bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of antifibrinolytics on systemic and cerebral inflammation after traumatic brain injury
Authors: Wallen Taylor E. , Singer Kathleen E. , Baucom Matthew R. , England Lisa G. , Schuster Rebecca M. , Pritts Timothy A. , Goodman Michael D.
Published: March 2022

BACKGROUND

Administration of antifibrinolytic medications, including tranexamic acid (TXA), may reduce head injury–related mortality. The effect of these medications on post–traumatic brain injury (TBI) inflammatory response is unknown. The goal of this study was to investigate the role of available antifibrinolytic medications on both systemic and cerebral inflammation after TBI.

METHODS

An established murine weight drop model was used to induce a moderate TBI. Mice were administered 1, 10, or 100 mg/kg of TXA, 400 mg/kg of aminocaproic acid (Amicar, Hospira, Lake Forest, IL), 100 kIU/kg of aprotonin, or equivalent volume of normal saline (NS) 10 minutes after recovery. Mice were euthanized at 1, 6, or 24 hours. Serum and cerebral tissue were analyzed for neuron-specific enolase and inflammatory cytokines. Hippocampal histology was evaluated at 30 days for phosphorylated tau accumulation.

RESULTS

One hour after TBI, mice given TXA displayed decreased cerebral cytokine concentrations of tumor necrosis factor α (TNF-α) and, by 24 hours, displayed decreased concentrations of cerebral TNF-α, interleukin (IL)-6, and monocyte chemoattractant protein 1 compared with TBI-NS. However, serum concentrations of TNF-α and macrophage inflammatory protein 1α (MIP-1α) were significantly elevated from 1 to 24 hours in TBI-TXA groups compared with TBI-NS. The concentration of phosphorylated tau was significantly decreased in a dose-dependent manner in TBI-TXA groups compared with TBI-NS. By contrast, Amicar administration increased cerebral cytokine levels of IL-6 1 hour after TBI, with serum elevations noted in TNF-α, MIP-1α, and monocyte chemoattractant protein 1 at 24 hours compared with TBI-NS. Aprotonin administration increased serum TNF-α, IL-6, and MIP-1α from 1 to 24 hours without differences in cerebral cytokines compared with TBI-NS.

CONCLUSION

Tranexamic acid administration may provide acute neuroinflammatory protection in a dose-dependent manner. Amicar administration may be detrimental after TBI with increased cerebral and systemic inflammatory effects. Aprotonin administration may increase systemic inflammation without significant contributions to neuroinflammation. While no antifibrinolytic medication improved systemic inflammation, these data suggest that TXA may provide the most beneficial inflammatory modulation after TBI.
A Comorbidity Index and Pretransplant Physical Status Predict Survival in Older Kidney Transplant Recipients: A National Prospective Study
Authors: Tsarpali Vasiliki , Midtvedt Karsten , Lønning Kjersti , Bernklev Tomm , Åsberg Anders , Fawad Haris , von der Lippe Nanna , Reisæter Anna Varberg , Røysland Kjetil , Heldal Kristian
Published: March 2022

Background.

Kidney transplantation (KT) is considered the best treatment for end-stage kidney disease (ESKD). In the increasing elderly ESKD population, KT should be reserved for carefully selected candidates who are expected to experience favorable outcomes. We aimed to prospectively evaluate pretransplant recipient factors that may predict patient survival and can eventually guide therapeutic decisions in elderly with ESKD.

Methods.

Recipient factors were evaluated in KT candidates aged ≥65 y. Comorbidity was assessed at waitlisting according to the Liu comorbidity index (LCI). Health-related quality of life outcomes were measured using the Kidney Disease Quality of Life Short Form, version 1.3. The Cox proportional hazard regression was used to evaluate predictors of patient survival.

Results.

We included 192 recipients, with a mean age of 72.1 (4.1) y, who were transplanted with kidneys from deceased brain-dead donors. During a median observation period of 4.6 (3.2–6.3) y, 66 recipients died. Elevated LCI consistently predicted poor patient survival. In recipients with LCI ≥4, dialysis >2 y comprised a 2.5-fold increase in mortality risk compared with recipients on dialysis ≤2 y. Self-reported pretransplant physical function was also proven to be a significant positive predictor of survival.

Conclusion.

The implementation of LCI and a physical function score during the evaluation of older kidney transplant candidates may improve the selection and thereby optimize posttransplant outcomes.
Social dynamics and individual hunting tactics of white sharks revealed by biologging
Authors: Papastamatiou Yannis P. , Mourier Johann , TinHan Thomas , Luongo Sarah , Hosoki Seiko , Santana-Morales Omar , Hoyos-Padilla Mauricio
Published: March 2022

Social foraging, where animals forage in groups, takes many forms but is less studied in marine predators as measuring social associations in the wild is challenging. We used biologging (activity, cameras and telemetry receivers) sensors to measure social associations and simultaneous behaviour, in white sharks (
Carcharodon carcharias
) off Guadalupe Island, Mexico. Animal-borne telemetry receivers revealed that sharks varied in the number of associations they formed and occurred most often when sharks were swimming in straight paths or when they were turning frequently. While many associations were likely random, there was evidence of some stronger associations. Sharks varied in the depths they used and their activity, with some individuals more active in shallow water while others were more active 200–300 m deep. We propose that white sharks associate with other individuals so they can inadvertently share information on the location or remains of large prey. However, there may be a wide range of individual variability in both behaviour and sociality. Biologging now enables social associations of animals to be measured, concurrent with measures of their behaviour, so that social foraging of large marine predators can be quantified in the wild.
Inequality between identity groups and social unrest
Authors: Houle Christian , Ruck Damian J. , Bentley R. Alexander , Gavrilets Sergey
Published: March 2022

