bluuebunny/crossref_metadata_2025 huggingface dataset:
High burden of malaria among Malawian adults on antiretroviral therapy after discontinuing prophylaxis
Authors: Mungwira Randy G. , Laurens Matthew B. , Nyangulu Wongani , Divala Titus H. , Nampota-Nkomba Nginache , Buchwald Andrea G. , Nyirenda Osward M. , Mwinjiwa Edson , Kanjala Maxwell , Galileya Lufina Tsirizani , Earland Dominique E. , Adams Matthew , Plowe Christopher V. , Taylor Terrie E. , Mallewa Jane , van Oosterhout Joep J. , Laufer Miriam K.
Published: July 2022

Objective:

Many individuals living with the human immunodeficiency virus (HIV) infection and receiving antiretroviral therapy (ART) reside in areas at high risk for malaria but how malaria affects clinical outcomes is not well described in this population. We evaluated the burden of malaria infection and clinical malaria, and impact on HIV viral load and CD4+ cell count among adults on ART.

Design:

We recruited Malawian adults on ART who had an undetectable viral load and ≥250 CD4+ cells/μl to participate in this randomized trial to continue daily trimethoprim-sulfamethoxazole (TS), discontinue daily co-trimoxazole, or switch to weekly chloroquine (CQ).

Methods:

We defined clinical malaria as symptoms consistent with malaria and positive blood smear, and malaria infection as Plasmodium falciparum DNA detected from dried blood spots (collected every 4–12 weeks). CD4+ cell count and viral load were measured every 24 weeks. We used Poisson regression and survival analysis to compare the incidence of malaria infection and clinical malaria. Clinicaltrials.gov NCT01650558.

Results:

Among 1499 participants enrolled, clinical malaria incidence was 21.4/100 person-years of observation (PYO), 2.4/100 PYO and 1.9/100 PYO in the no prophylaxis, TS, and CQ arms, respectively. We identified twelve cases of malaria that led to hospitalization and all individuals recovered. The preventive effect of staying on prophylaxis was approximately 90% compared to no prophylaxis (TS: incidence rate ratio [IRR] 0.11, 95% confidence interval [CI] 0.08, 0.15 and CQ: IRR 0.09, 95% CI 0.06, 0.13). P. falciparum infection prevalence among all visits was 187/1475 (12.7%), 48/1563 (3.1%), and 29/1561 (1.9%) in the no prophylaxis, TS, and CQ arms, respectively. Malaria infection and clinical malaria were not associated with changes in CD4+ cell count or viral load.

Conclusion:

In clinically stable adults living with HIV on ART, clinical malaria was common after chemoprophylaxis stopped. However, neither malaria infection nor clinical illness appeared to affect HIV disease progression.
Gut-dependent inflammation and alterations of the intestinal microbiota in individuals with perinatal HIV exposure and different HIV serostatus
Authors: Tincati Camilla , Ficara Monica , Ferrari Francesca , Augello Matteo , Dotta Laura , Tagliabue Claudia , Diana Alfredo , Camelli Vittoria , Iughetti Lorenzo , Badolato Raffaele , Cellini Monica , Marchetti Giulia
Published: July 2022

Objective:

HIV-exposed infected (HEI) and uninfected (HEU) children represent the two possible outcomes of maternal HIV infection. Modifications of the intestinal microbiome have been linked to clinical vulnerability in both settings, yet whether HEI and HEU differ in terms of gut impairment and peripheral inflammation/activation is unknown.

Design:

We performed a cross-sectional, pilot study on fecal and plasma microbiome as well as plasma markers of gut damage, microbial translocation, inflammation and immune activation in HIV-infected and uninfected children born from an HIV-infected mother.

Methods:

Fecal and plasma microbiome were determined by means of 16S rDNA amplification with subsequent qPCR quantification. Plasma markers were quantified via ELISA.

Results:

Forty-seven HEI and 33 HEU children were consecutively enrolled. The two groups displayed differences in fecal beta-diversity and relative abundance, yet similar microbiome profiles in plasma as well as comparable gut damage and microbial translocation. In contrast, monocyte activation (sCD14) and systemic inflammation (IL-6) were significantly higher in HEI than HEU.

Conclusion:

In the setting of perinatal HIV infection, enduring immune activation and inflammation do not appear to be linked to alterations within the gut. Given that markers of activation and inflammation are independent predictors of HIV disease progression, future studies are needed to understand the underlying mechanisms of such processes and elaborate adjuvant therapies to reduce the clinical risk in individuals with perinatal HIV infection.
Skeletal muscle mitochondrial dysfunction in contemporary antiretroviral therapy: a single cell analysis
Authors: Hunt Matthew , McNiff Megan M. , Vincent Amy E. , Sabin Caroline , Winston Alan , Payne Brendan A.I.
Published: July 2022

Objective:

To quantify mitochondrial function in skeletal muscle of people treated with contemporary antiretroviral therapy.

Design:

Cross-sectional observational study.

Methods:

Quantitative multiplex immunofluorescence was performed to determine mitochondrial mass and respiratory chain complex abundance in individual myofibres from tibialis anterior biopsies. Individual myofibres were captured by laser microdissection and mitochondrial DNA (mtDNA) content and large-scale deletions were measured by real-time PCR.

