bluuebunny/crossref_metadata_2025 huggingface dataset:
Oral Versus Intravenous Antibiotics for Pediatric Osteoarticular Infection: When and to Whom?
Authors: Alcobendas Rueda Rosa M. , Núñez Esmeralda , Martín Laura , Hernández María Belén , Saavedra-Lozano Jesús , Udaondo Clara , Murias Sara , Remesal Agustin , Calvo Cristina ,   on behalf of the Rioped Group
Published: June 2022

Background:

Osteoarticular infections (OAIs) are typically treated initially with intravenous antibiotics. The objective of this study was to evaluate whether an exclusive oral treatment in selected children may be appropriate.

Methods:

The Spanish Network of Osteoarticular Infections is a nationwide multicenter registry comprising 37 hospitals in Spain. The registry prospectively includes clinical characteristics and outcome of children with OAI. One of the hospitals from RioPed offers oral treatment to children meeting certain criteria. Patients were classified into 2 groups. Group 1: management with initial intravenous antibiotic therapy. Group 2: patients exclusively treated with oral antibiotics. A comparison between the 2 groups was performed.

Results:

We compared 893 children who initially received intravenous antibiotics (group 1) with 64 children who received exclusively oral therapy (group 2). Patients from group 2 were younger (33.9 vs. 20.3 months; P = 0.001), had a lower percentage of Staphylococcus aureus (23.3% vs. 3.1%; P < 0.001), a higher proportion of Kingella kingae (12.1% vs. 28.1%; P = 0.001), higher erythrocyte sedimentation rate/C-reactive protein (CRP) ratio (1.4 interquartile range 0.6–3.6 vs. 3.3 interquartile range 1.7–5.7; P < 0.001) and showed lower rate of fever (63% vs. 48.8%; P = 0.024) than in group 1. Complications were not found in group 2.

Conclusions:

An exclusively oral administration could be a safe option in selected patients with OAI. Low-risk criteria are proposed: good general condition, no underlying disease, 6 months to 3 years old, appropriate oral tolerance, C-reactive protein <80 mg/L, erythrocyte sedimentation rate/C-reactive protein ratio ≥0.67, no skin injury, no recent surgery, no cervical spondylodiscitis and no local complications at onset.
Bilateral endophthalmitis after cataract surgery causing scleral melt and intraocular lens exposure
Authors: Kim Daniel S. , Shortell Justin D.
Published: June 2022

Introduction:

Postsurgical endophthalmitis is a rare but serious complication most commonly occurring after cataract surgery. As immediately sequential bilateral cataract surgery (ISBCS) becomes more used, it is important to recognize the risk for bilateral endophthalmitis leading to permanent vision loss. This report reviews a devastating complication of ISBCS.

Patient and Clinical Findings:

We report a 64-year-old man who underwent ISBCS, who presented with severe headache and eye pain late in the course of bilateral endophthalmitis. The right eye was disorganized with shrinkage in addition to superior scleral rupture/melt and prolapsed uveal tissue. The left eye showed superior complete scleral thinning with an exposed intraocular lens.

Diagnosis, Intervention, and Outcomes:

Computed tomography maxillofacial study confirmed bilateral endophthalmitis with deformation of the globes with abscess formation. A culture of the exposed purulent material revealed multidrug-resistant Pseudomonas aeruginosa. Owing to the severity of the infection, a primary bilateral enucleation was performed, which was tolerated well without signs of systemic infection.

Conclusions:

Surgeons should proceed with caution, given the devastating complications that can come with ISBCS. Stricter criteria for patient selection may avoid complications when patient reliability or incomplete medical history is of concern.
Cochlear Implantation in Young Mandarin-Speaking Children: One Year After First Fitting
Authors: Gao Zhiqiang , Wang Suju , Yang Hua , Feng Guodong , Shang Yingying , Wang Bin , Tian Xu , Li Ying , Wei Xingmei , Shu Zhi , Chiusso Francesco
Published: June 2022

Introduction

Bilateral cochlear implantation has been shown to be beneficial in terms of sound localization and speech recognition in children with congenital deafness. However, little is known about the benefits of bilateral cochlear implantationin children who communicate in a tonal language such as Mandarin. This study aims to investigate the auditory perception and speech intelligibility of Mandarin-speaking children 1 year after first fitting.

Materials and Methods

Twenty-nine children aged between 11.5 and 17.9 months with severe-to-profound bilateral sensorineural hearing loss were recruited; 10 were unilaterally implanted and 19 were bilaterally implanted. A test battery was used to monitor improvements during the first year of cochlear implant use.

Results

Bilaterally implanted children scored better in the spatial domain of the Speech, Spatial and Qualities of hearing scale for Parents (SSQ-P) in comparison to unilaterally implanted children. Significant improvements were observed in auditory performance and speech intelligibility at 6 and 12 months after first fitting for both groups of children.

