bluuebunny/crossref_metadata_2025 huggingface dataset:
Subcutaneous implantable cardioverter-defibrillators: long-term results of the EFFORTLESS study
Authors: Lambiase Pier D , Theuns Dominic A , Murgatroyd Francis , Barr Craig , Eckardt Lars , Neuzil Petr , Scholten Marcoen , Hood Margaret , Kuschyk Jȕrgen , Brisben Amy J , Carter Nathan , Stivland Timothy M , Knops Reinoud , Boersma Lucas V A
Published: December 2021

Aims

To report 5-year outcomes of EFFORTLESS registry patients with early generation subcutaneous implantable cardioverter-defibrillator (S-ICD) devices.

Methods and results

Kaplan–Meier, trend and multivariable analyses were performed for mortality and late (years 2–5) complications, appropriate shock (AS) and inappropriate shock (IAS) rates. Nine hundred and eighty-four of 994 enrolled patients with diverse diagnoses (28% female, 48 ± 17 years, body mass index 27 ± 6 kg/m2, ejection fraction 43 ± 18%) underwent S-ICD implantation. Median follow-up was 5.1 years (interquartile range 4.7–5.5 years). All-cause mortality was 9.3% (95% confidence interval 7.2–11.3%) at 5 years; 703 patients remained in follow-up on study completion, 171 withdrew including 87 (8.8%) with device explanted, and 65 (6.6%) lost to follow-up. Of the explants, only 20 (2.0%) patients needed a transvenous device for pacing indications. First and final shock efficacy for discrete ventricular arrhythmias was consistent at 90% and 98%, respectively, with storm episode final shock efficacy at 95.2%. Time to therapy remained unaltered. Overall 1- and 5-year complication rates were 8.9% and 15.2%, respectively. Early complications did not predict later complications. There were no structural lead failures. Inappropriate shock rates at 1 and 5 years were 8.7% and 16.9%, respectively. Self-terminating inappropriately sensed episodes predicted late IAS. Predictors of late AS included self-terminating appropriately sensed episodes and earlier AS.

Conclusion

In this diverse S-ICD registry population, spontaneous shock efficacy was consistently high over 5 years. Very few patients underwent S-ICD replacement with a transvenous device for pacing indications. Treated and self-terminating arrhythmic episodes predict future shock events, which should encourage more personalized device optimization.
FlyPhoneDB: an integrated web-based resource for cell–cell communication prediction in Drosophila
Authors: Liu Yifang , Li Joshua Shing Shun , Rodiger Jonathan , Comjean Aram , Attrill Helen , Antonazzo Giulia , Brown Nicholas H , Hu Yanhui , Perrimon Norbert
Published: December 2021

Multicellular organisms rely on cell–cell communication to exchange information necessary for developmental processes and metabolic homeostasis. Cell–cell communication pathways can be inferred from transcriptomic datasets based on ligand–receptor expression. Recently, data generated from single-cell RNA sequencing have enabled ligand–receptor interaction predictions at an unprecedented resolution. While computational methods are available to infer cell–cell communication in vertebrates such a tool does not yet exist for Drosophila. Here, we generated a high-confidence list of ligand–receptor pairs for the major fly signaling pathways and developed FlyPhoneDB, a quantification algorithm that calculates interaction scores to predict ligand–receptor interactions between cells. At the FlyPhoneDB user interface, results are presented in a variety of tabular and graphical formats to facilitate biological interpretation. To illustrate that FlyPhoneDB can effectively identify active ligands and receptors to uncover cell–cell communication events, we applied FlyPhoneDB to Drosophila single-cell RNA sequencing data sets from adult midgut, abdomen, and blood, and demonstrate that FlyPhoneDB can readily identify previously characterized cell–cell communication pathways. Altogether, FlyPhoneDB is an easy-to-use framework that can be used to predict cell–cell communication between cell types from single-cell RNA sequencing data in Drosophila.
Palaeomagnetic indication for India–Asia collision at 12°N and maximum 810 km Greater India extent in the western suture zone
Authors: Dannemann Sven , Appel Erwin , Rösler Wolfgang , Neumann Udo , Liebke Ursina , Nag Debarati
Published: December 2021

Knowing the pre-collisional extent of the northern Indian Plate margin (‘Greater India’) is vital to understanding the tectonic evolution of the India–Asia collision and the formation of the Himalayan–Tibetan orogen. However, suitable geological units for palaeomagnetic investigations along the Himalayan belt are limited, which makes it difficult to reconstruct Greater India during the pre-collisional period in Late Cretaceous to Palaeogene. Often the palaeomagnetic results from the Zongpu Formation at Gamba in southern Tibet (∼88.5°E) were used for estimates of Greater India, but their validity was recently questioned. As a contribution to closing the data gap, we performed a palaeomagnetic study of the Palaeocene/Lower Eocene Dibling limestone (DL) in the western Tethyan Himalaya of Zanskar (34.0°N/76.6°E). The results from 27 sites revealed a well grouping (k = 71.7) syntectonic magnetization with best grouping at 52 per cent unfolding. The remagnetization of the DL was acquired shortly after ∼54 Ma, at the latest at ∼49 Ma, and is probably carried by fine-grained magnetite formed during the early orogenic phase. Assuming proportional tilting of the fold limbs, the corresponding palaeolatitude of 11.8 ± 2.4°N suggests a maximum Greater India extent of 810 ± 420 km and a first continental contact with the southern Eurasian margin at ∼12°N in the western part of the suture zone. The tectonostratigraphic equivalence of the DL with the Zongpu Formation at Gamba and a great similarity in their magnetic properties supports a secondary origin of the Gamba results. Through understanding the mechanism of remagnetization in the DL, an early orogenic remanence acquisition is also indicated for the Zongpu Formation, and thus the Gamba results deserve further credit for Greater India reconstructions. However, we note a large inconsistency of the available Late Cretaceous and Palaeogene palaeolatitude data from the Tethyan Himalaya by up to ∼20°, corresponding to differences of up to ∼2000 km in the size of Greater India. These discrepancies require further palaeomagnetic work in the Tethyan Himalaya, and in particular we recommend comparative studies at same locations and of same units.
Learning Implicit Biases from Fiction
Authors: Goffin Kris , Friend Stacie
Published: December 2021