Results:

Forty-five antiretroviral therapy (ART)-treated people with HIV (PWH, mean age 58 years, mean duration of ART 125 months) were compared with 15 HIV negative age-matched controls. Mitochondrial complex I (CI) deficiency was observed at higher proportional levels in PWH than negative controls (P = 0.008). Myofibre mitochondrial mass did not differ by HIV status. No ART class was significantly associated with mitochondrial deficiency, including prior exposure to historical NRTIs (nucleoside analogue reverse transcriptase inhibitors) associated with systemic mitochondrial toxicity. To exclude an effect of untreated HIV, we also studied skeletal muscle from 13 ART-naive PWH (mean age 37). These showed negligible CI defects, as well as comparable myofibre mitochondrial mass to ART-treated PWH. Most CI-deficient myofibres contained mtDNA deletions. No mtDNA depletion was detected.

Conclusion:

Here, we show that PWH treated with contemporary ART have mitochondrial dysfunction in skeletal muscle, exceeding that expected due to age alone. Surprisingly, this was not mediated by prior exposure to mitochondrially toxic NRTIs, suggesting novel mechanisms of mitochondrial dysfunction in contemporary ART-treated PWH. These findings are relevant for better understanding successful ageing in PWH.
Long-term antiretroviral therapy mitigates mortality and morbidity independent of HIV tropism: 18 years follow-up in a women's cohort
Authors: Weiser Barbara , Shi Binshan , Kemal Kimdar , Burger Harold , Minkoff Howard , Shi Qiuhu , Gao Wei , Robison Esther , Holman Susan , Schroeder Tamara , Gormley Alissa , Anastos Kathryn , Ramirez Christina
Published: July 2022

Objective:

CXCR4 (X4)-tropic HIV-1 was found previously to herald CD4+ cell depletion and disease progression in individuals who were antiretroviral-naive or took combination antiretroviral therapy (cART) for less than 5 years. We updated this finding by investigating whether the deleterious effect of X4-tropic strains is mitigated by long-term cART.

Design:

We examined morbidity and mortality in relation to HIV-1 tropism and cART in 529 participants followed up to 18 years in the Women's Interagency HIV Study; 91% were women of color.

Methods:

Plasma-derived HIV-1 tropism was determined genotypically.

Results:

We categorized participants according to the number of visits reported on cART after initiation. Group 1: three or less visits, 74% of these participants reporting no cART; group 2: at least four visits and less than 70% of visits on cART; group 3: at least 70% of visits on cART. AIDS mortality rates for participants in each group with X4 virus compared with those with R5 virus exclusively were, respectively: 62 vs. 40% (P = 0.0088); 23% vs. 22% [nonsignificant (NS)]; 7% vs. 14% (NS). Kaplan–Meier curves showed accelerated progression to AIDS death or AIDS-defining illness in participants with three or less cART visits and X4 viruses (P = 0.0028) but no difference in progression rates stratified by tropism in other groups. Logistic regression found that HIV-1 suppression for at least 10 semiannual visits (≥5 years total) mitigated X4 tropism's deleterious effect on mortality, controlling for maximal viral load, and CD4+ nadir.

Conclusion:

Long-term cART markedly mitigated the deleterious effect of X4 viruses on AIDS morbidity and mortality. Mitigation was correlated with duration of viral suppression, supporting HIV-1 suppression as a crucial goal.
Donors with human immunodeficiency virus and hepatitis C virus for solid organ transplantation: what's new
Authors: Lushniak Stephanie A. , Durand Christine M.
Published: July 2022

Purpose of the review

Passage of the HOPE Act and the advent of direct-acting antiviral (DAA) therapies have allowed for expansion of the donor organ pool to include donors with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), thus providing new opportunities for waitlist candidates. This article provides updates on recent studies in solid organ transplantation (SOT) utilizing donors with HIV and HCV.

Recent findings

The first pilot studies of kidney and liver transplantation from donors-with-HIV to recipients-with-HIV (HIV D+/R+) show robust patient survival, comparable graft survival to transplantation from donors without HIV (HIV D-/R+) and no increased rates of HIV breakthrough. The number of HIV D+ organs utilized has been lower than initial estimates due to several potential factors. With high numbers of overdose deaths from the opioid epidemic, there have been more HCV D+ organs available, leading to transplantation in recipients without HCV (HCV D+/R-) in combination with DAAs. Outcomes in both abdominal and thoracic HCV D+/R transplantation are excellent.

With recent findings of good outcomes in both HIV D+/R+ and HCV D+/R- SOT, we feel the evidence supports both practices as standard clinical care options to mitigate organ shortage and reduce waitlist mortality.
Hospital water as the source of healthcare-associated infection and antimicrobial-resistant organisms
Authors: Hayward Claire , Brown Melissa H. , Whiley Harriet
Published: July 2022

Purpose of review

Drinking water is considered one of the most overlooked and underestimated sources of healthcare-associated infections (HAIs). Recently, the prevention and control of opportunistic premise plumbing pathogens (OPPPs) in healthcare water systems has been receiving increasing attention in infection control guidelines. However, these fail to address colonization of pathogens that do not originate from source water. Subsequently, this review explores the role of water and premise plumbing biofilm in HAIs. The potential mechanisms of contamination and transmission of antimicrobial-resistant (AMR) pathogens originating both from supply water and human microbiota are discussed.

Recent findings

OPPPs, such as Legionella pneumophila, Pseudomonas aeruginosa and Mycobacterium avium have been described as native to the plumbing environment. However, other pathogens, not found in the source water, have been found to proliferate in biofilms formed on outlets devices and cause HAI outbreaks.