Discussion

Young children that speak a tonal language, such as Mandarin, can obtain significant improvements in hearing and speech abilities within the first year of cochlear implant use. Furthermore, bilateral implantation provides users with better spatial hearing in comparison to unilateral implantation.
Effect of AR42 in Primary Vestibular Schwannoma Cells and a Xenograft Model of Vestibular Schwannoma
Authors: Misztal Carly , Bracho Olena , Bas Esperanza , Estivill Michael , Ivan Michael E. , Morcos Jacques , Bhatia Rita , Telischi Fred , Liu Xue-Zhong , Gultekin Sakir H. , Fernandez-Valle Cristina , Dinh Christine T.
Published: June 2022

Hypothesis

AR42, a histone deacetylase (HDAC) inhibitor, reduces viability of primary vestibular schwannoma (VS) cells and delays tumor progression and hearing loss (HL) in a xenograft model of VS.

Background

The impact of HDAC expression on AR42 response in primary VS cells is unknown, as well as the effects of AR42 on VS-associated HL and imbalance.

Methods

Primary human VS cells (n = 7) were treated with AR42 (0–3.0 μM), and viability assays were conducted. Immunohistochemistry and western blotting for phosphorylated-HDAC2 (pHDAC2) were performed on tumor chunks. Pharmacokinetic studies were conducted in Fischer rats using mass spectrometry. Merlin-deficient Schwann cells were grafted onto cochleovestibular nerves of immunodeficient rats and treated with vehicle (n=7) or AR42 (25 mg/kg/day for 4weeks; n=12). Tumor bioluminescence imaging, auditory brainstem response (ABR), and rotarod tests were conducted to 6weeks. Final tumor weight and toxicities were measured.

Results

AR42 caused dose-dependent reductions in viability of VS cells. Tumors with higher pHDAC2:HDAC2 ratios had greater reductions in viability with AR42. On pharmacokinetic studies, AR42 reached peak levels in nerve ~24 hours after oral administration. Although AR42-treated rats demonstrated mean ABR threshold shifts ~10 to 20 dB lower than controls, this did not persist nor reach significance. When compared to controls, AR42 did not affect tumor bioluminescence, tumor weight, and rotarod measurements.

Conclusions

Response of primary VS cells to AR42 may be influenced by pHDAC2 expression in tumor. Although AR42 may delay HL in our xenograft model, it did not halt tumor growth or vestibular dysfunction. Further investigations are warranted to evaluate the AR42 effectiveness in NF2-associated VS.
Efficacy of Balloon Tuboplasty for Baro-Challenge-Induced Eustachian Tube Dysfunction: A Systematic Review and a Retrospective Cohort Study of 39 Patients
Authors: Oehlandt Heidi , Laakso Juha , Lindfors Oskari , Toivonen Joonas , Poe Dennis , Sinkkonen Saku T.
Published: June 2022

Objective

Baro-challenge-induced Eustachian tube dysfunction (ETD) manifests due to inadequate Eustachian tube (ET) function during rapid ambient pressure changes, although ET function may be normal in normobaric situations. This systematic review and retrospective cohort study aimed to evaluate the effectiveness of balloon Eustachian tuboplasty (BET) for the treatment of baro-challenge-induced ETD.

Data Sources

PubMed, the Cochrane Library, Scopus, and Helsinki University Hospital cohort.

Methods

A systematic literature search was conducted in November 2020 and resulted in 174 articles. Eight articles fulfilled the inclusion criteria. Data was available altogether from 74 adult baro-challenge-induced ETD patients. In addition, we retrospectively evaluated 39 BET operations at Helsinki University Hospital from 2011 to 2020. Data from these 39 patients were collected from medical charts, and a questionnaire was sent to the patients. Meta-analysis was used to evaluate subjective symptom improvement, changes in ETD Questionnaire-7 (ETDQ-7) scores, and Valsalva maneuver performance.

Results

In the systematic review, the outcome parameters varied between studies. Improvement was reported in subjective symptoms, Valsalva maneuver, ETDQ-7, tubomanometry, and pressure chamber test. Response rate for the Helsinki University Hospital cohort study was 72% (28/39). Mean follow-up time from the BET to the questionnaire was 4 years 8 months (SD 26months). Of those patients 93% (26/28) found the operation beneficial. Meta-analysis including up to 113 patients showed improvement in Valsalva maneuver, ETDQ-7, and improvement in subjective symptoms. Overall improvement in symptoms was noted in 81% of the patients.

Conclusion

BET seems to be effective in the majority of patients with baro-challenge-induced ETD.
Analysis of Bone Mineral Density and Bithermal Caloric Test Results in Unilateral Idiopathic Benign Paroxysmal Positional Vertigo Patients
Authors: Jiang Xiuwen , Ding Haibing , Shen Bin , Wu Ziying , Luo Baozhen
Published: June 2022

Objective

Benign paroxysmal positional vertigo (BPPV) is the most frequently diagnosed type of peripheral vestibular vertigo. Studies have reported a possible association between BPPV and osteoporosis; however, there is still a lack of evidence. This study aimed to investigate the characteristics of bone mineral density (BMD) and bithermal caloric test results in patients with unilateral posterior canal idiopathic benign paroxysmal positional vertigo (pc-iBPPV).

Methods

BMD was measured in 65pc-iBPPV menopausal female patients and 65 healthy controls using dual-energy xray absorptiometry and then compared the T-score of BMD between the two groups. The bithermal caloric test was also performed with video nystagmography and the relationship between canal paresis, directional preponderance, T-score, and recurrence were analyzed.