Economic, social and political inequality between different identity groups is an important contributor to violent conflicts within societies. To deepen our understanding of the underlying social dynamics, we develop a mathematical model describing cooperation and conflict in a society composed of multiple factions engaged in economic and political interactions. Our model predicts that growing economic and political inequality tends to lead to the collapse of cooperation between factions that were initially seeking to cooperate. Certain mechanisms can delay this process, including the decoupling of political and economic power through rule of law and allegiance to the state or dominant faction. Counterintuitively, anti-conformity (a social norm for independent action) can also stabilize society, by preventing initial defections from cooperation from cascading through society. However, the availability of certain material resources that can be acquired by the state without cooperation with other factions has the opposite effect. We test several of these predictions using a multivariate statistical analysis of data covering 75 countries worldwide. Using social unrest as a proxy for the breakdown of cooperation in society, we find support for many of the predictions from our theory.
Child protection contact among children of culturally and linguistically diverse backgrounds: a South Australian linked data study
Authors: Abdul Rahim Nur Razlyn , Pilkington Rhiannon M , Procter Alexandra Marie , Montgomerie Alicia , Mittinty Murthy N , D'Onise Katina , Lynch John
Published: March 2022

Aim
To determine the cumulative incidence of child protection (CP) system contact, maltreatment type, source of reports up to age 7, and sociodemographic characteristics for Culturally and Linguistically Diverse (CALD) Australian children.

Methods
A South Australian (SA) whole-of-population linked administrative data study of children followed from birth up to age 7, using child protection, education, health, and birth registrations data. Participants: SA born children enrolled in their first year of school from 2009-2015 (N = 76 563). CALD defined as non-Aboriginal or Torres Strait Islander, spoken language other than English, Indigenous or Sign, or had at least one parent born in a non-English speaking country. Outcomes measures: For CALD and non-CALD children the cumulative incidence of CP reports up to age 7, relative risk and risk differences for all CP contact (reporting through to out-of-home care (OOHC)) and age, primary maltreatment type, reporter type, and socioeconomic characteristics were estimated. Sensitivity analyses explored population selection and different CALD definitions.

Results
By age 7, 11.2% of CALD children were screened in compared to 18.8% of non-CALD (RD 7.6 percentage points (95% CI: 6.9-8.3)), and 0.6% of CALD children experienced OOHC compared to 2.2% of non-CALD (RD 1.6 percentage points (95% CI: 1.3-1.8)). Among both groups, most common abuse type was emotional and the most common reporter types were police and education sector. Socioeconomic characteristics were broadly similar. Sensitivity analyses results were consistent with primary analyses.

Conclusion
By age 7, contact with any level of child protection was lower for CALD compared to non-CALD children. Estimates based on primary and sensitivity analyses suggested CALD children were 5 to 9 percentage points less likely have a report screened-in, and from 1.0 to 1.7 percentage points less likely to have experienced OOHC.
Biofabrication of multiplexed electrochemical immunosensors for simultaneous detection of clinical biomarkers in complex fluids
Authors: Sharma Timilsina Sanjay , Ramasamy Mohanraj , Durr Nolan , Ahmad Rushdy , Jolly Pawan , Ingber Donald E.
Published: March 2022

Simultaneous detection of multiple disease biomarkers in unprocessed whole blood is considered the gold standard for accurate clinical diagnosis. Here, we report the development of a 4-plex electrochemical (EC) immunosensor with on-chip negative control capable of detecting a range of biomarkers in small volumes (15 μL) of complex biological fluids, including serum, plasma, and whole blood. A framework for fabricating and optimizing multiplexed sandwich immunoassays is presented that is enabled by use of EC sensor chips coated with an ultra-selective, antifouling, nanocomposite coating. Cyclic voltammetry evaluation of sensor performance was carried out by monitoring the local precipitation of an electroactive product generated by horseradish peroxidase linked to a secondary antibody. EC immunosensors demonstrated high sensitivity and specificity without background signal with a limit of detection in single-digit pg/mL in multiple complex biological fluids. These multiplexed immunosensors enabled simultaneous detect of four different biomarkers in plasma and whole blood with excellent sensitivity and selectivity. This rapid and cost-effective biosensor platform can be further adapted for use with different high affinity probes for any biomarker, and thereby create for a new class of highly sensitive and specific multiplexed diagnostics.
Post- intravitreal injection endophthalmitis pattern during the COVID-19 pandemic with implementation of patient masking
Authors: Mirghorbani Masoud , Bazvand Fatemeh , Riazi Esfahani Hamid , Mehrabi Bahar Mohammadreza , Yaseri Mehdi , Zarei Mohammad
Published: March 2022