Philosophers and psychologists have argued that fiction can ethically educate us: fiction supposedly can make us better people. This view has been contested. It is, however, rarely argued that fiction can morally “corrupt” us. In this article, we focus on the alleged power of fiction to decrease one's prejudices and biases. We argue that if fiction has the power to change prejudices and biases for the better, then it can also have the opposite effect. We further argue that fictions are more likely to be a bad influence than a good one.
A Genome forBidens hawaiensis: A Member of a Hexaploid Hawaiian Plant Adaptive Radiation
Authors: Bellinger M Renee , Datlof Erin M , Selph Karen E , Gallaher Timothy J , Knope Matthew L
Published: December 2021

The plant genus Bidens (Asteraceae or Compositae; Coreopsidae) is a species-rich and circumglobally distributed taxon. The 19 hexaploid species endemic to the Hawaiian Islands are considered an iconic example of adaptive radiation, of which many are imperiled and of high conservation concern. Until now, no genomic resources were available for this genus, which may serve as a model system for understanding the evolutionary genomics of explosive plant diversification. Here, we present a high-quality reference genome for the Hawaiʻi Island endemic species B. hawaiensis A. Gray reconstructed from long-read, high-fidelity sequences generated on a Pacific Biosciences Sequel II System. The haplotype-aware, draft genome assembly consisted of ~6.67 Giga bases (Gb), close to the holoploid genome size estimate of 7.56 Gb (±0.44 SD) determined by flow cytometry. After removal of alternate haplotigs and contaminant filtering, the consensus haploid reference genome was comprised of 15 904 contigs containing ~3.48 Gb, with a contig N50 value of 422 594. The high interspersed repeat content of the genome, approximately 74%, along with hexaploid status, contributed to assembly fragmentation. Both the haplotype-aware and consensus haploid assemblies recovered >96% of Benchmarking Universal Single-Copy Orthologs. Yet, the removal of alternate haplotigs did not substantially reduce the proportion of duplicated benchmarking genes (~79% vs. ~68%). This reference genome will support future work on the speciation process during adaptive radiation, including resolving evolutionary relationships, determining the genomic basis of trait evolution, and supporting ongoing conservation efforts.
First Report of Culicoides Biting Midges (Diptera: Ceratopogonidae) Attacking People in Italy, With the Description of Extreme Larval Breeding Sites and Diurnal Activity of Culicoides riethi
Authors: Romiti Federico , Fochetti Romolo , Magliano Adele , Vinciguerra Vittorio , Ermenegildi Arianna , De Liberato Claudio
Published: December 2021

Biting midges of the genus Culicoides (Diptera: Ceratopogonidae) play a paramount role in medical and veterinary entomology worldwide, particularly as vectors of pathogens which cause animal diseases. Biting midges are also infamous for the nuisance they provoke to people involved in outdoor activities. Nonetheless, attacks to man by midges from any Culicoides species have not been reported in Italy. An entomological investigation was performed following repeated attacks to man in a nature park near Rome (central Italy). The study area is a natural degassing zone, characterized by widespread hazardous gas emissions of CO2 and H2S, with several water bodies including permanent lakes, ponds, and pools. The biting midge C. riethi Kieffer, 1914 was very active during daytime in the period April–June. The species has been identified as responsible for attacks on people in the area. An in-depth analysis of the extreme environmental conditions revealed the ability of larvae to thrive in several water bodies, characterized by an extremely low pH and a high concentration of sulfates.
Weight Change and Incident Distal Colorectal Adenoma Risk in the PLCO Cancer Screening Trial
Authors: He Shisi , Berndt Sonja I , Kunzmann Andrew T , Kitahara Cari M , Huang Wen-Yi , Barry Kathryn Hughes
Published: December 2021

Background

Although obesity is a known risk factor, the impact of weight change on colorectal adenoma risk is less clear and could have important implications in disease prevention. We prospectively evaluated weight change in adulthood and incident colorectal adenoma.

Methods

We assessed weight change during early-late (age 20 years to baseline, ie, ages 55-74 years), early-middle (20-50 years), and middle-late (50 years-baseline) adulthood using self-reported weight data in relation to incident distal adenoma in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (cases = 1053; controls = 16 576). For each period, we defined stable weight as greater than −0.5 kg to less than or equal to 1 kg/5 years, weight loss as less than or equal to −0.5 kg/5 years, and weight gain as greater than 1-2, greater than 2-3, or greater than 3 kg/5 years. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression; all tests were 2-sided.

Results

Compared with stable weight, weight loss during early-late adulthood was associated with reduced adenoma risk (OR = 0.54, 95% CI = 0.34 to 0.86), particularly among those who were overweight or obese at age 20 years (OR = 0.39, 95% CI = 0.18 to 0.84). Results were similar for early-middle adulthood but less pronounced for middle-late adulthood. Weight gain greater than 3 kg/5 years during early-late adulthood was associated with increased risk (OR = 1.30, 95% CI = 1.07 to 1.58, Ptrend < .001). Findings appeared stronger among men (OR for >3 kg/5 years = 1.41, 95% CI = 1.11 to 1.80) than women (OR = 1.09, 95% CI = 0.79 to 1.50, Pinteraction = .21).

