thought to contribute to the therapeutic efficacy. Translesion synthesis (TLS) is a mechanism whereby special repair DNA polymerases accommodate and tolerate various DNA lesions to allow for damage bypass and continuation of DNA replication (Yang and Gao, 2018). This class of proteins is best characterized by the Y-family, encompassing DNA polymerases (Pols) Kappa, Eta, Iota, and Rev1. While best studied for their ability to bypass physical lesions on the DNA, there is accumulating evidence for these proteins in coping with various natural replication fork barriers and alleviating replication stress. In this mini-review, we will highlight some of these recent advances, and discuss why targeting the TLS pathway may be a mechanism of enhancing cancer-associated replication stress. Exacerbation of replication stress can lead to increased genome instability, which can be toxic to cancer cells and represent a therapeutic vulnerability.

Deciphering the interstrand crosslink DNA repair network expressed by Trypanosoma brucei Publication date: June 2019 Source: DNA Repair, Volume 78 Author(s): Ambika Dattani, Shane R. Wilkinson Abstract Interstrand crosslinks (ICLs) represent a highly toxic form of DNA damage that can block essential biological processes including DNA replication and transcription. To combat their deleterious effects all eukaryotes have developed cell cycle-dependent repair strategies that co-opt various factors from 'classical' DNA repair pathways to resolve such lesions. Here, we report the first systematic dissection of how ICL repair might operate in the Trypanosoma brucei, the causative agent of African trypanosomiasis, and demonstrated that this diverged eukaryote expresses systems that show some intriguing differences to those mechanisms present in other organisms. Following the identification of trypanosomal homologues encoding for CSB, EXO1, SNM1, MRE11, RAD51 and BRCA2, gene deletion coupled with phenotypic studies demonstrated that all the above factors contribute to this pathogen's ICL REPAIRtoire with their activities split across two epistatic groups. We postulate that one network, which encompasses TbCSB, TbEXO1 and TbSNM1, may operate throughout the cell cycle to repair ICLs encountered by transcriptional detection mechanisms while the other relies on homologous recombination enzymes (MRE11, RAD51 and BRCA2) that together help resolve lesions responsible for the stalling of DNA replication forks. This study not only sheds light on the conservation and divergence of ICL repair in one of only a handful of protists that can be studied genetically, but offers the promise of developing or exploiting ICL-causing agents as new anti-parasite therapies.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Palaeogeography, Palaeoclimatology, Palaeoecology

Light at the end of the tunnels? The origins of microbial bioerosion in mineralised collagen Publication date: 1 September 2019 Source: Palaeogeography, Palaeoclimatology, Palaeoecology, Volume 529 Author(s): Gordon Turner-Walker Abstract Microbial bioerosion, in all its manifestations, is one of the major factors determining the long-term survival of archaeologically and environmentally important artefacts and ecofacts made from mineralised collagen – bones, antler, teeth and ivory. The bone diagenesis literature contains extensive descriptions of different morphologies and classifications of microbial bioerosion – microscopical focal destruction, Wedl tunnels, linear longitudinal, budded and lamellate tunnelling, etc. but the causative agents remain to be discovered. Palaeontologists are in a similar situation when describing ichnofossils where bioerosion is classified by its characteristic morphology and only tentatively assigned to specific causes. In archaeological bones, Wedl tunnels have traditionally been ascribed to fungi but a re-examination of Wedl's original paper and subsequent literature has shown that all the early specimens examined came from aquatic environments and that euendolithic microflora (cyanobacteria or chlorophytes) might have been responsible. These microorganisms are known to tunnel into marine shells. Linear longitudinal, budded and lamellate tunnelling have all been ascribed to bacteria. However, analyses using a combination of backscatter SEM (BSEM) and mercury intrusion porosimetry (HgIP) of bones excavated from terrestrial soils suggest that the various tunnelling morphologies described by earlier researchers are actually all manifestations of a single architecture, the differences arising from the inherent variability of bone microstructure and the hydrology of the burial environment. An examination of the BSEM and HgIP data also indicates that the bacteria responsible may spread through dead bone tissues by expanding the canalicular network (or dentinal tubules in teeth) rather than creating new tunnels. Long-term field burial experiments using de-fleshed cow bone specimens have now demonstrated that bacterial tunnelling develops over decades rather than months as was previously thought, even in warm tropical soils. This has obvious implications for the origin of the bacteria responsible (soil bacteria versus endogenous gut bacteria) since the bone specimens were quickly isolated from gut contents. Although no attempt is made here to identify a specific organism or organisms responsible for tunnelling in terrestrial archaeological bones a tentative model is proposed for how cycles of wetting and drying, or changes in local dissolved oxygen levels, could lead a common gram positive soil bacterium to produce the pattern of bacterial bioerosion seen in exhumed bones. This soil organism may act in a similar way to Staphylococcus aureus which proliferates in living bone (causing osteomyelitis) by infiltrating and enlarging the canalicular network.