Biofilms formed on outlet devices, such as tap faucets, showers and drains provide an ideal niche for the dissemination of antimicrobial resistance. Thus, comprehensive surveillance guidelines are required to understand the role that drinking water and water-related devices play in the transmission of AMR HAIs and to improve infection control guidelines.
Navigating the unknown: the coronavirus disease 2019 pandemic and solid organ transplantation
Authors: Safa Kassem , Kotton Camille N.
Published: July 2022

Purpose of review

This review summarizes the impact of coronavirus disease 2019 (COVID-19) on solid organ transplantation and the most recent data pertinent to disease course and outcomes in this patient population.

Recent findings

The COVID-19 pandemic negatively impacted solid organ transplantation with decreased transplant rates in 2020 but improved in 2021, albeit not entirely to prepandemic levels. Mortality rates of COVID-19 in this patient population continued to be higher, although have improved with more available therapeutic options and vaccination. Immunosuppressed patients were found to require additional vaccine doses given blunted response and continue to be more vulnerable to the infection. Data on immunosuppression alteration when patients have COVID-19 are not available and is an area of ongoing research. Significant interaction with the metabolism of immunosuppression limits the use of some of the new antiviral therapies in patients with organ transplants. Finally, many logistical challenges continue to face the transplantation discipline, especially with pretransplant vaccine hesitancy, however acceptance of organs from donor who had COVID-19 recent infection or died from the infection is increasing.

Immunosuppressed solid organ transplant recipients continue to be vulnerable to COVID-19 infection with a blunted response to the available vaccines and will likely remain more susceptible to infection.
The American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Secondary and Tertiary Renal Hyperparathyroidism
Authors: Dream Sophie , Kuo Lindsay E. , Kuo Jennifer H. , Sprague Stuart M. , Nwariaku Fiemu E. , Wolf Myles , Olson John A. , Moe Sharon M. , Lindeman Brenessa , Chen Herbert
Published: July 2022

Objective:

To develop evidence-based recommendations for safe, effective, and appropriate treatment of secondary (SHPT) and tertiary (THPT) renal hyperparathyroidism.

Background:

Hyperparathyroidism is common among patients with chronic kidney disease, end-stage kidney disease, and kidney transplant. The surgical management of SHPT and THPT is nuanced and requires a multidisciplinary approach. There are currently no clinical practice guidelines that address the surgical treatment of SHPT and THPT.

Methods:

Medical literature was reviewed from January 1, 1985 to present January 1, 2021 by a panel of 10 experts in SHPT and THPT. Recommendations using the best available evidence was constructed. The American College of Physicians grading system was used to determine levels of evidence. Recommendations were discussed to consensus. The American Association of Endocrine Surgeons membership reviewed and commented on preliminary drafts of the content.

Results:

These clinical guidelines present the epidemiology and pathophysiology of SHPT and THPT and provide recommendations for work-up and management of SHPT and THPT for all involved clinicians. It outlines the preoperative, intraoperative, and postoperative management of SHPT and THPT, as well as related definitions, operative techniques, morbidity, and outcomes. Specific topics include Pathogenesis and Epidemiology, Initial Evaluation, Imaging, Preoperative and Perioperative Care, Surgical Planning and Parathyroidectomy, Adjuncts and Approaches, Outcomes, and Reoperation.

Conclusions:

Evidence-based guidelines were created to assist clinicians in the optimal management of secondary and tertiary renal hyperparathyroidism.
Implementation and Outcome of Robotic Liver Surgery in the Netherlands
Authors: Görgec Burak , Zwart Maurice , Nota Carolijn L. , Bijlstra Okker D. , Bosscha Koop , de Boer Marieke T. , de Wilde Roeland F. , Draaisma Werner A. , Gerhards Michael F. , Liem Mike S. , Lips Daan J. , Marsman Hendrik A. , Mieog J. Sven D. , Molenaar Quintus I. , Nijkamp Maarten , Te Riele Wouter W. , Terkivatan Türkan , Vahrmeijer Alexander L. , Besselink Marc G. , Swijnenburg Rutger-Jan , Hagendoorn Jeroen ,   for the Dutch Liver Collaborative Group
Published: July 2022

Objective:

To determine the nationwide implementation and surgical outcome of minor and major robotic liver surgery (RLS) and assess the first phase of implementation of RLS during the learning curve.

Background:

RLS may be a valuable alternative to laparoscopic liver surgery. Nationwide population-based studies with data on implementation and outcome of RLS are lacking.

Methods:

Multicenter retrospective cohort study including consecutive patients who underwent RLS for all indications in 9 Dutch centers (August 2014–March 2021). Data on all liver resections were obtained from the mandatory nationwide Dutch Hepato Biliary Audit (DHBA) including data from all 27 centers for liver surgery in the Netherlands. Outcomes were stratified for minor, technically major, and anatomically major RLS. Learning curve effect was assessed using cumulative sum analysis for blood loss.