Conclusions

Weight loss in adulthood was associated with reduced adenoma risk, particularly for those who were overweight or obese, whereas weight gain greater than 3 kg/5 years increased risk. Findings underscore the importance of healthy weight maintenance throughout adulthood in preventing colorectal adenoma.
Clinical characteristics and risk factors for maternal deaths due to COVID-19 in Brazil: a nationwide population-based cohort study
Authors: Siqueira Thayane Santos , de Souza Edyankya Karolyne Gomes , Martins-Filho Paulo Ricardo , Silva José Rodrigo Santos , Gurgel Ricardo Queiroz , Cuevas Luis Eduardo , Santos Victor Santana
Published: December 2021

Background

Monitoring the characteristics and associated factors for death among pregnant and postpartum women with coronavirus disease 19 (COVID-19) is necessary. We investigated the clinical characteristics and risk factors associated with maternal deaths in a nationwide cohort of Brazil.

Methods

This was a population-based cohort of all pregnant and postpartum women hospitalised with COVID-19 notified to the Sistema de Informação de Vigilância Epidemiológica da Gripe of Brazil (SIVEP-Gripe), from February 2020 to September 2021. The primary outcome was time to in-hospital death, with risk factors analysed with univariable and multivariable Cox proportional hazards regression models.

Results

Cumulative observation time was 248 821 person-days from hospital admission to the end of follow-up for 15 105 individuals. There were 1858 deaths (12.3%) for a maternal mortality rate of 7.5 (95% CI 7.1–7.8) per 1000 patients-days. The cumulative mortality increased over time. Black/Brown ethnicity had a higher risk of death than women self-identifying as White. Women in the North, Northeast, Central-West and Southeast regions had higher risk of death than women in the South region. The characteristics independently associated with death were a postpartum status on admission [adjusted hazard ratio, HR 1.4 (95% confidence interval, CI 1.2–1.6)], pre-existing clinical conditions [adjusted HRs 1.2 (95%CI 1.1–1.3) for one and 1.3 (95%CI 1.1–1.5) for two comorbidities], hypoxaemia on admission [adjusted HR 1.2 (95%CI 1.1–1.4)] and requiring non-invasive [adjusted HR 2.6 (95%CI 2.1–3.3)] or invasive ventilatory support [adjusted HR 7.1 (95%CI 5.6–9.2)].

Conclusion

In Brazil, the in-hospital maternal mortality rate due to COVID-19 is high and the risk of death increases with the length of hospitalisation. Socio-demographic and biological factors are associated with an increased risk of maternal death. The presence of respiratory signs and symptoms should be considered early markers of disease severity and an adequate management is necessary. Our findings reinforce the need for vaccination of pregnant and postpartum women against COVID-19.
What really makes an accretion disc MAD
Authors: Begelman Mitchell C , Scepi Nicolas , Dexter Jason
Published: December 2021

Magnetically arrested accretion discs (MADs) around black holes (BHs) have the potential to stimulate the production of powerful jets and account for recent ultra-high-resolution observations of BH environments. Their main properties are usually attributed to the accumulation of dynamically significant net magnetic (vertical) flux throughout the arrested region, which is then regulated by interchange instabilities. Here, we propose instead that it is mainly a dynamically important toroidal field – the result of dynamo action triggered by the significant but still relatively weak vertical field – that defines and regulates the properties of MADs. We suggest that rapid convection-like instabilities, involving interchange of toroidal flux tubes and operating concurrently with the magnetorotational instability (MRI), can regulate the structure of the disc and the escape of net flux. We generalize the convective stability criteria and disc structure equations to include the effects of a strong toroidal field and show that convective flows could be driven towards two distinct marginally stable states, one of which we associate with MADs. We confirm the plausibility of our theoretical model by comparing its quantitative predictions to simulations of both MAD and SANE (standard and normal evolution; strongly magnetized but not ‘arrested’) discs, and suggest a set of criteria that could help to distinguish MADs from other accretion states. Contrary to previous claims in the literature, we argue that MRI is not suppressed in MADs and is probably responsible for the existence of the strong toroidal field.
A framework for simultaneously measuring field densities and the high-z luminosity function
Authors: Trapp A C , Furlanetto Steven R , Yang Jinghong
Published: December 2021

Cosmic variance from large-scale structure will be a major source of uncertainty for galaxy surveys at $z \gtrsim 6$, but that same structure will also provide an opportunity to identify and study dense environments in the early Universe. Using a robust model for galaxy clustering, we directly incorporate large-scale densities into an inference framework that simultaneously measures the high-z ($z \gtrsim 6$) UV luminosity function and the average matter density of each distinct volume in a survey. Through this framework, we forecast the performance of several major upcoming James Webb Space Telescope (JWST) galaxy surveys. We find that they can constrain field matter densities down to the theoretical limit imposed by Poisson noise and unambiguously identify over-dense (and under-dense) regions on transverse scales of tens of comoving Mpc. We also predict JWST will measure the luminosity function with a precision at z = 12 comparable to existing Hubble Space Telescope’s constraints at z = 8 (and even better for the faint-end slope). We also find that wide-field surveys are especially important in distinguishing luminosity function models.
A multiparametric pharmacogenomic strategy for drug repositioning predicts therapeutic efficacy for glioblastoma cell lines
Authors: Shah Ashish H , Suter Robert , Gudoor Pavan , Doucet-O’Hare Tara T , Stathias Vasileios , Cajigas Iahn , de la Fuente Macarena , Govindarajan Vaidya , Morell Alexis A , Eichberg Daniel G , Luther Evan , Lu Victor M , Heiss John , Komotar Ricardo J , Ivan Michael E , Schurer Stephan , Gilbert Mark R , Ayad Nagi G
Published: December 2021

Background

Poor prognosis of glioblastoma patients and the extensive heterogeneity of glioblastoma at both the molecular and cellular level necessitates developing novel individualized treatment modalities via genomics-driven approaches.