Origin of chert in Lower Silurian Longmaxi Formation: Implications for tectonic evolution of Yangtze Block, South China Publication date: 1 September 2019 Source: Palaeogeography, Palaeoclimatology, Palaeoecology, Volume 529 Author(s): Zihui Lei, Shahin E. Dashtgard, Jian Wang, Mou Li, Qinglai Feng, Qian Yu, Ankun Zhao, Lintao Du Abstract Upper Ordovician (Katian) to Lower Silurian (Rhuddanian) strata in the Middle–Upper Yangtze Block, South China contain extensive chert beds, although the origin of microcrystalline silica in these cherts is largely unknown. In this study, the mineralogy and structure of chert as well as major, trace, and rare earth elements are used to determine the origin of microcrystalline silica in 29 chert samples from Longmaxi Formation (Rhuddanian) in Baizitian outcrop, west of Kangdian Uplift (KU). Results show that 21 of the 29 chert samples have a biogenic origin, 2 indicate a hydrothermal origin, and 6 show a mixed origin. Cherts from Baizitian outcrop are compared to contemporaneous cherts deposited east of KU. Cherts both east and west of KU are mainly biogenic in origin, which is attributed to high productivity in the paleo-seaway. Hydrothermal microcrystalline silica is relatively uncommon in the Longmaxi Formation across the Middle-Upper Yangtze Block, and only occurs in Baizitian outcrop. Terrigenous influx contributed to chert accumulation both east and west of KU; however, cherts east of KU received much more clastic material than those in Baizitian outcrop. A comparison of chert composition and geochemistry to geological reconstructions of the Middle-Upper Yangtze Block reveal that accumulation of hydrothermal chert is closely linked to tectonic evolution. During the Early Silurian, the Middle-Upper Yangtze Block was in a compressional tectonic regime with limited heat supply, and hence, low hydrothermal circulation; this is manifested in the paucity of hydrothermal microcrystalline silica in cherts east of KU. In contrast, hydrothermal microcrystalline silica in cherts west of KU is interpreted to have formed in an extensional tectonic regime with sufficient heat supply. This research demonstrates that chert source is, in part, tectonic controlled, and chert geochemistry can be used in reconstructing paleoenvironments.

The expression of the Oceanic Anoxic Event 2 (OAE2) in the northeast of Brazil (Sergipe-Alagoas Basin) Publication date: 1 September 2019 Source: Palaeogeography, Palaeoclimatology, Palaeoecology, Volume 529 Author(s): Bruno Valle, Patrick Führ Dal' Bó, Marcelo Mendes, Julia Favoreto, Ariely Luparelli Rigueti, Leonardo Borghi, Joalice de Oliveira Mendonça, Roberto Silva Abstract Global oceanic anoxic events occurred throughout the Cretaceous and changed the sedimentation patterns in many sedimentary basins around the world. There is still a lack of data and the need to identify new sections affected by these events in the Southern Hemisphere in order to provide insights on the extent of low-oxygen oceanic conditions. This study presents sedimentological, petrographic, and geochemical data from a continuous 439-m-thick well core drilled in the Sergipe-Alagoas Basin. The analytical data suggest that anoxic conditions prevailed at the end of Cenomanian and the beginning of Turonian, being globally correlatable to the Oceanic Anoxic Event 2 (OAE2). The results on the delimitation and extent of the OAE2 in the Sergipe-Alagoas Basin aid to better define the paleoceanographic changes that occurred in the South Atlantic Ocean during OAE2 and provide a new set of data that enables further studies and correlation to other sections distributed worldwide.

Characterization of bone surface modifications on an Early to Middle Pleistocene bird assemblage from Mata Menge (Flores, Indonesia) using multifocus and confocal microscopy Publication date: 1 September 2019 Source: Palaeogeography, Palaeoclimatology, Palaeoecology, Volume 529 Author(s): Hanneke J.M. Meijer, Francesco d'Errico, Alain Queffelec, Iwan Kurniawan, Erick Setiabudi, Indra Sutisna, Adam Brumm, Gerrit D. van den Bergh Abstract Island Southeast Asia (ISEA) is a key region for the study of human evolution. New fossil and archaeological evidence, from several islands, suggests an Early to Middle Pleistocene colonisation date by hominins. A taphonomic framework, however, such as that exists for Africa, is currently lacking, and taphonomical studies of ISEA vertebrate assemblages are very limited. In this paper, we apply multifocus and confocal microscopy to surface modifications on an Early to Middle Pleistocene avian assemblage from Mata Menge, in the So'a Basin of central Flores, Indonesia, with the aim of characterizing material and testing the relevance of 3D reconstructions to study the taphonomy of ISEA bone assemblages. Our observations document a number of bone surface modifications, including individual parallel grooves, overlapping spindle-like striations, elongated impacts, short composite grooves, and rows of pits. These features suggest that several taphonomic agents were at play during and after the accumulation of the Mata Menge small vertebrate assemblage. We find no unambiguous evidence for the exploitation of birds by the So'a Basin hominins, or for hominins being a significant accumulating agent of avian remains at Mata Menge. However, our work should be seen as preliminary, as direct comparative data on relevant biological agents are lacking. The markedly distinct faunal composition and climatic regimes of many Southeast Asian islands, and the potential use of different tools by hominins, warrants the development of a comprehensive taphonomical framework that is specifically relevant for ISEA.