Results

Lower T-scores were observed in pc-iBPPV patients compared with the normal subjects. Among 65 pc-iBPPV patients, free recurrence was observed in 38 (58.5%), single recurrence was noted in 14 (21.5%), and multiple recurrences were seen in 13 (20%) patients. The proportion of positive T-score and CP value increased with the pc-BPPV recurrence frequency. Statistically, a significant difference was found only in T-score, indicating that recurrence was raised with a decrement of T-score. The proportion of positive CP values tended to increase as BMD decreased.

Conclusion

The decrement of BMD might be one of the pathogeneses in patients with unilateral pc-iBPPV and associated with multiple recurrences. Moreover, positive CP value cannot be regarded as a predictive factor for recurrence; however, there is a clear association between CP and BMD.
Gastrointestinal effects of diets low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols
Authors: Quigley Eamonn M.M.
Published: June 2022

Purpose of review

Food ingestion is an exacerbator of gastrointestinal symptoms, regardless of origin. Sufferers mistakenly assume that they have suffered an allergic reaction to a given food. Although classical IgE-mediated allergic reactions are rarely culpable, evidence for a role for intolerance to certain carbohydrates in irritable bowel syndrome (IBS) and related conditions increases. This review assesses the status of a commonly implicated group of poorly absorbed carbohydrates (fermentable oligosaccharides, disaccharides, monosaccharides and polyols – FODMAPs) in gastrointestinal pathophysiology.

Recent findings

Although evidence of efficacy for low FODMAP diets in IBS accumulates, the magnitude of this effect has declined in recent studies. Comparisons to other dietary approaches have revealed conflicting results; some suggest superiority, others find parity. Concerns had been raised regarding long-term nutritional, psychological and microbiological impacts of FODMAP restriction; providing that the diet is administered in the recommended manner, these do not appear to be clinically important. The mechanisms whereby FODMAPs cause gastrointestinal symptoms continue to be explored.

FODMAPS induce gastrointestinal symptoms in susceptible individuals and their restriction provides clinical benefits. The magnitude of these benefits, the superiority of FODMAP restriction over other dietary approaches and the mechanisms of its effects continue to be defined.
Integrating new and emerging therapies into inflammatory bowel disease clinical practice
Authors: Sekhri Shaina , Yarur Andres J.
Published: June 2022

Purpose of review

The purpose of this review is to highlight new and emerging therapies in inflammatory bowel disease (IBD) and provide insight on how these therapies can be integrated into clinical practice.

Recent findings

The article covers clinical and real-world data for Janus kinase inhibitors, anti-interleukin antibodies, sphingosine-1-phosphate receptor modulators, and anti-integrin therapies. It also explores the potential role of antifibrotic agents, microbiota-based innovations, and for personalized medicine in IBD.

The treatment of IBD has evolved significantly in the last two decades, with a host of new treatment options available and arising for patients. With these advancements, positioning these drugs in a treatment algorithm to create a more personalized approach to improve efficacy and prognosis is critical.
Interobserver and intraobserver reliabilities of determining the ventilatory thresholds in subjects with a lower limb amputation and able-bodied subjects during a peak exercise test on the combined arm-leg (Cruiser) ergometer
Authors: Simmelink Elisabeth K. , Dijkstra Pieter U. , de Bruijn Matthijs C. , Geertzen Jan H.B. , van der Woude Lucas H.V , Wempe Johan B. , Dekker Rienk
Published: June 2022

The first (VT1) and second ventilator (VT2) (anaerobic) thresholds are used to individually prescribe exercise training programs. The purpose of this research was to analyze inter- and intraobserver reliabilities of determining VT1 and VT2 in subjects with lower limb amputation (LLA) and able-bodied (AB) subjects during a peak exercise test on the arm-leg (Cruiser) ergometer. Previously published data of exercise tests on the Cruiser ergometer of subjects with LLA (n = 17) and AB subjects (n = 30) were analyzed twice by two observers. The VT1 and VT2 were determined based on ventilation plots. Differences in determining the VT1 and VT2 between the observers for the first and second analyses were analyzed. To quantify variation in measurement a variance component analysis was performed. Bland–Altmann plots were made, and limits of agreement were calculated. The number of observations in which thresholds could not be determined differed significantly between observers and analysis. Variation in VT1 between and within observers was small (0–1.6%) compared with the total variation, for both the subjects with an LLA and AB subjects. The reliability coefficient for VT1 was more than 0.75, and the limits of agreement were good. In conclusion, based on the results of this study on a population level, VT1 can be used to prescribe exercise training programs after an LLA. In the current study, the determination of VT2 was less reliable than VT1. More research is needed into the clinical application of VT1 and VT2 during a peak exercise test on the Cruiser ergometer.
Exploring definitions of retention in care for people living with HIV in the United States in the modern treatment era
Authors: Lesko Catherine R. , Mugavero Michael J. , Shen Nicola M. , Fojo Anthony T. , Moore Richard D. , Keruly Jeanne C. , Cachay Edward R. , Napravnik Sonia , Mayer Kenneth H. , Christopoulos Katerina A. , Jacobson Jeffrey M. , Rebeiro Peter F. , Chander Geetanjali ,   for the CNICS
Published: June 2022

Objective:

To describe retention in HIV care based on various definitions of retention in the modern treatment era.