Methods

This study leverages numerous pharmacogenomic and tissue databases to examine drug repositioning for glioblastoma. RNA-seq of glioblastoma tumor samples from The Cancer Genome Atlas (TCGA, n = 117) were compared to “normal” frontal lobe samples from Genotype-Tissue Expression Portal (GTEX, n = 120) to find differentially expressed genes (DEGs). Using compound gene expression data and drug activity data from the Library of Integrated Network-Based Cellular Signatures (LINCS, n = 66,512 compounds) CCLE (71 glioma cell lines), and Chemical European Molecular Biology Laboratory (ChEMBL) platforms, we employed a summarized reversal gene expression metric (sRGES) to “reverse” the resultant disease signature for GBM and its subtypes. A multiparametric strategy was employed to stratify compounds capable of blood-brain barrier penetrance with a favorable pharmacokinetic profile (CNS-MPO).

Results

Significant correlations were identified between sRGES and drug efficacy in GBM cell lines in both ChEMBL(r = 0.37, P < .001) and Cancer Therapeutic Response Portal (CTRP) databases (r = 0.35, P < 0.001). Our multiparametric algorithm identified two classes of drugs with highest sRGES and CNS-MPO: HDAC inhibitors (vorinostat and entinostat) and topoisomerase inhibitors suitable for drug repurposing.

Conclusions

Our studies suggest that reversal of glioblastoma disease signature correlates with drug potency for various GBM subtypes. This multiparametric approach may set the foundation for an early-phase personalized -omics clinical trial for glioblastoma by effectively identifying drugs that are capable of reversing the disease signature and have favorable pharmacokinetic and safety profiles.
Immune deconvolution and temporal mapping identifies stromal targets and developmental intervals for abrogating murine low-grade optic glioma formation
Authors: de Andrade Costa Amanda , Chatterjee Jit , Cobb Olivia , Cordell Elizabeth , Chao Astoria , Schaeffer Suzanne , Goldstein Andrea , Dahiya Sonika , Gutmann David H
Published: December 2021

Background

Brain tumor formation and progression are dictated by cooperative interactions between neoplastic and non-neoplastic cells. This stromal dependence is nicely illustrated by tumors arising in the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, where children develop low-grade optic pathway gliomas (OPGs). Using several authenticated Nf1-OPG murine models, we previously demonstrated that murine Nf1-OPG growth is regulated by T cell function and microglia Ccl5 production, such that their inhibition reduces tumor proliferation in vivo. While these interactions are critical for established Nf1-OPG tumor growth, their importance in tumor formation has not been explored.

Methods

A combination of bulk and single-cell RNA mouse optic nerve sequencing, immunohistochemistry, T cell assays, and pharmacologic and antibody-mediated inhibition methods were used in these experiments.

Results

We show that T cells and microglia are the main non-neoplastic immune cell populations in both murine and human LGGs. Moreover, we demonstrate that CD8+ T cells, the predominant LGG-infiltrating lymphocyte population, are selectively recruited through increased Ccl2 receptor (Ccr4) expression in CD8+, but not CD4+, T cells, in a NF1/RAS-dependent manner. Finally, we identify the times during gliomagenesis when microglia Ccl5 production (3–6 weeks of age) and Ccl2-mediated T cell infiltration (7-10 weeks of age) occur, such that temporally-restricted Ccl2 or Ccl5 inhibition abrogates tumor formation >3.5 months following the cessation of treatment.

Conclusions

Collectively, these findings provide proof-of-concept demonstrations that targeting stromal support during early gliomagenesis durably blocks murine LGG formation.
A Systematic Review and Meta-Analysis of Efficacy of Ultrasound-Guided Single-Shot Quadratus Lumborum Block for Postoperative Analgesia in Adults Following Total Hip Arthroplasty
Authors: Behera Bikram Kishore , Misra Satyajeet , Sarkar Satyaki , Mishra Nitasha
Published: December 2021

Study objective

To evaluate the efficacy of ultrasound-guided single-shot quadratus lumborum block (QLB) for postoperative analgesia in adults following total hip arthroplasty (THA).

Design

Systematic review and meta-analysis.

Setting

Perioperative period.

Patients

Adult patients undergoing THA.

Methods

Studies were identified by performing searches in the following electronic databases, PubMed (Medline), Cochrane Central Registry of Trials (CENTRAL), and Google Scholar. We sought studies in adult patients undergoing THA, comparing QLB with a control group (no block, sham block or any other ultrasound guided regional nerve blocks). A total of 774 patients from 10 studies (7 randomized controlled, one controlled clinical and two retrospective study) were included in this meta-analysis.

Main results

The 24 hour opioid consumption was similar in both the groups (WMD −4.09; 95% CI [−9.00, 0.83]; P = 0.10; I2 = 95%). The pain scores at rest at 24 hours was significantly less in QLB group (WMD −0.62; 95% CI [−1.15, −0.10]; P = 0.02; I2 = 75%). The difference in pain scores was however not clinically significant. The pain scores on movement at 24 hours, time to first analgesic request, and time to discharge from hospital were similar in both the groups.