Redox conditions and manganese metallogenesis in the Cryogenian Nanhua Basin: Insight from the basal Datangpo Formation of South China Publication date: 1 September 2019 Source: Palaeogeography, Palaeoclimatology, Palaeoecology, Volume 529 Author(s): Zhixin Ma, Xiting Liu, Wenchao Yu, Yuansheng Du, Qiuding Du Abstract In South China, the Datangpo Formation was deposited during the Cryogenian interglacial stage between the Sturtian and Marinoan glaciations. The variations in paleoocean chemistry recorded in the Datangpo Formation are important to understand the formation of Mn ore as well as the early evolution of animals, which are not well constrained. Based on lithological observation and multi-geochemical proxies (iron speciation, Mo, U, V, Mn, Al and pyrite sulfur isotope) from drill core ZK43-6 from southeastern Chongqing, South China, the results indicate an anoxic (mostly euxinic) water condition for the lower black shales of the Datangpo Formation, which can be further divided into four intervals (I, II, III, IV). Among of them, very high Mn content and manganese metallogenesis is related to the suboxic Interval II between two euxinic depositions (Interval I and Interval III). Thus, our new findings suggest that the general euxinic condition at the basal Datangpo Formation is interrupted by a suboxic deposition (Interval II) where the manganese deposits formed. An updated model is proposed to shed light on the evolution in redox conditions of the Datangpo Formation as a function of sea-level and terrigenous input, and the genesis of "Datangpo-type" manganese in light of the temporal seawater redox conditions and microbial activity.

Advances in characterizing the cyclostratigraphy of binary chert-mudstone lithologic successions, Permian (Roadian-lower Capitanian), Chaohu, Lower Yangtze, South China Publication date: 15 August 2019 Source: Palaeogeography, Palaeoclimatology, Palaeoecology, Volume 528 Author(s): Xu Yao, Linda A. Hinnov Abstract Successions of Mesozoic and Paleozoic radiolarian-bedded cherts display a "binary" cyclic hierarchy of cm-scale chert and mudstone couplets. Some of these couplet successions contain an apparent imprint of Milankovitch cycles, in which the couplets may reflect changes in silica deposition related to Milankovitch forcing, for example, high insolation for chert deposition, and low insolation for mudstone. The challenge has been how to represent such binary lithologic series in a format that is suitable for signal processing to search for Milankovitch cycles. Here we present an analysis of chert-mudstone binary series by considering, in lieu of a "boxcar" linear interpolation, a "midpoint-triangle" linear interpolation. The procedure is demonstrated first on synthetic data, then on the binary chert-mudstone stratigraphic series of the Permian (Guadalupian: Roadian-lower Capitanian) Gufeng Formation, Chaohu, Lower Yangtze, South China. We assign −1 to the midpoint of each mudstone bed and 1 to the midpoint of each chert bed, then linearly interpolate from midpoint to midpoint along the succession. Time-frequency analysis of the midpoint-triangle series highlights a previously unnoticed stratigraphic alternation of obliquity and precession band power. Finally, we present a revised astrochronology for the Gufeng succession that is anchored at 270 Ma at the base of the Jinogondolella nankingensis conodont zone (base of Roadian stage) and ending at 264.6 Ma in the undifferentiated Follicucullus scholasticus-Ruzhencivisponus uralicas radiolarian zone (mid-Capitanian Stage), for a duration of 5.4 Myr.