Purpose: To evaluate the role of patient facial mask on the occurrence of post- intravitreal injection (IVI) endophthalmitis in a real word setting.
Design: Retrospective cohort.
Participants: Patients receiving IVIs between 20 February 2019 and 20 February 2021; a 12-month period before the official beginning of COVID-19 epidemic in Iran and a 12-month period after that.
Intervention: In the pre-COVID era patients underwent IVI without a facial mask while in the COVID era patients were treated with an untapped facial mask. Physicians and staff had facial mask in both periods. IVIs were administered in a dedicated operating room and no strict talk policy was followed.
Main outcome measure: The rate of post- IVI endophthalmitis.
Results: A total number of 53927 injections was performed during the study period: 34277 in pre-COVID and 19650 in COVID periods; with a 42.7 % decrease in the number of injections. The endophthalmitis occurred in 7 eyes (0.02%) in pre-COVID and 7 eyes (0.03%) in COVID era (p=0.40). In multivariate analysis, after adjustment for intercorrelations between eyes and multiple injections in one patient, there was no statistically significant association between wearing facial masks by the patients and risk of endophthalmitis (relative risk= 1.47, 95% confidence interval of 0.97-2.22; p=0.071).
Conclusion: Patient facial masking is probably not associated with increased risk of post- injection endophthalmitis.
Dynamics of anti-SARS-CoV-2 seroconversion in individual patients and at the population level
Authors: Szewczyk-Dąbrowska Alina , Budziar Wiktoria , Baniecki Krzysztof , Pikies Aleksandra , Harhala Marek , Jędruchniewicz Natalia , Kaźmierczak Zuzanna , Gembara Katarzyna , Klimek Tomasz , Witkiewicz Wojciech , Nahorecki Artur , Barczyk Kamil , Grata-Borkowska Urszula , Dąbrowska Krystyna
Published: March 2022

The immune response and specific antibody production in COVID-19 are among the key factors that determine both prognostics for individual patients and the global perspective for controlling the pandemics. So called “dark figure”, that is, a part of population that has been infected but not registered by the health care system, make it difficult to estimate herd immunity and to predict pandemic trajectories.

Here we present a follow up study of population screening for hidden herd immunity to SARS-CoV-2 in individuals who had never been positively diagnosed against SARS-CoV-2; the first screening was in May 2021, and the follow up in December 2021. We found that specific antibodies targeting SARS-CoV-2 detected in May as the “dark figure” cannot be considered important 7 months later due to their significant drop. On the other hand, among participants who at the first screening were negative for anti-SARS-CoV-2 IgG, and who have never been diagnosed for SARS-CoV-2 infection nor vaccinated, 26% were found positive for anti-SARS-CoV-2 IgG. This can be attributed to of the “dark figure” of the recent, fourth wave of the pandemic that occurred in Poland shortly before the study in December. Participants who were vaccinated between May and December demonstrated however higher levels of antibodies, than those who undergone mild or asymptomatic (thus unregistered) infection. Only 7% of these vaccinated participants demonstrated antibodies that resulted from infection (anti-NCP). The highest levels of protection were observed in the group that had been infected with SARS-CoV-2 before May 2021 and also fully vaccinated between May and December.

These observations demonstrate that the hidden fraction of herd immunity is considerable, however its potential to suppress the pandemics is limited, highlighting the key role of vaccinations.
Synthesizing evidence from the earliest studies to support decision-making: to what extent could the evidence be reliable?
Authors: Yu Tianqi , Lin Lifeng , Furuya-Kanamori Luis , Xu Chang
Published: March 2022

In evidence-based practice, new topics generally only have a few studies available for synthesis. As a result, the evidence of such meta-analyses raised large concerns. We investigated the robustness of the evidence of meta-analyses from these earliest studies. Real-world data from the Cochrane Database of Systematic Reviews (CDSR) were collected. We emulated meta-analyses with the earliest 1 to 10 studies through cumulative meta-analysis from eligible meta-analyses. The magnitude and the direction of meta-analyses with the earliest few studies were compared to the full meta-analyses. From the CDSR, we identified 20,227 meta-analyses of binary outcomes and 7,683 meta-analyses of continuous outcomes. Under the tolerable difference of 20% on the magnitude of the effects, the convergence proportion ranged from 24.24% (earliest 1 study) to 77.45% (earliest 10 studies) for meta-analyses of few earliest studies with binary outcomes. For meta-analyses of continuous outcomes, the convergence proportion ranged from 13.86% to 56.52%. In terms of the direction on the effects, even when only 3 studies were available at the earliest stage, the majority had the same direction to full meta-analyses; Only 19% for binary outcomes and 12% for continuous outcomes changed the direction as further evidence accumulated. Synthesizing evidence from the earliest studies is feasible to support urgent decision-making, and in most cases, the decisions would be reasonable. Considering the potential uncertainties, it is essential to evaluate the confidence of the evidence of these meta-analyses and update the evidence when necessary.
Home Care Follow up determine the point of inversion of IL-6 levels in relation to C-Reactive Protein as the cytokine storm marker in COVID-19
Authors: de Mello Mendes Filho Sérgio Paulo , Martins Fernanda Simão , Giroldi Paulo Jose , Melo Raul Honorato e , de Oliveira Edcleia Lopes , dos Santos Anibal Borin , Medeiros Dayse Cristina Oliveira , de Almeida Basano Sergio , Lopes Jéssica Amaral , Chaves Yury Oliveira , Pinheiro Rebeca Sousa , Camargo Luís Marcelo Aranha , Zuliani Juliana Pavan , Nogueira Paulo Afonso
Published: March 2022