Conclusions

QLB as part of multimodal analgesia did not result in any significant analgesic benefits in patients undergoing hip arthroplasty in terms of either postoperative opioid consumption or pain scores at rest and on movement. Overall, the level of certainty is low. Further, well-designed trials are required to verify the results.
Association Among Pelvic Girdle Pain, Diastasis Recti Abdominis, Pubic Symphysis Width, and Pain Catastrophizing: A Matched Case–Control Study
Authors: Starzec-Proserpio Małgorzata , Lipa Daria , Szymański Jacek , Szymańska Agata , Kajdy Anna , Baranowska Barbara
Published: December 2021

Objective

Pregnancy-related pelvic girdle pain (PGP) may persist or occur postpartum and negatively affects women’s lives. There is uncertainty regarding the association between the structures of the bony pelvis, diastasis recti abdominis (DRA), pain processing, and PGP and to what extent these factors should be considered during physical therapy. This study aimed to evaluate the differences between women with and without PGP shortly after delivery regarding the separation of a pubic symphysis, DRA, and pain catastrophizing.

Methods

Women diagnosed with PGP 24 to 72 hours after vaginal delivery were matched to pain-free controls according to age and parity. Ultrasound evaluations of diastasis recti (interrecti distance [IRD]) during rest and curl-up task and pubic symphysis (interpubic width) were performed. The Pain Catastrophizing Scale was used to assess the level of catastrophizing. A special Cox regression model was used to fit a conditional logistic regression for a 1:2 matched case–control study.

Results

Thirty-five women with clinically diagnosed PGP and 70 matched controls were included in the study. The PGP group had a significantly higher pre-pregnancy body mass index than the control group. After adjusting for body mass index in multiple conditional logistic regression, the interpubic distance (odds ratio = 1.64; 95% CI = 1.22 to 2.20) and IRD during curl-up (odds ratio = 2.01; 95% CI = 1.08 to 3.74) were significantly associated with PGP. Pain catastrophizing and IRD at rest were not associated with PGP in univariable or multivariable analysis.

Conclusions

Pain catastrophizing is similar for women with and without PGP early postpartum. However, the degree of the pubic symphysis and rectus abdominis separation during the curl-up task are positively associated with PGP shortly after delivery.

Impact

This study indicates that a reconsideration of the way we look at DRA is warranted. The development of a more comprehensive assessment including objective measurements and a biopsychosocial understanding is needed to inform directions for further postpartum physical therapy.
Co-producing Bioethics: How Biomedical Scientists and Applied Philosophers Established Bioethics in Australia
Authors: Mayes Christopher
Published: December 2021

This article examines the emergence of bioethics at Monash University and Australia during the late-1970s and early-1980s. Unlike bioethics in the USA, which was born a decade earlier during policy debates over human experimentation and withdrawal of treatment, bioethics in Australia initially emerged in the university context via interactions among research scientists working at the forefront of reproductive medicine and philosophers seeking to address issues of public concern. These interactions occurred in a rapidly changing university sector that was moving towards research translation and a new global knowledge economy. Drawing on oral histories with philosophers and medical scientists involved in these events, as well as archival materials, this article uses a co-productionist analytic lens to critically examine how changing institutional norms encouraged mutually beneficial interactions between philosophers and scientists, which shaped the emergence of a new and distinctive field of bioethics in Australia.
Persistence of the ‘Codeless Myriad’: The Indian Contract Act and a Puzzle Surrounding Common Law Codification
Authors: Swaminathan Shivprasad
Published: December 2021

The drafters of the Indian Contract Act, 1872 modelled the code after the will theory and deviated from the English law in a number of areas where it ran counter to the will theory. However, when one fast-forwards by a century, one finds that the Indian courts ended up construing the Act a way that it has come to be virtually indistinguishable from English contract law, warts and all. This article seeks to examine—with a study of provisions related to consideration, privity, and stipulated sums in the Indian Contract Act—the causes for dissonance between the case law and the code. It hypothesizes that the troubles for codification—which manifest in the trajectory taken by the Indian contract code—stem from certain underlying jurisprudential features of common law adjudication which neither the adherents nor the opponents of the codification project seem to have fully grasped. These features make adjudication track the antediluvian common law rather than the ‘code’ which it is supposed to supplant. At the heart of the common law is a form of normativity (normless normativity) that at odds with the conception of normativity presupposed by a code (normativity with rules).
Study on the effect of dimple position on drag reduction of high-speed maglev train
Authors: Zhou Dan , Wu Liliang , Tan Changda , Hu Tian'en
Published: December 2021

Transient numerical simulations were carried out by placing dimples at the top, sides and bottoms of the tail car streamline area of a high-speed maglev train. The results of an improved delayed detached eddy simulation turbulence model using three-dimensional compressible Navier-Stokes and shear-stress transport K-Omega double equations were compared to the results of a wind tunnel test to verify the numerical simulation accuracy, within 5% of the ground truth, which is an acceptable precision range. The results show that dimples arranged on the streamline area atop the train tail car affected the locations at which the airflow at the top and bottom of the train met and weakened the strength of the wake. The aerodynamic drag and lift coefficient decreased by 3.40% and 4.27%, respectively. When the dimples were arranged on the streamline area at the sides or bottoms of the train tail car, they had little effect on the top of the tail car, so they did not destroy the balance of the airflow at the top and bottom. They also had little influence on the development of wake topology. Therefore, the aerodynamic drag and lift of the train changed little.
An online atlas of human plasma metabolite signatures of gut microbiome composition
Authors: Dekkers Koen F. , Sayols-Baixeras Sergi , Baldanzi Gabriel , Nowak Christoph , Hammar Ulf , Nguyen Diem , Varotsis Georgios , Brunkwall Louise , Nielsen Nynne , Eklund Aron C. , Holm Jacob Bak , Nielsen H. Bjørn , Ottosson Filip , Lin Yi-Ting , Ahmad Shafqat , Lind Lars , Sundström Johan , Engström Gunnar , Smith J. Gustav , Ärnlöv Johan , Orho-Melander Marju , Fall Tove
Published: December 2021