The mid-Homerian (Silurian) biotic crisis in offshore settings of the Prague Synform, Czech Republic: Integration of the graptolite fossil record with conodonts, shelly fauna and carbon isotope data Publication date: 15 August 2019 Source: Palaeogeography, Palaeoclimatology, Palaeoecology, Volume 528 Author(s): Štěpán Manda, Petr Štorch, Jiří Frýda, Ladislav Slavík, Zuzana Tasáryová Abstract The middle Homerian biotic crisis resulted in the almost complete eradication of graptolites. The shale-dominated Kosov Quarry section, central Bohemia, preserves the most complete graptolite record across the crisis in peri-Gondwanan Europe. The pre-extinction graptolite assemblage of the upper lundgreni Biozone, composed of ten species vanished in three extinction phases recognized in an interval 1.6 m thick. The crisis commenced with the increasing dominance of generalist taxa and subsequent extinction of several abundant species including Cyrtograptus lundgreni. The second phase coincided with the extinctions of genera Cyrtograptus and Testograptus, whereas long-ranging, generalist monograptids prevailed before they became extinct as the crisis culminated in its third phase in the flemingii Biozone. The lower part of the overlying parvus Biozone contains only Pristiograptus parvus, which became abundant in the upper part of the biozone, together with incoming Gothograptus nassa. The recovery interval is marked by a moderate diversification of monograptids and retiolitids. The extinction did not affect the diversity of pelagic cephalopods although their abundance was reduced. A bivalve-dominated benthic fauna disappeared throughout the extinction interval and re-appeared not earlier than in the latest Homerian. It was temporarily replaced by a time-specific fauna of anachronistic trilobites and brachiopods. The extinction interval coincided with sea-level fall, indicated by limestone slump-beds in a generally shaly succession. The post-extinction interval corresponds with a lowstand systems tract with deposition of condensed shelly limestone and burrowed shale. A positive carbon isotope excursion started in the flemingii Biozone and δ13C values increased up to the lower parvus Biozone above which the plateau of the first peak started. The beginning of the graptolite extinction predated the early phase of the late Homerian carbon isotope excursion. The terminal phase of the extinction, nevertheless coincided with the onset of the carbon isotope excursion and change in benthic fauna.

Astronomical constraints on deposition of the Middle Triassic Chang 7 lacustrine shales in the Ordos Basin, Central China Publication date: 15 August 2019 Source: Palaeogeography, Palaeoclimatology, Palaeoecology, Volume 528 Author(s): Rui Zhang, Zhijun Jin, Quanyou Liu, Peng Li, Zhenkai Huang, Juye Shi, Yunjin Ge, Kefeng Du Abstract The Middle Triassic was a key period that witnessed the evolution of Earth system processes and the commencement of a terrestrial lake in the Ordos Basin, Central China. A high-precision stratigraphic framework is the key to understanding the nature and pattern of critical geological events. Detailed time series analyses of magnetic susceptibility (MS) data were performed on the deep lacustrine shale-dominated Chang 7 Member of the Yanchang Formation from the Y1011 well core. The results reveal well documented cyclic variations with wavelengths of 5.37 m, 1.39–1.78 m, 0.48 m, and 0.24–0.30 m, which are driven by long-eccentricity, short-eccentricity, obliquity, and precession in the Middle Triassic. The stable 405-kyr tuned floating astrochronological time scale (FATS) reveals that the depositional duration of the Chang 7 Member is approximately 5 Myr, and the sedimentation rates range from 0.90 cm/kyr to 1.69 cm/kyr. In particular, the lower part of the Chang 7 Member is characterized by an organic-rich, black shale, called "Zhangjiatan Shale", whose depositional duration can be estimated at about 1.7 Myr. Along with the published biostratigraphic divisions and UPb age constraints, our FATS further confirms that the Chang 7 Member mainly developed in the Ladinian Stage, and that the upper part of the Chang 7 spanned the Middle/Late Triassic boundary. The duration of the Chang 7 deposition suggests a temporal and genetic linkage between the responses of the Chang 7 shales in the Ordos Basin and the Indosinian Orogeny in the Qinling orogenic belt. The Ladinian Stage of the Middle Triassic probably witnessed a dramatic shift in the evolution of the regional geodynamic system.

Are light-dark coupled laminae in lacustrine shale seasonally controlled? A case study using astronomical tuning from 42.2 to 45.4 Ma in the Dongying Depression, Bohai Bay Basin, eastern China Publication date: 15 August 2019 Source: Palaeogeography, Palaeoclimatology, Palaeoecology, Volume 528 Author(s): Ke Zhao, Xuebin Du, Yongchao Lu, Shipeng Xiong, Yong Wang Abstract As a typical sedimentary structure in fine-grained rocks, laminae are widely distributed in shales and mudstones in sedimentary basins. The Shahejie Formation (42.2–45.4 Ma) formed during the Eocene of the Paleogene in the Dongying Depression of China is recognized as a typical area to study lacustrine shale. According to the composition of different lamina, four types of couplets are identified, including carbonate-clay couplets, carbonate-organic couplets, clay-organic couplets and carbonate-clay-organic triplets. All couplets are composed of light and dark layers. A combination of core images, microscopic observations, mineral compositions, geochemical data, carbon and oxygen isotopes, and strontium isotopes verifies that the laminae are primarily developed in a saline and anoxic, or even euxinic environment, with a high organic matter (OM) flux. Through astronomical cycle analysis of the natural gamma ray (GR) curve from sample site well NY1, the data suggest that the lacustrine shale laminae are formed annually with an average duration of 1.34 yr. The formation of laminae is affected by the season, which is closely related to the seasonal growth and death of algae. During the period of algae growth, a large number of light-colored carbonate laminae are deposited, whereas when the algae dies, organic matter accumulates at the bottom of lakes and forms dark organic-rich laminae. The interbedded and lenticular laminae, which are subdivided by layering characteristics, are primarily affected by diagenesis in postdepositional processes. Study of the laminae is helpful in understanding the formation process of lacustrine shale, and it provides invaluable sources of information for paleoclimate reconstruction.