The IL-6 has been used for the characterization of the cytokine storm induced by SARS-CoV-2, but so far, no one has found out when and in whom the cytokine storm develops. Our study demonstrates how early and longitudinal clinical-based monitoring and dosing of five markers (C-reactive protein, IL-6, fibrinogen, ferritin and D-dimer) helped to identify who’d developed the cytokine storm. The peak of IL-6 in pg/mL proportionally higher than the peak of CRP in mg/L was sufficient to define the timing of the evolution of cytokine storm syndrome. The administration of antibiotic therapy, anticoagulant therapy and pulse therapy resolved the infection and prevented the progressive deterioration of the lung function of the patients with potential for development of severe COVID-19.
Design and methodological considerations for biomarker discovery and validation in the Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Program
Authors: Robbins Hilary A , Alcala Karine , Khodayari Moez Elham , Guida Florence , Thomas Sera , Zahed Hana , Warkentin Matthew , Smith-Byrne Karl , Brhane Yonathan , Muller David , Albanes Demetrius , Aldrich Melinda C , Arslan Alan A , Bassett Julie , Berg Christine D , Cai Qiuyin , Chen Chu , Davies Michael PA , Diergaarde Brenda , Field John K , Freedman Neal D , Huang Wen-Yi , Johansson Mikael , Jones Michael , Koh Woon-Puay , Lam Stephen , Lan Qing , Langhammer Arnulf , Liao Linda M , Liu Geoffrey , Malekzadeh Reza , Milne Roger L , Montuenga Luis M , Rohan Thomas , Sesso Howard D , Severi Gianluca , Sheikh Mahdi , Sinha Rashmi , Shu Xiao-Ou , Stevens Victoria L , Tammemägi Martin C , Tinker Lesley F , Visvanathan Kala , Wang Ying , Wang Renwei , Weinstein Stephanie J , White Emily , Wilson David , Yuan Jian-Min , Zhang Xuehong , Zheng Wei , Amos Christopher I , Brennan Paul , Johansson Mattias , Hung Rayjean J
Published: March 2022

The Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) program is an NCI-funded initiative with an objective to develop tools to optimize lung cancer screening. Here, we describe the rationale and design for the Risk Biomarker and Nodule Malignancy projects within INTEGRAL.

The overarching goal of these projects is to systematically investigate circulating protein markers to include on a panel for use (i) pre-LDCT, to identify people likely to benefit from screening, and (ii) post-LDCT, to differentiate benign versus malignant nodules. To identify informative proteins, the Risk Biomarker project measured 1,161 proteins in a nested-case control study within 2 prospective cohorts (n=252 lung cancer cases and 252 controls) and replicated associations for a subset of proteins in 4 cohorts (n=479 cases and 479 controls). Eligible participants had any history of smoking and cases were diagnosed within 3 years of blood draw. The Nodule Malignancy project measured 1,077 proteins among participants with a heavy smoking history within 4 LDCT screening studies (n=425 cases within 5 years of blood draw, 398 benign-nodule controls, and 430 nodule-free controls).

The INTEGRAL panel will enable absolute quantification of 21 proteins. We will evaluate its lung cancer discriminative performance in the Risk Biomarker project using a case-cohort study including 14 cohorts (n=1,696 cases and 2,926 subcohort representatives), and in the Nodule Malignancy project within 5 LDCT screening studies (n=675 cases, 648 benign-nodule controls, and 680 nodule-free controls). Future progress to advance lung cancer early detection biomarkers will require carefully designed validation, translational, and comparative studies.
Adverse events of iron and/or erythropoiesis-stimulating agent therapy in preoperatively anaemic elective surgery patients: a systematic review
Authors: Laermans Jorien , Van Remoortel Hans , Avau Bert , Bekkering Geertruida E , Georgsen Jorgen , Manzini Paola Maria , Meybohm Patrick , Ozier Yves , De Buck Emmy , Compernolle Veerle , Vandekerckhove Philippe
Published: March 2022

Background. Iron supplementation and erythropoiesis-stimulating agent (ESA) administration represent the hallmark therapies in preoperative anaemia treatment, as reflected in a set of evidence-based treatment recommendations made during the 2018 International Consensus Conference on Patient Blood Management. However, little is known about the safety of these therapies. This systematic review investigated the occurrence of adverse events (AEs) during or after treatment with iron and/or ESAs.

Methods. Five databases (The Cochrane Library, MEDLINE, Embase, Transfusion Evidence Library, Web of Science) and two trial registries (ClinicalTrials.gov, WHO ICTRP) were searched until November 6 2020. Randomized controlled trials (RCTs), cohort and case-control studies investigating any AE during or after iron and/or ESAs administration in adult elective surgery patients with preoperative anaemia were eligible for inclusion, and judged using the Cochrane Risk of Bias tools. The GRADE approach was used to assess the overall certainty of evidence.

Results. 26 RCTs and 16 cohort studies involving a total of 6062 patients were included, providing data on 6 comparisons: (1) Intravenous (IV) versus oral iron, (2) IV iron versus usual care/no iron, (3) IV ferric carboxymaltose versus IV iron sucrose, (4) ESA+iron versus control (placebo and/or iron, no treatment), (5) ESA+IV iron versus ESA+oral iron, and (6) ESA+IV iron versus ESA+IV iron (different ESA dosing regimens). Most AE data concerned mortality/survival (n=24 studies), thromboembolic (n=22), infectious (n=20), cardiovascular (n=19) and gastrointestinal (n=14) AEs. Very low-certainty of evidence was assigned to all but one outcome category. This uncertainty results from both low quantity and quality of AE data due to high risk of bias
caused by limitations in study design, data collection and reporting.