Results:

Of 9437 liver resections, 400 were RLS (4.2%) procedures including 207 minor (52.2%), 141 technically major (35.3%), and 52 anatomically major (13%). The nationwide use of RLS increased from 0.2% in 2014 to 11.9% in 2020. The proportion of RLS among all minimally invasive liver resections increased from 2% to 28%. Median blood loss was 150 mL (interquartile range 50–350 mL] and the conversion rate 6.3% (n=25). The rate of Clavien-Dindo grade ≥III complications was 7.0% (n=27), median length of hospital stay 4 days (interquartile range 2–5) and 30-day/in-hospital mortality 0.8% (n=3). The R0 resection rate was 83.2% (n=263). Cumulative sum analysis for blood loss found a learning curve of at least 33 major RLS procedures.

Conclusions:

The nationwide use of RLS in the Netherlands has increased rapidly with currently one-tenth of all liver resections and one-fourth of all minimally invasive liver resections being performed robotically. Although surgical outcomes of RLS in selected patient seem favorable, future prospective studies should determine its added value.
Surface wave across crack-tip in a lattice model
Authors: Sharma Basant Lal
Published: July 2022

For a triangular lattice of particles, with nearest neighbour interactions and a traction free boundary, there exists a surface wave band for out-of-plane motion. Interactions between such a surface wave and stationary crack tip in mode III are investigated. The discrete Helmholtz equation for scattered waves, that incorporates an anisotropy parameter for unequal spring constants in horizontal versus slant directions, is solved exactly. The coefficient of transmission from one crack face to another, as well as that owing to reflection on the same face, is obtained in a closed form; the same leads to an estimate of energy fraction of incident wave that is leaked at the crack tip via bulk waves. It is found, in terms of surface wave band, that the transmission coefficient attains its maximum magnitude above the mid-band while the energy leak is minimum at the upper-band limit. Besides surface wave propagation across crack tip, surface wave excitation due to incident bulk wave is also discussed.

This article is part of the theme issue ‘Wave generation and transmission in multi-scale complex media and structured metamaterials (part 1)’.
Absorption characteristics of large acoustic metasurfaces
Authors: Schnitzer O. , Brandão R.
Published: July 2022

Metasurfaces formed of arrays of subwavelength resonators are often tuned to ‘critically couple’ with incident radiation, so that at resonance dissipative and radiative damping are balanced and absorption is maximized. Such design criteria are typically derived assuming an infinite metasurface, whereas the absorption characteristics of finite metasurfaces, even very large ones, can be markedly different in certain frequency intervals. This is due to the excitation of surface waves, intrinsic to resonant metasurfaces and especially meta-resonances, namely collective resonances where the surface waves form standing-wave patterns over the planar metasurface domain. We illustrate this issue using a detailed model of a Helmholtz-type acoustic metasurface formed of cavity-neck pairs embedded into a rigid substrate, with geometric and dissipation effects included from first principles (R. Brandão and O. Schnitzer, Wave Motion,
97
, 102583, 2020).

This article is part of the theme issue ‘Wave generation and transmission in multi-scale complex media and structured metamaterials (part 1)’.
Localized waves in elastic plates with perturbed honeycomb arrays of constraints
Authors: Haslinger S. G. , Frecentese S. , Carta G.
Published: July 2022

In this paper, we study wave propagation in elastic plates incorporating honeycomb arrays of rigid pins. In particular, we demonstrate that topologically non-trivial band-gaps are obtained by perturbing the honeycomb arrays of pins such that the ratio between the lattice spacing and the distance of pins is less than 3; conversely, a larger ratio would lead to the appearance of trivial stop-bands. For this purpose, we investigate band inversion of modes and calculate the valley Chern numbers associated with the dispersion surfaces near the band opening, since the present problem has analogies with the quantum valley Hall effect. In addition, we determine localized eigenmodes in strips, repeating periodically in one direction, that are subdivided into a topological and a trivial section. Finally, the outcomes of the dispersion analysis are corroborated by numerical simulations, where a time-harmonic point source is applied to a plate with finite arrays of rigid pins to create localized waves immune to backscattering.

This article is part of the theme issue ‘Wave generation and transmission in multi-scale complex media and structured metamaterials (part 1)’.
Systematic functional interrogation of SARS-CoV-2 host factors using Perturb-seq
Authors: Sunshine Sara , Puschnik Andreas S. , Replogle Joseph M. , Laurie Matthew T. , Liu Jamin , Zha Beth Shoshana , Nuñez James K. , Byrum Janie R. , McMorrow Aidan H. , Frieman Matthew B. , Winkler Juliane , Qiu Xiaojie , Rosenberg Oren S. , Leonetti Manuel D. , Ye Chun Jimmie , Weissman Jonathan S. , DeRisi Joseph L. , Hein Marco Y.
Published: July 2022

Genomic and proteomic screens have identified numerous host factors of SARS-CoV-2, but efficient delineation of their molecular roles during infection remains a challenge. Here we use Perturb-seq, combining genetic perturbations with a single-cell readout, to investigate how inactivation of host factors changes the course of SARS-CoV-2 infection and the host response in human lung epithelial cells. Our high-dimensional data resolve complex phenotypes such as shifts in the stages of infection and modulations of the interferon response. However, only a small percentage of host factors showed such phenotypes upon perturbation. We further identified the NF-κB inhibitor IκBα (NFKBIA), as well as the translation factors EIF4E2 and EIF4H as strong host dependency factors acting early in infection. Overall, our study provides massively parallel functional characterization of host factors of SARS-CoV-2 and quantitatively defines their roles both in virus-infected and bystander cells.
Illuminating the Druggable Genome through Patent Bioactivity Data
Authors: Magariños María Paula , Gaulton Anna , Félix Eloy , Kizilören Tevfik , Arcila Ricardo , Oprea Tudor , Leach Andrew R.
Published: July 2022