Summary paragraph

The human gut microbiota produces a variety of small compounds, some of which enter the bloodstream and impact host health. Conversely, various exogenous nutritional and pharmaceutical compounds affect the gut microbiome composition before entering circulation. Characterization of the gut microbiota–host plasma metabolite interactions is an important step towards understanding the effects of the gut microbiota on human health. However, studies involving large and deeply phenotyped cohorts that would reveal such meaningful interactions are scarce. Here, we used deep metagenomic sequencing and ultra-high-performance liquid chromatography linked to mass spectrometry for detailed characterization of the fecal microbiota and plasma metabolome, respectively, of 8,584 participants invited at age 50 to 64 of the Swedish CArdioPulmonary bioImage Study (SCAPIS). After adjusting for multiple comparisons, we identified 1,008 associations between species alpha diversity and plasma metabolites, and 318,944 associations between specific gut metagenomic species and plasma metabolites. The gut microbiota explained up to 50% of the variance of individual plasma metabolites (mean of 4.7%). We present all results as the searchable association atlas “GUTSY” as a rich resource for mining associations, and exemplify the potential of the atlas by presenting novel associations between oral medication and the gut microbiome, and microbiota species strongly associated with levels of the uremic toxin p-cresol sulfate. The association atlas can be used as the basis for targeted studies of perturbation of specific bacteria and for identification of candidate plasma biomarkers of gut flora composition.
Autism spectrum disorder trios from consanguineous populations are enriched for rare biallelic variants, identifying 32 new candidate genes
Authors: Harripaul Ricardo , Rabia Ansa , Vasli Nasim , Mikhailov Anna , Rodrigues Ashlyn , Pastore Stephen F. , Muhammad Tahir , Madanagopal Thulasi Thiruvallur , Hashmi Aisha Nasir , Tran Clinton , Stan Cassandra , Aw Katherine , Zai Clement , Azam Maleeha , Mahmood Saqib , Heidari Abolfazl , Qamar Raheel , French Leon , Tripathy Shreejoy , Agha Zehra , Iqbal Muhammad , Ghadami Majid , Santangelo Susan L. , Bozorgmehr Bita , Al Ayadhi Laila , Sasanfar Roksana , Maqbool Shazia , Knowles James A. , Ayub Muhammad , Vincent John B
Published: December 2021

Background

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects about 1 in 36 children in the United States, imposing enormous economic and socioemotional burden on families and communities. Genetic studies of ASD have identifiedde novocopy number variants (CNVs) and point mutations that contribute significantly to the genetic architecture, but the majority of these studies were conducted in populations unsuited for detecting autosomal recessive (AR) inheritance. However, several ASD studies in consanguineous populations point towards AR as an under-appreciated source of ASD variants.

Methods

We used whole exome sequencing to look for rare variants for ASD in 115 proband-mother-father trios from populations with high rates of consanguinity, namely Pakistan, Iran, and Saudi Arabia. Consanguinity was assessed through microarray genotyping.

Results

We report 84 candidate disease-predisposing single nucleotide variants and indels, with 58% biallelic, 25% autosomal dominant/de novo, and the rest X-linked, in 39 trios. 52% of the variants were loss of function (LoF) or putative LoF (pLoF), and 47% nonsynonymous. We found an enrichment of biallelic variants, both in sixteen genes previously reported for AR ASD and/or intellectual disability (ID) and 32 previously unreported AR candidate genes (includingDAGLA,ENPP6,FAXDC2,ILDR2,KSR2,PKD1L1,SCN10A,SHH, andSLC36A1). We also identified eight candidate biallelic exonic loss CNVs.

Conclusions

The significant enrichment for biallelic variants among individuals with high Frohcoefficients, compared with low Froh, either in known or candidate AR genes, confirms that genetic architecture for ASD among consanguineous populations is different to non-consanguineous populations. Assessment of consanguinity may assist in the genetic diagnostic process for ASD.
Intrahost evolution of the HIV-2 capsid correlates with progression to AIDS
Authors: Boswell M. T. , Nazziwa J. , Kuroki K. , Palm A. , Karlson S. , Månsson F. , Biague A. , da Silva Z. J. , Onyango C.O. , de Silva T.I. , Jaye A. , Norrgren H. , Medstrand P. , Jansson M. , Maenaka K. , Rowland-Jones S. L. , Esbjörnsson J. ,   the SWEGUB CORE group
Published: December 2021

Background

HIV-2 infection will progress to AIDS in most patients without treatment, albeit at approximately half the rate of HIV-1 infection. HIV-2 p26 amino acid variations are associated with lower viral loads and enhanced processing of T cell epitopes, which may lead to protective Gag-specific CTL responses common in slower disease progressors. Lower virus evolutionary rates, and positive selection on conserved residues in HIV-2 env have been associated with slower progression to AIDS. We therefore aimed to determine if intrahost evolution of HIV-2 p26 is associated with disease progression.