n-Alkane distribution in ombrotrophic peatlands from the northeastern Alberta, Canada, and its paleoclimatic implications Publication date: 15 August 2019 Source: Palaeogeography, Palaeoclimatology, Palaeoecology, Volume 528 Author(s): Dashuang He, Haiping Huang, Gabriela Gonzalez Arismendi Abstract In this paper, the stratigraphic occurrence of n-alkanes (Cn) is investigated in three peat cores (Mildred, JPH4 and McMurray) from the ombrotrophic peatlands in northeastern Alberta, Canada, to determine their origin, biomass input, and paleoclimatic significance. The molecular composition of n-alkanes is dominated by the >C21 medium- to long-chain homologues, with a strong odd over even predominance. A number of n-alkane-based indices (e.g. predominant n-alkane, C23/C29, C23/(C27 + C31), Paq, ACL, and CPI), show changing conditions in the organic matter (OM) input from Sphagnum species or terrestrial vascular plants, which increasingly contributed upwards in the peat profiles, and through time. Paq and C23/(C27 + C31) proxies are similar in the three cores, and allow us to infer vegetation variations that coincide with the climate alternations of the Medieval Warm Period (MWP), Little Ice Age (LIA), and modern Recent Warming (RW). The utilization of ACL-ket and (C23 + C25)/(C27 + C29 + C31)-ket proxies, performed in comparison with n-alkane proxies, further support the biomarker-based reconstructions of paleoclimate variations over recent centuries. This study suggests that n-alkane homologues are sensitive to vegetation and climate changes and thus are reliable biomarkers for tracking past shifts in vegetation and climate variations in peat archives.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Philosophy & Technology

The Bow and Arrow and Early Human Sociality: an Enactive Perspective on Communities and Technical Practice in the Middle Stone Age Abstract In this paper, I draw on postphenomenology and material engagement theory to consider the material and emergent character of sociality in Homo faber. I approach this through the context of the bow and arrow, which is a technology that has received recent attention in cognitive archeology as a proxy for assessing criteria that made early human cognition distinct from that of other hominins. Through an ethnographic case study, I scrutinize the forms of knowledge that are required to use the technology in the dynamic field of environmental practices that constitute the hunt. I demonstrate that the learning of the skill is a transformational process where beginners develop self and intentionality by attuning subjective capacities for sensory awareness and creative responsiveness. Through mutual participation, the bow and arrow aligns disposition and rapport among those whose life processes are shaped by the skill. As a mechanism of shared experience, the bow and arrow generates a community can together perceive and act creatively in an impermanent world. Through these observations, I argue that early human sociality was built not on a pre-evolved capacity for symbolic representation but on technical experience, and I consider important questions this raises about the nature of evolutionary processes at work in the development of communities through time.

How Stone Tools Shaped Us: Post-Phenomenology and Material Engagement Theory Abstract The domain of early hominin stone tool making and tool using abilities has received little scholarly attention in mainstream philosophy of technology. This is despite the fact that archeological evidence of stone tools is widely seen today as a crucial source of information about the evolution of human cognition. There is a considerable archeological literature on the cognitive dimensions of specific hominin technical activities. However, within archeology and the study of human evolution the standard perception is stone tools are mere products of the human mind (or brain or innate cognitive capacities). A number of recent approaches to cognition challenges this simplistic one-way-causal-arrow view and emphasizes instead the functional efficiency of tools or artifacts in transforming and augmenting human (or hominin) cognitive capacities. As a result, the very idea that tools or artifacts are intimately tied to human cognitive processes is fast becoming an alternative within the cognitive sciences and a few allied disciplines. The present study intends to explore its implications for philosophy of technology. The central objective of this paper is to examine the dynamic and intricate tool-mediated activities of the early hominins through the lens of Don Ihde's post-phenomenological theory of human-technology relations and Lambros Malafouris' Material Engagement Theory. Highlighting the key points where these two research approaches, despite their subtle nuances, converge and look capable of mutually catalyzing each other, the paper attempts to show why it is important to bring these approaches together for a more refined understanding of the controversial role these stone tools played in human evolution.