The patent literature is a potentially valuable source of bioactivity data. The SureChEMBL database (https://www.surechembl.org/) is a publicly available large-scale resource that contains compounds extracted on a daily basis from the full text, images and attachments of patent documents, through an automated text and image-mining pipeline. In this paper we describe a process to prioritise 3.7 million life science relevant patents obtained from SureChEMBL, according to how likely they were to contain bioactivity data for potent small molecules on less-studied targets, according to the classification developed by the Illuminating the Druggable Genome (IDG) project. The overall goal was to select a smaller number of patents that could be manually curated and incorporated into the ChEMBL database. We describe the approach taken, the results obtained, and provide some illustrative examples.
Linear Mixed-effects model to quantify the association between somatic cell count and milk production in Italian dairy herds
Authors: Luo Tiantian , Steeneveld Wilma , Nielen Mirjam , Zanini Lucio , Zecconi Alfonso
Published: July 2022

Milk production loss due to mastitis in dairy herds is economically important. Before estimating the economic impacts of mastitis, it is crucial to quantify the association between mastitis and milk production. The objective of this study was to estimate the association between somatic cell count (SCC, as an indicator of intramammary infection due to mastitis) and milk production for dairy cows in Lombardy (Italy). The test-day (TD) records data of 3,816 dairy herds located in 3 different geographical areas of Lombardy from January 2016 to December 2018 were used. After data editing, the final dataset comprised 10,445,464 TD records from 2,970 farms and 826,831 cows. The analysis was carried out by using a mixed-effects model with seven fixed effects (geographical area, breed, days in milk, parity, season and year) and nested random effects for each cow and herd. The results indicated that the SCC had a negative association with milk production. When the SCC increased every two-fold, the milk production lost 0.830 (95% CI: −0.832, −0.828) kg/cow/day in the whole Lombardy. These results can be used for economic calculations on the costs of mastitis
Localized heterochrony integrates overgrowth potential of oncogenic clones
Authors: Blum Nicola , Harris Matthew P.
Published: July 2022

Somatic oncogenic mutations are frequent and can occur early during development. The result is the formation of a patchwork of mutant clones. Such mosaicism has been implicated in a broad range of developmental anomalies however their etiology is poorly understood. Patients carrying a common somatic oncogenic mutation in either PIK3CA or AKT1, can present with disproportionally large digits or limbs. How mutant clones, carrying an oncogenic mutation that often drives unchecked proliferation leads to controlled and coordinated overgrowth is unknown. We use the zebrafish to explore growth dynamics of oncogenic clones during development. In subset of clones, we observe a local increase in proportion of the fin skeleton closely resembling patient overgrowth phenotypes. We unravel the cellular and developmental mechanisms of these overgrowths and pinpoint the cell type and timing of clonal expansion. Coordinated overgrowth is associated with rapid clone expansion during early pre-chondrogenic phase of bone development inducing a heterochronic shift that drives the change in bone size. Our study details how development integrates and translates growth potential of oncogenic clones, thereby shaping the phenotypic consequences of somatic mutations.
Testing the Limits of SMILES-based De Novo Molecular Generation with Curriculum and Deep Reinforcement Learning
Authors: Mokaya Maranga , Imrie Fergus , van Hoorn Willem P. , Kalisz Aleksandra , Bradley Anthony R. , Deane Charlotte M.
Published: July 2022

1

Deep reinforcement learning methods have been shown to be potentially powerful tools for de novo design. Recurrent neural network (RNN)-based techniques are the most widely used methods in this space. In this work, we examine the behaviour of RNN-based methods when there are few (or no) examples of molecules with the desired properties in the training data. We find that targeted molecular generation is often possible, but the diversity of generated molecules is often reduced, and it is not possible to control the composition of generated molecular sets. To help overcome these issues, we propose a new curriculum learning-inspired, recurrent Iterative Optimisation Procedure that enables the optimisation of generated molecules for seen and unseen molecular profiles and allows the user to control whether a molecular profile is explored or exploited. Using our method, we generate specific and diverse sets of molecules with up to 18 times more scaffolds than standard methods for the same sample size. However, our results also point to significant limitations of one-dimensional molecular representations as used in this space. We find that the success or failure of a given molecular optimisation problem depends on the choice of SMILES.
Distinguishing imported cases from locally acquired cases within a geographically limited genomic sample of an infectious disease
Authors: Didelot Xavier , Helekal David , Kendall Michelle , Ribeca Paolo
Published: July 2022

The ability to distinguish imported cases from locally acquired cases has important consequences for the selection of public health control strategies. Genomic data can be useful for this, for example using a phylogeographic analysis in which genomic data from multiple locations is compared to determine likely migration events between locations. However, these methods typically require good samples of genomes from all locations, which is rarely available. Here we propose an alternative approach that only uses genomic data from a location of interest. By comparing each new case with previous cases from the same location we are able to detect imported cases, as they have a different genealogical distribution than that of locally acquired cases. We show that, when variations in the size of the local population are accounted for, our method has good sensitivity and excellent specificity for the detection of imports. We applied our method to data simulated under the structured coalescent model and demonstrate relatively good performance even when the local population has the same size as the external population. Finally, we applied our method to several recent genomic datasets from both bacterial and viral pathogens, and show that it can, in a matter of seconds or minutes, deliver important insights on the number of imports to a geographically limited sample of a pathogen population.
Cell Type Specific DNA Signatures of Transcription Factor Binding
Authors: Awdeh Aseel , Turcotte Marcel , Perkins Theodore J.
Published: July 2022