Methods

Twelve treatment-naïve, HIV-2 mono-infected participants from the Guinea-Bissau Police cohort with longitudinal CD4+ T cell data and clinical follow-up were included in the analysis. CD4% change over time was analysed via linear regression models to stratify participants into relative faster and slower disease progressor groups. Gag amplicons of 735 nucleotides which spanned the p26 region were amplified by PCR and sequenced. We analysed p26 sequence diversity evolution, measured site-specific selection pressures and evolutionary rates, and determined if these evolutionary parameters were associated with progression status. Amino acid polymorphisms were mapped to existing p26 protein structures.

Results

In total, 369 heterochronous HIV-2 p26 sequences from 12 male patients with a median age of 30 (IQR: 28–37) years at enrolment were analysed. Faster progressors had lower CD4% and faster CD4% decline rates. Median pairwise sequence diversity was higher in faster progressors (5.7×10−3 versus 1.4×10−3 base substitutions per site, P<0.001). p26 evolved under negative selection in both groups (dN/dS=0.12). Virus evolutionary rates were higher in faster than slower progressors – synonymous rates: 4.6×10−3 vs. 2.3×10−3; and nonsynonymous rates: 6.9×10−4 vs. 2.7×10−4 substitutions/site/year, respectively. Virus evolutionary rates correlated negatively with CD4% change rates (ρ = -0.8, P=0.02), but not CD4% level. However, Bayes factor (BF) testing indicated that the association between evolutionary rates and CD4% kinetics was supported by weak evidence (BF=0.5). The signature amino acid at p26 positions 6, 12 and 119 differed between faster (6A, 12I, 119A) and slower (6G, 12V, 119P) progressors. These amino acid positions clustered near to the TRIM5α/p26 hexamer interface surface.

Conclusions

Faster p26 evolutionary rates were associated with faster progression to AIDS and were mostly driven by synonymous substitutions. Nonsynonymous evolutionary rates were an order of magnitude lower than synonymous rates, with limited amino acid sequence evolution over time within hosts. These results indicate the HIV-2 p26 may be an attractive vaccine or therapeutic target.
COVID-19 mRNA Booster Vaccines Elicit Strong Protection Against SARS-CoV-2 Omicron Variant in Patients with Cancer
Authors: Zeng Cong , Evans John P. , Chakravarthy Karthik , Qu Panke , Reisinger Sarah , Song No Joon , Rubinstein Mark P. , Shields Peter G. , Li Zihai , Liu Shan-Lu
Published: December 2021

Following its emergence in late November of 2020, the SARS-CoV-2 Omicron (B.1.1.529) variant has caused major global public health concerns. We recently demonstrated that in healthy adults the Omicron variant exhibits strong resistance to immunity induced by two doses of the mRNA vaccines, but a booster mRNA vaccine dose can provide strong protection against Omicron. However, it is currently unknown how well these mRNA vaccine boosters protect immunocompromised groups, including cancer patients, from the Omicron variant. Here we show that (1) neutralizing antibody (nAb) titers against the Delta and Omicron variants in cancer patients after two-dose mRNA vaccines are 4.2-fold and 21.3-fold lower, respectively, compared to the ancestral D614G, and (2) nAb titers against the Delta and Omicron variants in boosted cancer patients are 3.6-fold and 5.1-fold lower, respectively, compared to D614G. Our findings highlight the effectiveness and need for booster vaccination strategies in immunocompromised groups including cancer patients to protect from the Omicron variant.
A Bioinformatics Pipeline for Estimating Mitochondria DNA Copy Number and Heteroplasmy Levels from Whole Genome Sequencing Data
Authors: Battle Stephanie L , Puiu Daniela ,   TOPMed mtDNA Working Group, Boerwinkle Eric , Taylor Kent D , Rotter Jerome I , Rich Stephan S , Grove Megan L , Pankratz Nathan , Fetterman Jessica L , Liu Chunyu , Arking Dan E
Published: December 2021

Mitochondrial diseases are a heterogeneous group of disorders that can be caused by mutations in the nuclear or mitochondrial genome. Mitochondrial DNA variants may exist in a state of heteroplasmy, where a percentage of DNA molecules harbor a variant, or homoplasmy, where all DNA molecules have a variant. The relative quantity of mtDNA in a cell, or copy number (mtDNA-CN), is associated with mitochondrial function, human disease, and mortality. To facilitate accurate identification of heteroplasmy and quantify mtDNA-CN, we built a bioinformatics pipeline that takes whole genome sequencing data and outputs mitochondrial variants, and mtDNA-CN. We incorporate variant annotations to facilitate determination of variant significance. Our pipeline yields uniform coverage by remapping to a circularized chrM and recovering reads falsely mapped to nuclear-encoded mitochondrial sequences. Notably, we construct a consensus chrM sequence for each sample and recall heteroplasmy against the sample’s unique mitochondrial genome. We observe an approximately 3-fold increased association with age for heteroplasmic variants in non-homopolymer regions and, are better able to capture genetic variation in the D-loop of chrM compared to existing software. Our bioinformatics pipeline more accurately captures features of mitochondrial genetics than existing pipelines that are important in understanding how mitochondrial dysfunction contributes to disease.
Differential regulation of prelimbic and thalamic transmission to the basolateral amygdala by acetylcholine receptors
Authors: Tryon Sarah C. , Bratsch-Prince Joshua X. , Warren James W. , Jones Grace C. , McDonald Alexander J. , Mott David D.
Published: December 2021