Design:

A cohort study of people enrolled in care at seven mostly urban HIV clinics across the United States, 2010–2018.

Methods:

We estimated retention based on missed visits, kept visits, kept encounters (clinical visits, CD4 counts, and viral loads), and HIV labs. We contrasted risk factors for retention by different definitions and estimated odds ratios for of viral suppression and hazard ratios for mortality in 2 years immediately following the year in which retention was defined (the study year).

Results:

Across 108 171 person-years (N = 21 481 people), in 71% of years people kept ≥75% of scheduled visits; in 78%, people kept ≥2 visits >90 days apart; in 74%, people had ≥2 HIV labs >90 days apart; and in 47%, people had no gaps >6 months in clinic visits. Missing >25% of scheduled visits despite attending ≥2 visits >90 days apart was associated with nonwhite non-Hispanic race/ethnicity, history of injection drug use, and prior AIDS diagnosis. In contrast, attending ≥75% of scheduled visits while not attending ≥2 visits >90 days apart was associated with male sex, white race, no injection drug use history, and no prior AIDS diagnosis. Subsequent viral nonsuppression was more strongly associated with missed- than kept-visit measures of retention; 2-year mortality was only associated with failure to be retained by missed-visit measures.

Discussion:

Missed and kept-visit definitions of retention capture different constructs. Missed-visit measures are more strongly associated with poor HIV outcomes.
Cognitive, Behavioural, Speech, Language and Developmental Outcomes Associated with Pathogenic Variants in the ERF Gene
Authors: Care Helen , Luscombe Carrie , Wall Steven A. , Dalton Louise , Johnson David , Wilkie Andrew O.M.
Published: June 2022

Pathogenic variants of the ERF gene were previously associated with craniosynostosis, craniofacial dysmorphism and Chiari malformation. This study investigates cognitive, behavioural, speech, language, and developmental outcomes in the first 5 children identified at the Oxford Craniofacial Unit as having ERF-related craniosynostosis, together with three of their carrier parents.

There were no consistent findings related to overall intelligence. However, a pattern of cognitive difficulties is described, which includes poor attention, impulsivity and difficulties with functional fine motor skills, such as handwriting. A high frequency of speech, language and communication difficulties was evident, which was most often related to early language difficulties, speech sound difficulties, hyponasal resonance and concern regarding social communication skills and emotional immaturity.

It was common for these children to have needed input from ear, nose and throat services. Problems with tonsils and/or adenoids and/ or fluctuating conductive hearing loss were found which may be contributors to early speech, language and communication difficulties.

The authors make recommendations regarding the need for formal assessment of a range of developmental aspects upon diagnosis of a pathogenic variant in the ERF gene. The aim of this report is to give clinical guidance to anyone who may have care of patients with the ERF-related mutation.
Novel engineered chimeric engulfment receptors trigger T-cell effector functions against SIV infected CD4+ T cells
Authors: Corey Daniel , Haeseleer Francoise , Corey Lawrence
Published: June 2022

Adoptive therapy with genetically engineered T cells offers potential for infectious disease treatment in immunocompromised persons. HIV/simian immunodeficiency virus (SIV) infected cells express phosphatidylserine (PS) early post-infection. We tested whether chimeric engulfment receptor (CER) T cells designed to recognize PS-expressing cells could eliminate SIV infected cells. Lentiviral CER constructs comprised of the extracellular domain of T-cell immunoglobulin and mucin domain containing 4 (TIM-4), the PS receptor, and engulfment signaling domains were transduced into primary rhesus macaque (RM) T cells. We measured PS binding and T-cell engulfment of RM CD4+ T cells infected with SIV expressing GFP. As chimeric antigen receptor (CAR) T cells induce PS and subsequent TIM-4 binding, we evaluated in vitro killing of CAR and CER T-cell combinations. We found that recombinant TIM-4 bound to SIV infected cells. In vitro, CER CD4+ T cells effectively killed SIV infected cells, which was dependent on TIM-4 binding to PS. Enhanced killing of SIV infected CD4+ T cells by CER and CAR T-cell combinations was observed. This installation of innate immune functions into T cells presents an opportunity to enhance elimination of SIV infected cells and offers potential to augment functional cure of SIV/HIV infection.
Bone Surface Mapping: a new method for recording detailed human bone surface variation
Authors: Paris Sarah E. , Foley Robert A.
Published: June 2022

This paper presents a new method for mapping surface features on bone (e.g. presence and distribution of ochre, surface cuts and scratches, pathologies, etc.). It is an accessible and quantifiable alternative to photogrammetry or three-dimensional scanning. It breaks each bone down into a number of two-dimensional geometric faces that can be utilised in statistical analyses. The number of faces differs depending on the skeletal development of the individual, with children having fewer faces. The recording method allows faces to be grouped by anatomical plane, bone type, side, and region of the body. These selective groupings facilitate flexible categories for hypothesis testing. The technique was developed to enable a detailed recording of ochre staining on human skeletal remains from Khok Phanom Di, Thailand, used in conjunction with a novel recording method to quantify pigment use across the body, and some exemplary results are presented here. While the technique was developed for recording bone surface staining it could also be used to map other variations on bone surfaces, such as in palaeopathological, forensic or taphonomic contexts.
Self-paced treadmill controller algorithm based on position and speed of centre of mass
Authors: Mokhtarzzadeh Hossein , Richards Rosie , Geijtenbeek Thomas
Published: June 2022