Conclusions. It remains unclear if ESA and/or iron therapy is associated with AEs in preoperatively anaemic elective surgery patients. Future trial investigators should pay more attention to the systematic collection, measurement, documenting and reporting of AE data.
Pre-exposure prophylaxis with Evusheld™ elicits limited neutralizing activity against the omicron variant in kidney transplant patients
Authors: Benotmane Ilies , Velay Aurélie , Thaunat Olivier , Vargas Gabriela Gautier , Olagne Jérôme , Fafi-Kremer Samira , Caillard Sophie
Published: March 2022

The combination of cilgavimab-tixagevimab (Evusheld™, Astra Zeneca) became the mainstay for protecting transplant recipients with poor response to vaccination against the omicron variant. Serum neutralizing capacity against SARS-CoV-2 is positively associated with protection against severe forms of Covid-19.

Both anti-RBD IgG titers and neutralizing antibody titers against the omicron BA.1 variant were measured in serum samples collected from 63 adult kidney transplant recipients who received prophylactic injections of Evusheld™. Patients who received prophylactic Ronapreve™ (casirivimab-imdevimab, n = 39) and those who were infected with SARS-CoV-2 during the fifth wave of the pandemic (n = 14) served as negative and positive controls, respectively.

After a median interval from injection of 29 days (interquartile range 29-33 days), only 9.5% of patients who received Evusheld™ were able to neutralize the omicron variant compared to 71% of patients who were infected with SARS-CoV-2 and 2.6% of those who received Ronapreve™. Interestingly, convalescent patients displayed higher levels of neutralizing antibodies than those who received EvusheldTM (median: 2.3 log IC50, IQR: 1.5-2.7 versus 0.00 log IC50, IQR: 0&[ndash] 0.05; p<0.001). A high interindividual variability in anti-RBD IgG titers was observed after Evusheld™ (range: 262-7032 BAU/mL). This variability was largely explained by the patients’body mass index, which showed an inverse correlation with anti-RBD IgG titers.

These findings suggest that Evusheld™ given at a dose of 300 mg is not sufficient to elicit an anti-RDB titer that confers in vivo neutralizing activity and support recent FDA recommendations, derived from in vitro models, regarding the need to increase the dose of Evusheld™
Prevalence and determinants of peripheral arterial disease in children with nephrotic syndrome
Authors: Akinyosoye Gbenga , Solarin Adaobi U , Adekunle Motunrayo O , Oladimeji Alaba B , Owolabi Adeola O , Akinsola Clement M , Dada Adeyemi , Animasahun Barakat A , Njokanma Fidelis O
Published: March 2022

Peripheral arterial disease (PAD) is the least studied complication of nephrotic syndrome (NS). Risk factors which predispose children with NS to developing PAD include hyperlipidaemia, hypertension and prolonged use of steroids. The development of PAD significantly increases the morbidity and mortality associated with NS as such children are prone to sudden cardiac death. The ankle brachial index (ABI) is a tool that has been proven to have high specificity and sensitivity in detecting PAD even in asymptomatic individuals. We aimed to determine the prevalence of PAD in children with NS and to identify risk factors that can independently predict its development. A comparative cross-sectional study was conducted involving 200 subjects (100 with NS and 100 apparently healthy comparative subjects that were matched for age, sex and socioeconomic class). Systolic blood pressures were measured in all limbs using the pocket Doppler machine (Norton Doppler scan machine). ABI was calculated as a ratio of ankle to arm systolic blood pressure. PAD was defined as ABI less than 0.9. The prevalence of PAD was significantly higher in children with NS than matched comparison group (44.0% vs 6.0%, p < 0.001). Average values of waist and hip circumference were significantly higher in subjects with PAD than those without PAD (61.68± 9.1cm and 67.6± 11.2 cm vs 57.03 ± 8.3cm and 65.60± 12.5cm respectively, p< 0.005). Serum lipids (triglyceride, very low density lipoprotein, total cholesterol and low density lipoprotein) were also significantly higher in subjects with PAD than those without PAD [106.65mg/dl (67.8-136.7) vs 45.72mg/dl (37.7-61.3), 21.33mg/dl (13.6-27.3) vs 9.14mg/dl (7.5-12.3), 164.43mg/dl (136.1-259.6) vs 120.72mg/dl (111.1-142.1) and 93.29mg/dl (63.5-157.3) vs 61.84mg/dl (32.6-83.1), respectively p< 0.05]. Increasing duration since diagnosis of NS, having a steroid resistant NS and increasing cumulative steroid dose were independent predictors of PAD in children with NS; p< 0.05 respectively).
Regulation of multiple dimeric states of E-cadherin by adhesion activating antibodies revealed through Cryo-EM and X-ray crystallography
Authors: Maker Allison , Bolejack Madison , Schecterson Leslayann , Hammerson Brad , Abendroth Jan , Edwards Tom E , Staker Bart , Myler Peter J , Gumbiner Barry M
Published: March 2022