Transcription factors (TFs) bind to different parts of the genome in different types of cells. These differences may be due to alterations in the DNA-binding preferences of a TF itself, or mechanisms such as chromatin accessibility, steric hindrance, or competitive binding, that result in a DNA “signature” of differential binding. We propose a method called SigTFB (Signatures of TF Binding), based on deep learning, to detect and quantify cell type specificity in a TF’s DNA-binding signature. We conduct a wide scale investigation of 194 distinct TFs across various cell types. We demonstrate the existence of cell type specificity in approximately 30% of the TFs. We stratify our analysis by different antibodies for the same TF, to rule out the possibility of certain technical artifacts, yet we find that cell type specificity estimates are largely consistent when the same TF is assayed with different antibodies. To further explain the biology behind a TF’s cell type specificity, or lack thereof, we conduct a wide scale motif enrichment analysis of all TFs in question. We show that the presence of alternate motifs correlates with a higher degree of cell type specificity in TFs, such as ATF7, while finding consistent motifs throughout is usually associated with the absence of cell type specificity in a TF, such as CTCF. In particular, we observe that several important TFs show distinct DNA binding signatures in different cancer cell types, which may point to important differences in modes of action. Moreover, we find that motif enrichment sometimes correlates with gene expression in TFs with higher cell type specificity. Our comprehensive investigation provides a basis for further study of the mechanisms behind differences in TF-DNA binding in different cell types.
Atypical hypnotic compound ML297 restores sleep architecture following emotionally-valenced learning, to promote memory consolidation and hippocampal network activation during recall
Authors: Martinez Jessy D. , Brancaleone William P. , Peterson Kathryn G. , Wilson Lydia G. , Aton Sara J.
Published: July 2022

Sleep plays a critical role in consolidating many forms of hippocampus-dependent memory. While various classes of hypnotic drugs have been developed in recent years, it remains unknown whether, or how, some of them affect sleep-dependent memory consolidation mechanisms. We find that ML297, a recently-developed candidate hypnotic agent targeting a new mechanism (activating GIRK1-subunit containing G-protein coupled inwardly rectifying potassium [GIRK] channels), alters sleep architecture in mice over the first 6 h following a single-trial learning event. Following contextual fear conditioning (CFC), ML297 reversed post-CFC reductions in NREM sleep spindle power and REM sleep amounts and architecture, renormalizing sleep features to what was observed at baseline, prior to CFC. Renormalization of post-CFC REM sleep latency, REM sleep amounts, and NREM spindle power were all associated with improved contextual fear memory (CFM) consolidation. We find that improvements in CFM consolidation due to ML297 are sleep-dependent, and are associated with increased numbers of highly-activated dentate gyrus (DG), CA1, and CA3 neurons during CFM recall. Together our findings suggest that GIRK1 channel activation restores normal sleep architecture - including REM sleep, which is normally suppressed following CFC - and increases the number of hippocampal neurons incorporated into the CFM engram during memory consolidation.

Significance Statement

Both REM and NREM sleep are thought to be important for consolidating hippocampus-dependent memories. We find that GIRK1 activator ML297, administered after single-trial fear learning, restores REM sleep that is normally suppressed after learning fearful associations. This restoration is associated with improvements in fear memory storage, resulting in more robust hippocampus activation in the context of subsequent memory recall. Thus this drug, which also has antiepileptic and anxiolytic properties, may be useful for promoting normal, restorative sleep that benefits memory storage.
The roles of isolation and interspecific interaction in generating the functional diversity of an insular mammal radiation
Authors: Nations Jonathan A. , Kohli Brooks A. , Handika Heru , Achmadi Anang S. , Polito Michael J. , Rowe Kevin C. , Esselstyn Jacob A.
Published: July 2022

Communities that occupy similar environments but vary in the richness of closely related species can illuminate how functional variation and species richness interact to fill ecological space in the absence of abiotic filtering, though this has yet to be explored on an oceanic island where the processes of community assembly may differ from continental settings. In discrete montane communities on the island of Sulawesi, local murine rodent (rats and mice) richness ranges from 7 to 23 species. We measured 17 morphological, ecological, and isotopic traits, both individually and grouped into 5 multivariate traits in 40 species, to test for the expansion or packing of functional space among nine murine communities. We employed a novel probabilistic approach for integrating intraspecific and community-level trait variance into functional richness. Trait-specific and phylogenetic diversity patterns indicate dynamic community assembly due to variable niche expansion and packing on multiple niche axes. Locomotion and covarying traits such as tail length emerged as a fundamental axis of ecological variation, expanding functional space and enabling the niche packing of other traits such as diet and body size. Though trait divergence often explains functional diversity in island communities, we found that phylogenetic diversity facilitates functional space expansion in some conserved traits such as cranial shape, while more labile traits are overdispersed both within and between island clades, suggesting a role of niche complementarity. Our results evoke interspecific interactions, differences in trait lability, and the independent evolutionary trajectories of each of Sulawesi’s 6 murine clades as central to generating the exceptional functional diversity and species richness in this exceptional, insular radiation.
Mechanisms of spontaneous Ca2+ release-mediated arrhythmia in a novel 3D human atrial myocyte model: II. Ca2+-handling protein variation
Authors: Zhang X. , Smith C.E.R. , Morotti S. , Edwards A.G. , Sato D. , Louch W.E. , Ni H. , Grandi E.
Published: July 2022