Background

Self-paced treadmills are increasingly used in clinical and research settings. Using self-paced (SP) treadmills, researchers can simulate overground walking while participants can walk with different but comfortable gait speeds in a controlled environment. Several algorithms have been designed for self-paced treadmills based on data from force plates, motion capture, and even marker-less systems such as 3D depth cameras.

Methods

We present a non-linear controller that implements a self-paced algorithm integrated with treadmills. This algorithm uses the subject’s centre-of-mass (CoM) position and velocity, relative to the front and back end of the treadmill as inputs. The controller continuously adjusts the treadmill’s belt speed via belt acceleration. The algorithm attempts to prevent the subject reaching the front and back of treadmill via minimal treadmill acceleration.

Findings

This method has been safely used in previous studies with over 410 subjects in various populations. We simulated the use of the SP algorithm with three different sensitivities (0.2, 1 and 2). The belt speed predicted by algorithm simulation in matched well with the belt speeds of experiments in (Gait Realtime Analysis Interactive Lab (GRAIL) system.

Interpretation

This algorithm is integrated with a VR environment in which the subject can be immersed and even be mechanically perturbed. Additionally, this algorithm can be implemented in other treadmills where CoM position is known. We encourage researchers to use and build upon our well-established SP algorithm toward a more standardized SP algorithm in different gait scenarios across various instrumented treadmills with different populations.
Combining Backpropagation with Equilibrium Propagation to improve an Actor-Critic RL framework
Authors: Kubo Yoshimasa , Chalmers Eric , Luczak Artur
Published: June 2022

Backpropagation has been used to train neural networks for many years, allowing them to solve a wide variety of tasks like image classification, speech recognition, and reinforcement learning tasks. But the biological plausibility of backpropagation as a mechanism of neural learning has been questioned. Equilibrium Propagation (EP) has been proposed as a more biologically plausible alternative and achieves comparable accuracy on the CIFAR-10 image classification task. This study proposes the first EP-based reinforcement learning architecture: an actor-critic architecture with the actor network trained by EP. We show that this model can solve the basic control tasks often used as benchmarks for BP-based models. Interestingly, our trained model demonstrates more consistent high-reward behavior than a comparable model trained exclusively by backpropagation.
Spatial distribution and physicochemical properties of respirable volcanic ash from the 16-17 August 2006 Tungurahua eruption (Ecuador), and alveolar epithelium responsein-vitro
Authors: Eychenne Julia , Gurioli Lucia , Damby David , Belville Corinne , Schiavi Federica , Marceau Geoffroy , Szczepaniak Claire , Blavignac Christelle , Laumonier Mickael , Le Pennec Jean-Luc , Nedelec Jean-Marie , Blanchon Loïc , Sapin Vincent
Published: June 2022

Background

Tungurahua volcano (Ecuador) intermittently emitted ash between 1999 and 2016, enduringly affecting the surrounding rural area and its population, but its health impact remains poorly documented.

Objectives

We aim at assessing the respiratory health hazard posed by the 16-17 August 2006 most intense eruptive phase of Tungurahua.

Methods

Based on detailed field surveys and grain size analyses, we mapped the spatial distribution of the health-relevant ash size fractions produced by the eruption in the area impacted by ash fallout. We used Scanning Electron Microscopy and Raman Spectroscopy to quantify the mineralogy, composition, surface texture and morphology of a respirable ash sample isolated by aerodynamic separation. The cytotoxicity and pro-inflammatory potential of this respirable ash towards lung tissues was assessedin-vitrousing A549 alveolar epithelial cells, by Electron Microscopy and biochemical assays (LDH assay, RT-qPCR, multiplex immunoassays).

Results

The eruption produced a high amount of inhalable and respirable ash (12.0-0.04 kg/m2of sub-10 µm and 5.3-0.02 kg/m2of sub-4 µm ash deposited). Their abundance and proportion vary greatly across the deposit within the first 20 km from the volcano. The respirable ash is characteristic of an andesitic magma and no crystalline silica is detected. Morphological features and surface textures are complex and highly variable, with few fibres observed.In-vitroexperiments show that respirable volcanic ash are internalized by A549 cells and processed in the endosomal pathway, causing little cell damage, but some changes in cell morphology and membrane texture. The ash trigger a weak pro-inflammatory response.