E-cadherin adhesion is regulated at the cell surface, a process that can be replicated by activating antibodies. We use cryo-EM and X-ray crystallography to examine functional states of the cadherin adhesive dimer. This dimer is mediated by N-terminal beta strand-swapping involving Trp2, and forms via a different transient X-dimer intermediate. X-dimers are observed in cryo-EM along with monomers and strand-swap dimers, indicating that X-dimers form stable interactions. A novel EC4-mediated dimer was also observed. Activating Fab binding caused no gross structural changes in E-cadherin monomers but can facilitate strand swapping. Moreover, activating Fab binding is incompatible with the formation of the X-dimer. Both cryo-EM and X-ray crystallography reveal a distinctive twisted strand-swap dimer conformation caused by an outward shift in the N-terminal beta strand that may represent a strengthened state. Thus, regulation of adhesion involves changes in cadherin dimer configurations.
Dynamic coastal pelagic habitat drives rapid changes in growth and condition of juvenile sockeye salmon (Oncorhynchus nerka) during early marine migration
Authors: Garzke Jessica , Forster Ian , Godwin Sean , Johnson Brett T. , Krkosek Martin , Mahara Natalie , Pakhomov Evgeny A. , Rogers Luke A. , Hunt Brian P.V.
Published: March 2022

Migrating marine taxa encounter diverse habitats that differ environmentally and in foraging conditions over a range of spatial scales. We examined body (RNA/DNA, length-weight residuals) and nutritional (fatty acid composition) condition of juvenile sockeye salmon (Oncorhynchus nerka) in British Columbia, while migrating through varied oceanographically waters. Fish were sampled in the stratified northern Strait of Georgia (NSoG); the highly mixed Johnstone Strait (JS); and the transitional zone of Queen Charlotte Strait (QCS). In 2015, body and nutritional condition were high in the NSoG and responded rapidly to reach lowest levels in JS with its low prey availability, and showing signs of compensatory growth in QCS. In 2016, juvenile salmon had significantly lower condition in the NSoG than in 2015, although zooplankton biomass was similar, condition remained low in JS, and no compensatory growth was observed in QCS. We provide evidence that differences in juvenile salmon condition between the two years being due to changes in the food quality available to juvenile fish. Further, we propose that the TGH needs to be extended to incorporate food quality as a parameter to understand changes in fish condition and survival between years.
Periodic spatial patterning with a single morphogen
Authors: Wang Sheng , Garcia-Ojalvo Jordi , Elowitz Michael B.
Published: March 2022

Multicellular development employs periodic spatial patterning to generate repetitive structures such as digits, vertebrae, and teeth. Turing patterning has long provided a key paradigm for understanding such systems. The simplest Turing systems are believed to require at least two signals, or morphogens, that diffuse and react to spontaneously generate periodic patterns. Here, using mathematical modeling, we show that a minimal circuit comprising an intracellular positive feedback loop and a single diffusible morphogen is sufficient to generate stable, long-range spatially periodic cellular patterns. The model considers cells as discrete entities as a key feature, and incorporates transient boundary conditions. Linear stability analysis reveals that this single-morphogen Turing circuit can support a broad range of spatial wavelengths, including fine-grain patterns similar to those generated by classic lateral inhibition systems. Further, signals emanating from a boundary can initiate and stabilize propagating modes with a well-defined spatial wavelength. Once formed, patterns are self-sustaining and robust to noise. Finally, while noise can disrupt patterning in pre-patterned regions, its disruptive effect can be overcome by a bistable intracellular circuit loop, or by considering patterning in the context of growing tissue. Together, these results show that a single morphogen can be sufficient for robust spatial pattern formation, and should provide a foundation for engineering pattern formation in the emerging field of synthetic developmental biology.
Arginine-dependent hypusination of the eukaryotic translation initiation factor (eIF)5A drives erythroid lineage differentiation
Authors: Gonzalez-Menendez Pedro , Phadke Ira , Olive Meagan E. , McGraw Kathy L. , Platon Jessica , Papoin Julien , Yan Hongxia , Daumur Marie , Paul Franciane , Mirmira Raghavendra , Joly Axel , Galtier Jeremy , Narla Anupama , Cartron Guillaume , Dardalhon Valérie , Zimmermann Valérie S. , Sitbon Marc , Dever Thomas E. , Mohandas Narla , Costa Lydie da , Udeshi Namrata D. , Blanc Lionel , Kinet Sandrina , Taylor Naomi
Published: March 2022

Metabolic programs contribute to hematopoietic stem and progenitor cell (HSPC) fate but it is not known whether the metabolic regulation of protein synthesis controls HSPC differentiation. We discovered that SLC7A1/CAT1-dependent arginine uptake and its catabolism to spermidine control the erythroid specification of HSPCs via activation of eukaryotic translation initiation factor 5A (eIF5A). eIF5A activity is dependent on the metabolism of spermidine to hypusine and inhibiting hypusine synthesis abrogates erythropoiesis and diverts EPO-stimulated HSPCs to a myeloid fate. Proteomic profiling reveals mitochondrial translation to be a critical target of hypusinated eIF5A and induction of mitochondrial function partially rescues erythropoiesis in the absence of hypusine. Within the hypusine network, ribosomal proteins are highly enriched and we identify defective eIF5A hypusination in erythroid pathologies caused by abnormal ribosome biogenesis. Thus, eIF5A-dependent protein synthesis is critical in the branching of erythro-myeloid differentiation and attenuated eIF5A activity characterizes ribosomal protein-linked disorders of ineffective erythropoiesis.
Detection and measurement of butterfly eyespot and spot patterns using convolutional neural networks
Authors: Cunha Carolina , Monteiro Antónia , Silveira Margarida
Published: March 2022