The amygdalar anterior basolateral nucleus (BLa) plays a vital role in emotional behaviors. This region receives dense cholinergic projections from basal forebrain which are critical in regulating neuronal activity and synaptic transmission. Cholinergic signaling in BLa is thought to occur through both a slow mode of volume transmission as well as a rapid, phasic mode. However, the relative effect of each mode of signaling in BLa is not understood. Here, we used electrophysiology and optogenetics in mouse brain slices to compare regulation of afferent input from cortex and thalamus to the BLa by these two modes of transmission. Phasic ACh release evoked by single pulse stimulation of cholinergic terminals had a biphasic effect on glutamatergic transmission at cortical input, producing rapid nicotinic receptor-mediated facilitation followed by slower muscarinic receptor (mAChR)-mediated depression. In contrast, tonic elevation of ACh through application of the cholinesterase inhibitor physostigmine suppressed glutamatergic transmission at cortical inputs through mAChRs only. This suppression was not observed at thalamic inputs to BLa. In agreement with this pathway-specificity, the mAChR agonist, muscarine more potently suppressed transmission at inputs from prelimbic cortex (PL) than thalamus. Muscarinic inhibition at PL input was dependent on presynaptic M4 mAChRs, while at thalamic input it depended upon M3 mAChR-mediated stimulation of retrograde endocannabinoid signaling. Muscarinic inhibition at both pathways was frequency-dependent, allowing only high frequency activity to pass. These findings demonstrate complex cholinergic regulation of afferent input to BLa that depends upon the mode of ACh release and is both pathway specific and frequency dependent.

Significance statement

Cholinergic modulation of the basolateral amygdala regulates formation of emotional memories, but the mechanisms underlying this regulation are not well understood. Here, we show, using mouse brain slices, that ACh differentially regulates afferent transmission to the BLa depending on the mode of cholinergic signaling. Rapid, phasic ACh produces a biphasic excitatory-inhibitory regulation of glutamatergic transmission mediated by nicotinic and muscarinic receptors, respectively. In contrast, slow, tonic ACh produces muscarinic inhibition only. Tonic regulation is pathway specific with cortical input regulated more strongly than thalamic input. This disparity is caused by differential regulation by M4 and M3 receptors at the two inputs. Specific targeting of these receptors may thus provide a therapeutic strategy to bias amygdalar processing and regulate emotional memory.
Extreme-Value Analysis of Intracellular Cargo Transport by Motor Proteins
Authors: Naoi Takuma , Kagawa Yuki , Nagino Kimiko , Niwa Shinsuke , Hayashi Kumiko
Published: December 2021

Extreme-value analysis (EVA) deals with deviations in the data from the median of the probability distributions. EVA serves various purposes such as predicting disasters and analyzing sports records. Herein, we extended the use of EVA to investigate the motility functions of nanoscale motor proteins in neurons of the living wormCaenorhabditis elegans(C. elegans). Motor proteins, such as kinesin and dynein, move along microtubules anterogradely and retrogradely, respectively, to deliver the cargo-containing materials needed for the cells. Although the essential difference between the two motors could not be inferred from the mean velocity values, the return-level EVA plots obtained from the velocity data revealed a difference. Shape parameters of the generalized extreme value distribution of EVAξ< 0 for anterograde transport andξ≥ 0 for retrograde transport. Our findings extend the possibility and applicability of EVA for analyzing motility data of nanoscale proteinsin vivo.
Nipah virus detection at bat roosts following spillover events in Bangladesh, 2012–2019
Authors: McKee Clifton D. , Islam Ausraful , Rahman Mohammed Ziaur , Khan Salah Uddin , Rahman Mahmudur , Satter Syed M. , Islam Ariful , Yinda Claude Kwe , Epstein Jonathan H. , Daszak Peter , Munster Vincent J. , Hudson Peter J. , Plowright Raina K. , Luby Stephen P. , Gurley Emily S.
Published: December 2021

Knowledge of the dynamics and genetic diversity of Nipah virus circulating in bats and at the human-animal interface is limited by current sampling efforts, which produce few detections of viral RNA. We report on a series of investigations at bat roosts identified near human Nipah cases in Bangladesh between 2012 and 2019. Pooled bat urine samples were collected from 23 roosts; seven roosts (30%) had at least one sample with Nipah RNA detected from the first visit. In subsequent visits to these seven roosts, RNA was detected in bat urine up to 52 days after the presumed exposure of the human case, although the probability of detection declined rapidly with time. These results suggest that rapidly deployed investigations of Nipah virus shedding from bat roosts near human cases could increase the success of viral sequencing compared to background surveillance and enhance our understanding of Nipah virus ecology and evolution.
Longitudinal analysis of invariant natural killer T cell activation reveals a cMAF-associated transcriptional state of NKT10 cells
Authors: Kane Harry , LaMarche Nelson M. , Scannail Áine Ní , Brenner Michael B. , Lynch Lydia
Published: December 2021

Innate T cells, including CD1d-restricted invariant natural killer T (iNKT) cells, are characterized by their rapid activation in response to non-peptide antigens, such as lipids. While the transcriptional profiles of naive, effector and memory adaptive T cells have been well studied, less is known about transcriptional regulation of different iNKT cell activation states. Here, using single cell RNA-sequencing, we performed longitudinal profiling of activated iNKT cells, generating a transcriptomic atlas of iNKT cell activation states. We found that transcriptional signatures of activation are highly conserved among heterogeneous iNKT cell populations, including NKT1, NKT2 and NKT17 subsets, and human iNKT cells. Strikingly, we found that regulatory iNKT cells, such as adipose iNKT cells, undergo blunted activation, and display constitutive enrichment of memory-like cMAF+ and KLRG1+ populations. Moreover, we identify a conserved cMAF-associated transcriptional network among NKT10 cells, providing novel insights into the biology of regulatory and antigen experienced iNKT cells.