Disruption of the transverse-axial tubule system (TATS) in diseases such as heart failure and atrial fibrillation occurs in combination with changes in the expression and distribution of key Ca2+- handling proteins. Together this ultrastructural and ionic remodeling is associated with aberrant Ca2+ cycling and electrophysiological instabilities that underly arrhythmic activity. However, due to the concurrent changes in TATs and Ca2+-handling protein expression and localization that occur in disease it is difficult to distinguish their individual contributions to the arrhythmogenic state. To investigate this, we applied our novel 3D human atrial myocyte model with spatially detailed Ca2+ diffusion and TATS to investigate the isolated and interactive effects of changes in expression and localization of key Ca2+-handling proteins and variable TATS density on Ca2+- handling abnormality driven membrane instabilities. We show that modulating the expression and distribution of the sodium-calcium exchanger, ryanodine receptors, and the sarcoplasmic reticulum (SR) Ca2+ buffer calsequestrin have varying pro and anti-arrhythmic effects depending on the balance of opposing influences on SR Ca2+ leak-load and Ca2+-voltage relationships. Interestingly, the impact of protein remodeling on Ca2+-driven proarrhythmic behavior varied dramatically depending on TATS density, with intermediately tubulated cells being more severely affected compared to detubulated and densely tubulated myocytes. This work provides novel mechanistic insight into the distinct and interactive consequences of TATS and Ca2+-handling protein remodeling that underlies dysfunctional Ca2+ cycling and electrophysiological instability in disease.

Key Points

In our companion paper we developed a 3D human atrial myocyte model, coupling electrophysiology and Ca2+ handling with subcellular spatial details governed by the transverse-axial tubule system (TATS).

Here we utilize this model to mechanistically examine the impact of TATS loss and changes in the expression and distribution of key Ca2+-handling proteins known to be remodeled in disease on Ca2+ homeostasis and electrophysiological stability.

We demonstrate that varying the expression and localization of these proteins has variable pro- and anti-arrhythmic effects with outcomes displaying dependence on TATS density.

Whereas detubulated myocytes typically appear unaffected and densely tubulated cells seem protected, the arrhythmogenic effects of Ca2+ handling protein remodeling are profound in intermediately tubulated cells.

Our work shows the interaction between TATS and Ca2+-handling protein remodeling that underlies the Ca2+-driven proarrhythmic behavior observed in AF and may help to predict the effects of antiarrhythmic strategies at varying stages of ultrastructural remodeling.
Impact of the extinct megaherbivore Steller’s sea cow (Hydrodamalis gigas) on kelp forest resilience
Authors: Roopnarine Peter D. , Banker Roxanne M. W. , Sampson Scott
Published: July 2022

Giant kelp forests off the west coast of North America are maintained primarily by sea otter (Enhydra lutris) and sunflower sea star (Pycnopodia helianthoides) predation of sea urchins. Human hunting of sea otters in historic times, together with a marine heat wave and sea star wasting disease epidemic in the past decade, have devastated these predators, leading to widespread occurrences of urchin barrens. Since the late Neogene, species of the megaherbivorous sirenian Hydrodamalis ranged throughout North Pacific giant kelp forests. The last species, H. gigas, was driven to extinction by human hunting in the mid-18th century. H. gigas was an obligate kelp canopy browser, and its body size implies that it would have had a significant impact on the system. Here we hypothesize that sea cow browsing would have promoted a denser understory algal assemblage than is typical today, thereby providing an alternative food resource for urchins, resulting in enhanced forest resilience. We tested this hypothesis with a mathematical model, comparing historical and modern community responses to marine heat waves, sea star wasting disease, and the presence of sea otters. We found that forest communities were highly resistant to marine heat waves, yet susceptible to sea star wasting disease, and to disease in combination with warming. Resistance was greatest among systems with both sea cows and sea otters present. Most simulations that transitioned to barrens did so temporarily, recovering after about 10 years. Historical communities, however, exhibited delayed transitions after perturbation relative to modern communities and faster recovery times. Sea cow browsing facilitated denser algal understories, enhancing resilience against modern perturbations. We propose that operationalizing these findings by mimicking the ecological impact of sea cow herbivory could enhance kelp forest resilience.
Genomic characterization of viruses associated with the parasitoid Anagyrus vladimiri (Hymenoptera: Encyrtidae)
Authors: Izraeli Yehuda , Lepetit David , Atias Shir , Mozes-Daube Netta , Wodowski Gal , Lachman Oded , Luria Neta , Steinberg Shimon , Varaldi Julien , Zchori-Fein Einat , Chiel Elad
Published: July 2022