Butterflies are increasingly becoming model insects where basic questions surrounding the diversity of their color patterns are being investigated. Some of these color patterns consist of simple spots and eyespots. To accelerate the pace of research surrounding these discrete and circular pattern elements we developed two distinct convolutional neural networks (CNNs) for detection and measurement of butterfly spots and eyespots on digital images of butterfly wings. We tested the accuracy of the detection and of the area measurements using manual identifications and measurements. These methods were able to identify and distinguish marginal eyespots from spots, as well as distinguish these patterns from less symmetrical patches of color. In addition, the measurements of an eyespot's central area and surrounding rings were highly accurate. These CNNs offer improvements of eyespot/spot detection and measurements relative to previous methods because it is not necessary to mathematically define the feature of interest. All that is needed is to point out the images that have those features to train the CNN.
Niche hypervolume analysis revealed that water pollution reduces reproductive success of endangered landlocked salmon but does not directly impact their population density
Authors: Yi-An Chung , Liu Mark , Tzu-Man Hung , Lin-Yan Liao , Shen Sheng-Feng
Published: March 2022

The critical information for conserving endangered species is to identify how different niche dimensions affect key life history stages of a population. However, it is often difficult to quantify how each ecological niche dimension affects different life history stages because environmental factors may affect each fitness component of organisms to various degrees. Here, we applied the recently developed hypervolume method that follows the idea of Hutchinson's n-dimensional hypervolume. We analyzed the niche space of different life history stages of the endangered landlocked salmon Oncorhynchus masou formosanus, the most southerly distributed of all salmonoids. We found no direct effect of water pollution on salmon population density but a significant negative effect on salmon reproductive success. Surprisingly, the niche hypervolume analysis showed that the size of hatching success niche hypervolume was only 17.9% and 18.4% of the natural redd site density or population density, respectively. This result demonstrates a much higher environmental requirement for salmon during the egg stage than that affecting population density or nesting environment. Our results suggest that understanding the behavioral and physiological mechanisms that influence crucial life history stages in the wild is critical to developing effective conservation programs, and the niche hypervolume is a valuable method to achieve this.
Optimizing sampling for surface localization in 3D-scanning microscopy
Authors: Burcklen Marie-Anne , Galland Frederic , le goff loic
Published: March 2022

3D-scanning fluorescence imaging of living tissue is in demand for less phototoxic acquisition process. For the imaging of biological surfaces, adaptive and sparse scanning schemes have been proven to efficiently reduce the light dose by concentrating acquisitions around the surface. In this paper, we focus on optimizing the scanning scheme at constant photon budget, when the problem is to estimate the position of a biological surface whose intensity profile is modeled as a Gaussian shape. We propose an approach based on the Cramer-Rao Bound to optimize the positions and number of scanning points, assuming signal-dependant Gaussian noise. We show that the optimization problem can be reduced to a few parameters, allowing to define quasi-optimal acquisition strategies, first when no prior knowledge on the surface location is available, and then when the user has a prior on this location.
Adipose mTORC2 is essential for arborization of sensory neurons in white adipose tissue and whole-body energy homeostasis
Authors: Frei Irina C , Weissenberger Diana , Ritz Danilo , Heusermann Wolf , Colombi Marco , Shimobayashi Mitsugu , Hall Michael N
Published: March 2022

Adipose tissue, via sympathetic and sensory neurons, communicates with the central nervous system (CNS) to mediate energy homeostasis. In contrast to the sympathetic nervous system, the morphology, role and regulation of the sensory nervous system in adipose tissue is poorly characterized. Taking advantage of recent progress in whole-mount three-dimensional imaging of adipose tissue, we identified a neuronal network of calcitonin gene-related protein (CGRP)-positive sensory neurons in white adipose tissue (WAT). Furthermore, we show that adipose mammalian target of rapamycin complex 2 (mTORC2), a major component of the insulin signaling pathway, mediates sensory innervation in WAT. Based on visualization of neuronal networks, mTORC2-deficient WAT displayed reduced arborization of (CGRP)-positive sensory neurons, while sympathetic neurons were unaffected. This selective loss of sensory innervation followed reduced expression of growth-associated protein 43 (GAP43) in CGRP-positive sensory neurons. Finally, we found that loss of sensory innervation in WAT correlated with systemic insulin resistance. Our findings suggest that adipose mTORC2 is necessary for sensory innervation in WAT which likely contributes to WAT-to-CNS communication.
Croatian Genetic Heritage: Renewed Y Chromosome Story Two Decades Later
Authors: Primorac Dragan , Škaro Vedrana , Projić Petar , Missoni Saša , Zanki Ivana Horjan , Merkaš Sinisa , Šarac Jelena , Novokmet Natalija , Ledić Andrea , Makar Adela , Lauc Gordan , Anđelinović Šimun , Bašić Željana , Kružić Ivana , Neuberg Marijana , Smolić Martina , Smolić Robert , Hrstić Irena , Trivanović Dragan , Konjhodžić Rijad , Salihefendić Lana , Jordamović Naida Babić , Marjanović Damir
Published: March 2022

Aim

To analyze an additional set of Y-Chromosome genetic markers to acquire a more detailed insight into the diversity of the Croatian population.