Discussion

These data provide the first understanding of the respirable ash hazard near Tungurahua, and the extent to which it varies spatially in a fallout deposit. Given the long exposure duration of the surrounding population, the chronic effects of this inhalable, weakly bio-reactive ash on health could be further investigated.
Global epistasis and the emergence of ecological function
Authors: Diaz-Colunga Juan , Skwara Abigail , Vila Jean C. C. , Bajic Djordje , Sánchez Álvaro
Published: June 2022

The emergence of community functions is the result of a complex web of interactions between organisms and their environment. This complexity poses a significant obstacle in quantitatively predicting ecological function from the species-level composition of a community. In this study, we demonstrate that the collective impact of interspecies interactions leads to the emergence of simple linear models that predict ecological function. These predictive models mirror the patterns ofglobal epistasisreported in genetics, and they can be quantitatively interpreted in terms of pairwise ecological interactions between species. Our results illuminate an unexplored path to quantitatively linking the composition and function of ecological communities, bringing the tasks of predicting biological function at the genetic, organismal, and ecological scales under the same quantitative formalism.
Where does the rainbow end? A case study of self-sustaining rainbow troutOncorhynchus mykisspopulations in tropical rivers
Authors: Nevoux Marie , Marie Amandine D. , Raitif Julien , Baglinière Jean-Luc , Lorvelec Olivier , Roussel Jean-Marc
Published: June 2022

The great physiological, behavioral and morphological plasticity of salmonids contributed to the success of their introduction into a wide range of habitats. However, rainbow trout (Oncorhynchus mykiss) is the only salmonid species to live in the tropics. Like for any cold-water species, water temperature is assumed to be a major constraint to the presence and expansion of rainbow trout. In this study, we collected detailed records of the introduction history of rainbow trout at 35 sites across the island over 80 years, and we document the presence of self-sustainable trout at each site. We explored the linear relationship between water temperature and elevation.
Geometric constraints within tripeptides and the existence of tripeptide reconstructions
Authors: O’Donnell Timothée , Agashe Viraj , Cazals Frédéric
Published: June 2022

Designing movesets providing high quality protein conformations remains a hard problem, especially when it comes to deform a long protein backbone segment, and a key building block to do so is the so-called tripeptide loop closure (TLC). Consider a tripeptide whose first and last segments (N1Cα;1andCα;3C3) are fixed, and so are all internal coordinates except the six {(ϕ,ψ)}i=1,2,3dihedral angles associated to the threeCαcarbons. Under these conditions, the TLC algorithm provides all possible values for these six dihedral angles–there exists at most 16 solutions. TLC moves atoms up to ~ 5Å in one step and retains low energy conformations, whence its pivotal role to design move sets sampling protein loop conformations.

In this work, we relax the previous constraints, allowing the last segment (Cα;3C3) to freely move in 3D space–or equivalently in a 5D configuration space. We exhibit necessary geometric constraints in this 5D space for TLC to admit solutions. Our analysis provides key insights on the geometry of solutions for TLC. Most importantly, when using TLC to sample loop conformations based onmconsecutive tripeptides along a protein backbone, we obtain an exponential gain in the volume of the 5m-dimensional configuration space to be explored.
Supplementation in vitamin B3 counteracts the negative effects of tryptophan deficiencies in bumble bees
Authors: Tissier M.L , Kraus S. , Gómez-Moracho T. , Lihoreau M.
Published: June 2022

Increasing evidence highlights the importance of diet content in 9 essential amino acids for bee physiological and behavioral performance. However, the tenth essential amino acid, tryptophan, has been overlooked as its experimental measurement requires a specific hydrolysis. Tryptophan is the precursor of serotonin and vitamin B3, which together modulate cognitive and metabolic functions in most animals. Here, we investigated how tryptophan deficiencies influence the longevity and behavior of bumble bees. Tryptophan-deficient diets led to a moderate increase in food intake, aggressiveness and mortality compared to the control diet. Vitamin B3 supplementation in tryptophan-deficient diets tended to buffer these effects on food intake and survival, and significantly reduced workers aggressiveness. Considering that the pollens of major crops and common plants, such as corn and dandelion, are deficient in tryptophan, these effects could have a strong impact on bee populations and their pollination service.
RetroFun-RVS: a retrospective family-based framework for rare variant analysis incorporating functional annotations
Authors: Mangnier Loïc , Ruczinski Ingo , Ricard Jasmin , Moreau Claudia , Girard Simon , Maziade Michel , Bureau Alexandre
Published: June 2022