Replacing Epiphenomenalism: a Pluralistic Enactive Take on the Metaplasticity of Early Body Ornamentation Abstract In the domain of evolutionary cognitive archaeology, the early body ornaments from the Middle Stone Age/Palaeolithic are generally treated as mere by-products of an evolved brain-bound cognitive architecture selected to cope with looming social problems. Such adaptive artefacts are therefore taken to have been but passive means of broadcasting a priori envisaged meanings, essentially playing a neutral role for the human mind. In contrast to this epiphenomenalist view of material culture, postphenomenology and the Material Engagement Theory (MET) have been making a case for the active role of artefacts on the count that they can actually shape and restructure the human mind. By bringing these dissenting voices together, the paper at hand employs an enactive way of thinking in order to challenge the epiphenomenalist take on early body ornaments. In fact, two variants of enactivism are presented, each advancing a unique explanation of how the engagement of early humans with body ornaments transformed their minds along the two postphenomenological categories of embodied and hermeneutic cognition. Our theoretical frameworks specifically seek to explore how early beadworks could have scaffolded the creation of semiotic categories and the development of cognitive processes. Despite relying on inherently different premises, both theories suggest that beads fostered the emergence of an epistemic apparatus which thoroughly transformed the way humans engaged with the world. Having concurred on the ornaments' transformative effects, we ultimately conclude that the epiphenomenalist paradigm best be replaced with an enactive approach grounded on the dictates of postphenomenology and the MET.

Homo faber Revisited: Postphenomenology and Material Engagement Theory Abstract Humans, more than any other species, have been altering their paths of development by creating new material forms and by opening up to new possibilities of material engagement. That is, we become constituted through making and using technologies that shape our minds and extend our bodies. We make things which in turn make us. This ongoing dialectic has long been recognised from a deep-time perspective. It also seems natural in the present in view of the ways new materialities and digital ecologies increasingly envelop our everyday life and thinking. Still the basic idea that humans and things are co-constituted continues to challenge us, raising important questions about the place and meaning of materiality and technical change in human life and evolution. This paper bridging perspectives from postphenomenology and Material Engagement Theory (MET) is trying to attain better understanding about these matters. Our emphasis falls specifically on the human predisposition for technological embodiment and creativity. We re-approach the notion Homo faber in a way that, on the one hand, retains the power and value of this notion to signify the primacy of making or creative material engagement in human life and evolution and, on the other hand, reclaims the notion from any misleading connotations of human exceptionalism (other animals make and use tools). In particular, our use of the term Homo faber refers to the special place that this ability has in the evolution and development of our species. The difference that makes the difference is not just the fact that we make things. The difference that makes the difference is the recursive effect that the things that we make and our skills of making seem to have on human becoming. We argue that we are Homo faber not just because we make things but also because we are made by them.

Democratizing Algorithmic Fairness Abstract Machine learning algorithms can now identify patterns and correlations in (big) datasets and predict outcomes based on the identified patterns and correlations. They can then generate decisions in accordance with the outcomes predicted, and decision-making processes can thereby be automated. Algorithms can inherit questionable values from datasets and acquire biases in the course of (machine) learning. While researchers and developers have taken the problem of algorithmic bias seriously, the development of fair algorithms is primarily conceptualized as a technical task. In this paper, I discuss the limitations and risks of this view. Since decisions on "fairness measure" and the related techniques for fair algorithms essentially involve choices between competing values, "fairness" in algorithmic fairness should be conceptualized first and foremost as a political question and be resolved politically. In short, this paper aims to foreground the political dimension of algorithmic fairness and supplement the current discussion with a deliberative approach to algorithmic fairness based on the accountability for reasonableness framework (AFR).

On Malfunction, Mechanisms and Malware Classification Abstract Malware has been around since the 1980s and is a large and expensive security concern today, constantly growing over the past years. As our social, professional and financial lives become more digitalised, they present larger and more profitable targets for malware. The problem of classifying and preventing malware is therefore urgent, and it is complicated by the existence of several specific approaches. In this paper, we use an existing malware taxonomy to formulate a general, language independent functional description of malware as transformers between states of the host system and described by a trust relation with its components. This description is then further generalised in terms of mechanisms, thereby contributing to a general understanding of malware. The aim is to use the latter in order to present an improved classification method for malware.

The Experiential Niche: or, on the Difference Between Smartphone and Passenger Driver Distraction Abstract It is sometimes argued that since it would be absurd to outlaw passenger conversation, we should not regulate the presumably equivalent act of using the phone while driving. To reveal the spuriousness of this argument and to help urge drivers to refrain from using the phone while behind the wheel, we must draw on two decades of data on smartphone-induced driving impairment, and we need to consider ideas from both the postphenomenological and embodied cognition perspectives. In what follows, I expand on the notion of the "cognitive niche" (that is, the idea that our cognitive processes are facilitated by our human-built environments) and develop the corollary notion of the "experiential niche" to describe how our surroundings can prompt a particular phenomenological quality and organization to our lived experience. I argue that conceiving of the car as a cognitive-experiential niche is useful for articulating the crucial differences between passenger and smartphone conversation and helps make the case that we must regulate smartphone use while driving.