Methods

The total number of 518 Yfiler™ Plus profiles were genotyped. Allele, haplotype frequencies, and haplotype diversity were calculated using the STRAF software package v2.0.4. Genetic distances were quantified byRst using AMOVA online tool from the YHRD. The evolutionary history was inferred using the neighbor-joining method of phylogenetic tree construction in MEGAX software. Whit Athey’s Haplogroup Predictor v5 was used for additional comparison with available regional and other European populations.

Results

The total of 507 haplotypes were used for genetic STR analysis. The interpopulation study on 17 Y-STR markers shows the lowest genetic diversity between the Croatian and Bosnian-Herzegovinian populations and the highest between the Croatian and Irish populations. Additional interpopulation comparison with the original 27 Y-STR markers (for the population with available data) was also performed. A total of 518 haplotypes were used in the determination of haplogroup diversity. Haplogroup I with its sublineage I2a expressed the highest prevalence. Haplogroup R, with its major sublineage R1a, is the second most abundant in the studied Croatian population, except for the subpopulation of Hvar, where E1b1b is the second most abundant haplogroup. Rare haplogroups also confirmed in this study are L, T, and Q. G1 is detected for the very first time in the Croatian population.

Conclusion

New insight into differences between examined subpopulations of Croatia and their possible (dis)similarities with neighboring abroad populations was notified.
Whole-brain modeling explains the context-dependent effects of cholinergic neuromodulation
Authors: Coronel-Oliveros Carlos , Gießing Carsten , Medel Vicente , Cofré Rodrigo , Orio Patricio
Published: March 2022

Integration and segregation are two fundamental principles of brain organization. The brain manages the transitions and balance between different functional segregated or integrated states through neuromodulatory systems. Recently, computational and experimental studies suggest a pro-segregation effect of cholinergic neuromodulation. Here, we studied the effects of the cholinergic system on brain functional connectivity using both empirical fMRI data and computational modeling. First, we analyzed the effects of nicotine on functional connectivity and network topology in healthy subjects during resting-state conditions and during an attentional task. Then, we employed a whole-brain neural mass model interconnected using a human connectome to simulate the effects of nicotine and investigate causal mechanisms for these changes. The drug effect was modeled decreasing both the global coupling and local feedback inhibition parameters, consistent with the known cellular effects of acetylcholine. We found that nicotine incremented functional segregation in both empirical and simulated data, and the effects are context-dependent: observed during the task, but not in the resting state. In-task performance correlates with functional segregation, establishing a link between functional network topology and behavior. Furthermore, we found in the empirical data that the regional density of the nicotinic acetylcholineα4β2correlates with the decrease in functional nodal strength by nicotine during the task. Our results confirm that cholinergic neuromodulation promotes functional segregation in a context-dependent fashion, and suggest that this segregation is suited for simple visual-attentional tasks.
Non-cell autonomous small RNA silencing in female gametes and early embryo of Arabidopsis
Authors: Schroeder Jens A , Bonnet Diane MV , Jullien Pauline E
Published: March 2022

In recent years, small RNA movement has been both hypothesized and shown to be an integral part of the epigenetic DNA methylation reprogramming occurring during plant reproduction. It was suggested that the release of epigenetic silencing in accessory cell types or tissues is necessary to reinforce epigenetic silencing in the gametes (egg cell and sperm cells) which would in turn ensure the genomic stability of the next generation plant. Small RNA movement was indeed shown to occur during male gametogenesis. However, the situation within the female gametophyte and in early seed development is mostly unknown. Here, we show that small RNA can induce non-cell autonomous silencing from the central cell towards the egg cell but also from the synergids to the egg cell and central cell. In addition, we also observe a non-cell-autonomous silencing from the central cell or endosperm towards the early embryo. Our data shows, that in addition to the movement of sRNAs during pollen development, sRNA movement also occurs in the female gametes.
Reactivity to conditioned threat cues is distinct from exploratory drive in the elevated plus-maze.
Authors: Hilton Joe R , Simpson Susannah R , Sherman Emily R , Raby-Smith Will , Azvine Keemia , Arribas Maite , Zhou Jiaqi , Deiana Serena , Hengerer Bastian , Cahill Emma N
Published: March 2022

Fear and anxiety are adaptive states that allow humans and animals alike to respond appropriately to threatening cues in their environment. Commonly used tasks for studying behaviour akin to fear and anxiety in rodent models are pavlovian threat conditioning and the elevated plus maze (EPM) respectively. In threat conditioning the rodents learn to associate an aversive event with a specific stimulus or context. The learnt association between the two stimuli (the memory) can then be recalled by re-exposing the subject to the conditioned stimulus. The elevated plus maze is argued to measure the agoraphobic avoidance of the brightly lit open maze arms in crepuscular rodents. These two tasks have been used extensively, yet research into whether they interact is scarce. We investigated whether recall of an aversive memory, across contextual, odour or auditory modalities, would potentiate anxiety-like behaviour in the elevated plus maze. The data did not support that memory recall, even over a series of timepoints, could influence EPM behaviour. Furthermore, there was no correlation between EPM behaviour and conditioned freezing in independent cohorts tested in the EPM before or after auditory threat conditioning. Further analysis found the production of 22kHz ultrasonic vocalisations revealed the strongest responders to a conditioned threat cue. These results are of particular importance for consideration when using the EPM and threat conditioning to identify individual differences, and the possibility to use the tasks in batteries of tests without cross-task interference.