The knowledge on symbiotic microorganisms of insects has increased in recent years, yet relatively little data is available on non-pathogenic viruses. Here we studied the virome of the parasitoid wasp Anagyrus vladimiri (Hymenoptera: Encyrtidae), a biocontrol agent of mealybugs. By high-throughput sequencing of viral nucleic acids, we revealed three novel viruses, belonging to the families Reoviridae (provisionally termed AnvRV [Anagyrus vladimiri reovirus]), Iflaviridae (AnvIFV) and Dicistroviridae (AnvDV). Phylogenetic analysis further classified the AnvRV in the genus Idnoreovirus, and the AnvDV in the genus Triatovirus. The genome of AnvRV is comprised of 10 distinct genomic segments ranging in length from 1.5 to 4.2 Kbp, but only two out of the 10 open reading frames (ORFs) have a known function. AnvIFV and AnvDV each have one polypeptide ORF, which is typical to iflaviruses but very un-common among dicistroviruses. AnvRV was found to be fixed in a mass-reared population of A. vladimiri, whereas it’s prevalence in field-collected wasps was ~15%. Similarly, the prevalence of AnvIFV and AnvDV were much higher in the mass rearing population than in the field population. Transmission electron micrographs of females’ ovaries revealed clusters and viroplasms of Reovirus-like particles in follicle cells. AnvRV was not detected in the mealybugs, suggesting that this virus is truly associated with the wasps. The possible effects of these viruses on A. vladimiri’s biology, and on biocontrol agents in general are discussed. Our findings identify RNA viruses as potential players involved in the multitrophic system of mealybugs, their parasitoids and other members of the holobiont.

Importance

Different biological control approaches use industrially mass-reared natural enemy insects to reduce damage of arthropod pests. Such mass-reared cultures may be positively and/or negatively affected by various microorganisms, including viruses. Yet, current knowledge on virus diversity, especially in arthropods, is limited. Here, we provide the first virome characterization of a member of the wasps family Encyrtidae - the member being the parasitoid Anagyrus vladimiri - a commercially important natural enemy of mealybug pests. We describe the genome of three previously unknown RNA viruses, co-inhabiting this parasitoid, and elaborate on the prevalence of those viruses in individual wasps of both mass-reared and environmental origins. Microscopy images suggest that at least one of the viruses is transmitted maternally via the ovaries. We discuss the genomic structure of the viruses and the possible relationship between those viruses and the A. vladimiri host, with implications on improvement of biocontrol of mealybug pests.
Finding Functionality: Rasch Analysis of the Functionality Appreciation Scale in community-dwelling adults including adults with spinal cord injury and neuropathic pain in the US
Authors: Feng Sarah , McDaniel Sydney , Van de Winckel Ann
Published: July 2022

The Functionality Appreciation Scale (FAS) measures an individual’s appreciation for the functions their body can perform, regardless of the individual’s physical limitations. To facilitate the use of this tool by researchers and clinicians, it is necessary to understand what ‘normal’ scoring looks like in healthy adults, as well as validate the scoring of this scale. We analyzed the FAS using Rasch Measurement Theory. FAS responses, demographic data, and clinical questionnaires were collected by the Brain Body Mind Lab (University of Minnesota) from 567 community-dwelling adults recruited at the Minnesota State Fair, including 14 adults with spinal cord injury. We evaluated item and person fit, targeting, unidimensionality, person separation reliability (PSR), local item dependence (LID), and differential item functioning (DIF) for demographic and clinical characteristics. We found a significant ceiling effect (26.98%) and a positive person mean location of 3.28±2.10 logits, indicating the FAS is too easy for the community-dwelling adults in the US. PSR was 0.79, indicating a capacity to differentiate groups of people according to their ability level of functional appreciation. We also compared the person mean location of adults who did or did not participate in body awareness training. Adults who practiced body awareness training had a higher person mean location (4.28, Interquartile Range [IQR] = 3.96 logits) than those who did not (2.73, IQR = 3.34), indicating a higher functionality appreciation. Overall, FAS demonstrated good item and person fit, but the current version of FAS will require more difficult items to be added to improve the targeting of the scale for use in a general population.
The association of typical and atypical symptoms on in-hospital mortality of older adults with COVID-19: a multicentre cohort study
Authors: Wong Eric Kai-Chung , Watt Jennifer , Zou Hanyan , Chandraraj Arthana , Zhang Alissa Wenyue , Brookes Jahnel , Verduyn Ashley , Berall Anna , Norman Richard , Piggott Katrina , Izukawa Terumi , Straus Sharon E. , Liu Barbara
Published: July 2022

Atypical disease presentations are common in older adults with COVID-19. The objective of this study was to determine the prevalence of atypical and typical symptoms in older adults with COVID-19 through progressive pandemic waves and the association of these symptoms with in-hospital mortality. This retrospective cohort study included consecutive adults aged over 65 years with confirmed COVID-19 infection who were admitted to seven hospitals in Toronto, Canada from March 1, 2020 to June 30, 2021. The median age for the 1786 patients was 78.0 years and 847 (47.5%) were female. Atypical symptoms (as defined by geriatric syndromes) occurred in 1187 patients (66.5%), but rarely occurred in the absence of other symptoms (n=106, 6.2%). The most common atypical symptoms were anorexia (n=598, 33.5%), weakness (n=519, 23.9%), and delirium (n=449, 25.1%). Dyspnea (adjusted odds ratio [aOR] 2.05, 95% confidence interval [CI] 1.62–2.62), tachycardia (aOR 1.87, 95% CI 1.14–3.04), and delirium (aOR 1.52, 95% CI 1.18–1.96) were independently associated with in-hospital mortality. In a cohort of older adults hospitalized with COVID-19 infection, atypical presentations frequently overlapped with typical symptoms. Further research should be directed at understanding the cause and clinical significance of atypical presentations in older adults.