Technological Environmentality: Conceptualizing Technology as a Mediating Milieu Abstract After several technological revolutions in which technologies became ever more present in our daily lives, the digital technologies that are currently being developed are actually fading away from sight. Information and Communication Technologies (ICTs) are not only embedded in devices that we explicitly "use" but increasingly become an intrinsic part of the material environment in which we live. How to conceptualize the role of these new technological environments in human existence? And how to anticipate the ways in which these technologies will mediate our everyday lives? In order to answer these questions, we draw on two approaches that each offers a framework to conceptualize these new technological environments: Postphenomenology and Material Engagement Theory. As we will show, each on their own, these approaches fail to do justice to the new environmental role of technology and its implications for human existence. But by bringing together Postphenomenology's account of technological mediation and Material Engagement Theory's account of engaging with environments, it becomes possible to sufficiently account for the new environmental workings of technology. To do justice to these new workings of environmental technologies, we introduce and develop the concept of "Technological Environmentality."

Understanding Error Rates in Software Engineering: Conceptual, Empirical, and Experimental Approaches Abstract Software-intensive systems are ubiquitous in the industrialized world. The reliability of software has implications for how we understand scientific knowledge produced using software-intensive systems and for our understanding of the ethical and political status of technology. The reliability of a software system is largely determined by the distribution of errors and by the consequences of those errors in the usage of that system. We select a taxonomy of software error types from the literature on empirically observed software errors and compare that taxonomy to Giuseppe Primiero's Minds and Machines 24: 249–273, (2014) taxonomy of error in information systems. Because Primiero's taxonomy is articulated in terms of a coherent, explicit model of computation and is more fine-grained than the empirical taxonomy we select, we might expect Primiero's taxonomy to provide insights into how to reduce the frequency of software error better than the empirical taxonomy. Whether using one software error taxonomy can help to reduce the frequency of software errors better than another taxonomy is ultimately an empirical question.

What the Jeweller's Hand Tells the Jeweller's Brain: Tool Use, Creativity and Embodied Cognition Abstract The notion that human activity can be characterised in terms of dynamic systems is a well-established alternative to motor schema approaches. Key to a dynamic systems approach is the idea that a system seeks to achieve stable states in the face of perturbation. While such an approach can apply to physical activity, it can be challenging to accept that dynamic systems also describe cognitive activity. In this paper, we argue that creativity, which could be construed as a 'cognitive' activity par excellence, arises from the dynamic systems involved in jewellery making. Knowing whether an action has been completed to a 'good' standard is a significant issue in considering acts in creative disciplines. When making a piece of jewellery, there a several criteria which can define 'good'. These are not only the aesthetics of the finished piece but also the impact of earlier actions on subsequent ones. This suggests that the manner in which an action is coordinated is influenced by the criteria by which the product is judged. We see these criteria as indicating states for the system, e.g. in terms of a space of 'good' outcomes and a complementary space of 'bad' outcomes. The skill of the craftworker is to navigate this space of available states in such a way as to minimise risk, effort and other costs and maximise benefit and quality of the outcome. In terms of postphenomonology, this paper explores Ihde's human-technology relations and relates these to the concepts developed here.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Organized Crime

Correction to: Accounting for turbulence in the Colombian underworld The original version of this article contained a typesetting mistake. Map 1 image was incorrect. The original article has been corrected.

Violence and electoral competition: criminal organizations and municipal candidates in Mexico Abstract This article evaluates the effects of violence related to the operations of drug-trafficking organizations (DTOs) on electoral competition, defined by the number of electoral alternatives or candidates in Mexico's municipal elections. I find that the killing and threatening of politicians, which are effective tools to influence politics, jeopardizes competition in violent Mexican municipalities by reducing the number of candidates. This result is not only probabilistically robust but also meaningful. The number of candidates can fall to one in the more violent municipalities. However, DTOs can also provide (illegal) funding to politicians to facilitate their candidacies. I find that as confrontation intensifies among DTOs, the negative effect of violence on electoral competition moderates. This finding suggests that DTOs finance candidates to capture municipal governments when facing intense competition and attacks from other DTOs. In addition, DTOs in this context may also provide protection to their preferred candidates from other competing organizations. These factors temper the negative effect of violence on electoral competition.

Brazilian criminal organizations as transnational violent non-state actors: a case study of the Primeiro Comando da Capital (PCC) Abstract This article aims to analyze the evolution of Brazilian criminal organization Primeiro Comando da Capital (PCC—First Command of the Capital), especially its transformation from a group advocating human rights to a transnational violent non-state actor. Created in the late 1990s by inmates at Taubate Prison, PCC is currently a key trigger of violence in South America. Since a massive attack performed in 2006 against security forces, the group continues to be highly operative, also coordinating drugs and arms smuggling in Brazil and abroad. A combination of sources supported this analysis of PCC's evolution, mainly Brazilian official judicial minutes, NGOs reports, and news released from reputable sources. The article shows that PCC has gained strength in the 2010s, expanding illicit business operations in cooperation with other criminal groups. The results suggest that PCC's expansion has changed significantly since their beginnings, into an actor that poses a challenge for the building of peaceful society in all of South America.