A large proportion of genetic variations involved in complex diseases are rare and located within non-coding regions, making the interpretation of underlying biological mechanisms a daunting task. Although technical and methodological progresses have been made to annotate the genome, current disease - rare-variant association tests incorporating such annotations suffer from two major limitations. Firstly, they are generally restricted to case-control designs of unrelated individuals, which often require tens or hundreds of thousands of individuals to achieve sufficient power. Secondly, they were not evaluated with region-based annotations needed to interpret the causal regulatory mechanisms. In this work we propose RetroFun-RVS, a new retrospective family-based score test, incorporating functional annotations. One of the critical features of the proposed method is to aggregate genotypes while measuring rare variant sharing among affected family members to compute the test statistic. Through extensive simulations, we have demonstrated that RetroFun-RVS integrating networks based on 3D genome contacts as functional annotations reaches greater power over the region-wide test, other strategies to include sub-regions and competing methods. Also, the proposed framework shows robustness to non-informative annotations, keeping a stable power when causal variants are spread across regions. We provide recommendations when dealing with different types of annotations or family structures commonly encountered in practice. Application of RetroFun-RVS is illustrated on whole genome sequence in the Eastern Quebec Schizophrenia and Bipolar Disorder Kindred Study with networks constructed from 3D contacts and epigenetic data on neurons. In summary we argue that RetroFun-RVS, by allowing integration of functional annotations corresponding to regions or networks with transcriptional impacts, is a useful framework to highlight regulatory mechanisms involved in complex diseases.
Clearance of defective muscle stem cells by senolytics reduces the expression of senescence-associated secretory phenotype and restores myogenesis in myotonic dystrophy type 1
Authors: Conte Talita C. , Duran-Bishop Gilberto , Orfi Zakaria , Mokhtari Inès , Deprez Alyson , Roussel Marie-Pier , Côté Isabelle , Pellerito Ornella , Maggiorani Damien , Benabdallah Basma , Leclerc Severine , Feulner Lara , Mathieu Jean , Gagnon Cynthia , Andelfinger Gregor , Beauséjour Christian , McGraw Serge , Duchesne Elise , Dumont Nicolas A.
Published: June 2022

Muscle weakness and atrophy are clinical hallmarks of myotonic dystrophy type 1 (DM1). Muscle stem cells, which contribute to skeletal muscle growth and repair, are also affected in this disease. However, the molecular mechanisms leading to this defective activity and the impact on the disease severity are still elusive. Here, we explored through an unbiased approach the molecular signature leading to myogenic cell defects in DM1. Single cell RNAseq data revealed the presence of a specific subset of DM1 myogenic cells expressing a senescence signature, characterized by the high expression of genes related to senescence-associated secretory phenotype (SASP). This profile was confirmed using different senescence markers in vitro and in situ. Accumulation of intranuclear RNA foci in senescent cells, suggest that RNA-mediated toxicity contribute to senescence induction. High expression of IL-6, a prominent SASP cytokine, in the serum of DM1 patients was identified as a biomarker correlating with muscle weakness and functional capacity limitations. Drug screening revealed that the BCL-XL inhibitor (A1155463), a senolytic drug, can specifically target senescent DM1 myoblasts to induce their apoptosis and reduce their SASP. Removal of senescent cells re-established the myogenic function of the non-senescent DM1 myoblasts, which displayed improved proliferation and differentiation capacity in vitro; and enhanced engraftment following transplantation in vivo. Altogether this study presents a well-defined senescent molecular signature in DM1 untangling part of the pathological mechanisms observed in the disease; additionally, we demonstrate the therapeutic potential of targeting these defective cells with senolytics to restore myogenesis.
A comparative study of the human, mouse, and zebrafish eye after staining with RGB trichrome
Authors: de la Torre Antonio Prieto , Gaytán Francisco
Published: June 2022

Eyesight plays essential roles for the survival of most animal species, and diseases leading to blindness or partial vision loss in humans have an enormous impact in life quality. The complex structure of the eye makes it ideal for the study of structure-function relationships, and to accomplish integration of histology with other disciplines, connecting basic anatomical sciences to clinical medicine. The RGB trichrome consists of the sequential staining with three dyes, fast green (as a general protein stain), picrosirius red and alcian blue (for two main components of the extracellular matrix, collagen and glycosaminoglycans respectively). Notably, this combination of primary colors matches the physiological color detection capacity of the human trichromatic eye. Application of RGB stain to human eye samples and to the eye of two widely used animal models, the mouse and the zebrafish (Danio rerio), gives rise to brilliant staining of eye connective tissues, with a range of colors from red to magenta depending on the extracellular matrix composition, and producing highly contrasted tissue interfaces, facilitating the observation of tissue structures, as well as histomorphometric analysis. Interestingly, staining of the retina resulted in differential staining of the retinal layers in the three species analyzed. These results support the effectiveness of RGB as a reliable general staining method, complementary to routine basic hematoxylin and eosin (H&E), applicable to the study of the eye in human pathology, basic preclinical research, as well as in histo(patho)logy teaching.
Direct encapsulation of biomolecules in semi-permeable microcapsules produced with double-emulsions
Authors: Michielin Grégoire , Maerkl Sebastian J.
Published: June 2022

Compartmentalization can serve different purposes such as the protection of biological active substances from the environment, or the creation of a unique combination of biomolecules for diagnostic, therapeutic, or other bioengineering applications. We present a method for direct encapsulation of molecules in biocompatible and semi-permeable microcapsules made from low-molecular weight poly(ethylene glycol) diacrylate (PEG-DA 258). Microcapsules are produced using a non-planar PDMS microfluidic chip allowing for one-step production of water-in-PEG-DA 258-in-water double-emulsions, which are polymerized with UV light into a poly-PEG-DA 258 shell. Semi-permeable PEG shells are obtained by adding an inert solvent to the PEG-diacrylate. Due to the favourable hydrophilicity of poly-PEG-DA 258, proteins didn’t adsorb to the capsule shell, and we demonstrate the direct encapsulation of enzymes, which can also be dried in the capsules to preserve activity. Finally, we leverage capsule permeability for the implementation of a two-layer communication cascade using compartmentalized DNA strand displacement reactions. This work presents the direct encapsulation of active biomolecules in semi-permeable microcapsules, and we expect our platform to facilitate the development of artificial cells and generating encapsulated diagnostics or therapeutics.
Endogenous circadian reporter cell lines as an efficient platform for studying circadian mechanisms
Authors: Park Jiyoung , Lee Kwangjun , Kim Hyeongseok , Shin Heungsop , Lee Choogon
Published: June 2022