Mexican cartel negotiative interactions with the state Abstract This research applies pure sociology to the negotiation activity of Mexican drug trafficking organizations (DTOs). By operationalizing status along several social dimensions, the author employs crisp set Qualitative Comparative Analysis (cs QCA) to identify unique status configurations associated with negotiative interactions with the state. The results indicate that high status configurations are unique to groups that utilize negotiations in a particular territory. These findings provide further insight into the different positions of strength from which DTOs will pursue non-violent activity.

Organized crime, violence, and territorial dispute in Mexico (2007–2011) Abstract In the wake of so-called "hardline policies" against criminal groups (persecution, militarization, strengthening of security apparatuses), we take a comprehensive approach to the study of violent territorial disputes. We offer features for studying the violence attributed to organized crime, particularly in Mexico from 2007 to 2011, a time known as the "War on Drugs"; we identify characteristics of the drug-related criminal organizations in Mexico; further we show different strategies for the use of and dispute for territory. We propose four components that give us a better understanding of organized-crime groups: economic activities, ability to negotiate with other cartels, relations with state authorities, and strength of local roots.

Accounting for turbulence in the Colombian underworld Abstract Organized crime groups (OCGs) fight against each other even if it harms their businesses and exposes them to law enforcement authorities. Why do some groups refrain from fighting, while others operate in the incessantly violent underworld? To explain this puzzle, we propose that the underworld conflict is related to the strategies of extra-legal governance adopted by OCGs. We suggest that such strategies have origins in the availability of resources within the groups reach at their entrance into the underworld. More specifically, OCGs with access to easily extractable resources develop limited governance, which leaves them vulnerable to internal and external challenges. OCGs without access to easily extractable resources invest in extended governance, reducing their risk of underworld conflict. This article illustrates this hypothesis in the comparative case study of the Colombian organized crime, supported by new quantitative data.

Organised crime in Latin America: an introduction to the special issue Abstract This article provides an introduction to the articles submitted to the special issue of Trends in Organised Crime on 'Organised Crime in Latin America'. The aim of the special issue is to draw together novel empirical research findings and theoretical accounts on various aspects of organised crime in the particular geographic context.

Policing labor trafficking in the United States Abstract Despite new mandates to identify and respond to labor trafficking crimes, US law enforcement struggles to integrate labor trafficking enforcement with traditional policing routines and roles. As a result, human trafficking enforcement has primarily focused on sex trafficking and few labor trafficking cases have been identified and prosecuted. This study utilizes data from 86 qualitative interviews with municipal, state, county and federal law enforcement, victim service providers and labor trafficking victims in four US communities to inform our understanding of police responses to labor trafficking in local communities. Through the coding of these interviews across a series of themes, we identify three major challenges that impact police identification and response to labor trafficking crimes. These include lack of clarity about the definition of labor trafficking, lack of institutional readiness to address labor trafficking, and routines of police work that undermine police responsiveness to labor trafficking in local communities. Considering these challenges, we explore strategies law enforcement can take to improve identification, including developing non-traditional partnerships with labor inspection and local regulatory agencies. Additionally, interview data suggest a role for the police in ensuring labor trafficking victims are safe and their needs are met, regardless of the outcomes of the criminal justice process. This is the first study to examine police responses to labor trafficking from the perspective of police, service providers and victims.

Criminal networks in a digitised world: on the nexus of borderless opportunities and local embeddedness Abstract This article presents the results of empirical analyses of the use of information technology (IT) by organized crime groups. In particular, it explores how the use of IT affects the processes of origin and growth of criminal networks. The empirical data presented in this article consist of 30 large scale criminal investigations into organized crime, including traditional organized crime, traditional organized crime in which IT is an innovative element, low tech cybercrimes and high tech cybercrimes. Networks involved in cybercrimes or traditional crimes with an innovative IT element can be characterized as a mixture of old school criminals that have a long criminal career, and a limited number of technically skilled members. Furthermore, almost all cases have a local dimension. Also the cybercrime cases. Dutch sellers of drugs on online marketplace, for example, mainly work for customers in the Netherlands and surrounding countries.

Criminal markets: the dark web, money laundering and counterstrategies - An overview of the 10th Research Conference on Organized Crime Abstract On 10–11 October 2018, the 10th Research Conference on Organized Crime took place in The Hague. This year's theme was Criminal Markets: The Dark Web, Money Laundering and Counterstrategies. Researchers, practitioners and policy makers gathered to discuss research results, trends and policy issues. This article looks into recent developments on the topics mentioned and gives an overview of the conference.

Alexandros Sfakianakis
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