Adverse consequences from having a faulty circadian clock include compromised sleep quality and poor performance in the short-term, and metabolic diseases and cancer in the long- term. However, our understanding of circadian disorders is limited by the incompleteness of our molecular models and our dearth of defined mutant models. Because it would be prohibitively expensive to develop live animal models to study the full range of complicated clock mechanisms, we developedPer1-lucandPer2-lucendogenous circadian reporters in a validated clock cell model, U2OS, where the genome can be easily manipulated, and functional consequences of mutations can be accurately studied. Using these reporter cells, we uncovered critical differences between two paralogs ofPerandCry, as well as working principles of the circadian phosphotimer. Our system can be used as an efficient platform to study circadian sleep disorders such as Familial Advanced Sleep Phase Syndrome (FASPS) and their underlying molecular mechanisms.
Two unique biological response-modifier glucans beneficially regulating gut microbiota and faecal metabolome in a non-alcoholic steatohepatitis animal model, with potential for applications in human health and disease
Authors: Preethy Senthilkumar , Ikewaki Nobunao , Levy Gary A , Raghavan Kadalraja , Dedeepiya Vidyasagar Devaprasad , Yamamoto Naoki , Srinivasan Subramaniam , Ranganathan Natarajan , Iwasaki Masaru , Senthilkumar Rajappa , Abraham Samuel JK
Published: June 2022

Objective

The gut microbiome and its metabolites, influenced by age and stress, reflect the metabolism and immune system’s health. We assessed the gut microbiota and faecal metabolome in a Stelic Animal Model of non-alcoholic steatohepatitis (NASH).

Design

This model was subjected to the following treatments: reverse osmosis water, AFO-202, N-163, AFO-202+N-163, and telmisartan. Faecal samples were collected at 6 weeks and 9 weeks of age. The gut microbiome was analysed using 16S ribosomal RNA sequence acquired by next-generation sequencing and the faecal metabolome using gas chromatography-mass spectrometry.

Results

The gut microbial diversity increased greatly in the AFO-202+N-163 group. Post-intervention, the abundance of Firmicutes decreased, while that of Bacteroides increased and was the highest in the AFO-202+N-163 group. The decrease in the Enterobacteria and other Firmicutes abundance and in the Turicibacter and Bilophila abundance was the highest in the AFO-202 and N-163 groups, respectively. The Lactobacillus abundance increased the most in the AFO-202+N-163 group. The faecal metabolites spermidine and tryptophan, beneficial against inflammation and NASH, respectively, were greatly increased in the N-163 group. Succinic acid, beneficial in neurodevelopmental and neurodegenerative diseases, increased in the AFO-202 group. Decrease in fructose was the highest in the AFO-202 group. Leucine and phenylalanine decreased, whereas ornithine, which is beneficial against chronic immune-metabolic-inflammatory pathologies, increased in the AFO-202+N-163 group.

Conclusion

AFO-202 treatment in mice is beneficial against neurodevelopmental and neurodegenerative diseases and has prophylactic potential against metabolic conditions. N-163 treatment has anti-inflammatory effects against organ fibrosis and neuroinflammatory conditions. In combination, they present anticancer activity.

Key messages

The influence of gut microbiome on fecal metabolome and their association to several diseases is already known.

This study proves the efficacy of 1,3-1,6 beta glucans with pre-biotic potentials, beneficially influencing both gut microbiome and metabolome.

These results recommends for an in-depth exploration of relationship among pre-biotics, gut microbiome and gut-multi-organ axes on the fundamentals of disease onset.

Hidden prophylactic and therapeutic solutions to non-contagious diseases with Aureobasidium pullulans produced 1,3-1,6 beta glucans may be unveiled.
Examining COVID-19 Mortality Rates by Race and Ethnicity Among Incarcerated People in U.S. State Prisons
Authors: Li Mimi Yen , Grebbin Shelby , Patil Ankita , Cowger Tori L. , Kunichoff Dennis , Feldman Justin , Jiménez Monik C.
Published: June 2022

Objective

To estimate coronavirus disease 2019 (COVID-19) mortality rates among individuals incarcerated in U.S. state prisons by race and ethnicity (RE).

Design

Retrospective population-based analysis

Setting

Data from state-level Departments of Corrections (DOCs) from March 1 through October 1, 2020.

Participants

Publicly available data collected by Freedom of Information Act requests representing adults in the custody of US state DOCs.

Main Outcomes

Cumulative COVID-19 death and custody population data. Crude RE-specific cumulative death rates per 1,000 persons, by state and in aggregate, using RE-specific custody population on March 1, 2020, as the denominator. Rate ratios (RR) and 95% confidence intervals (95%CI) compared state-level and aggregate cumulative age-adjusted mortality rates as of 10/01/2020 by RE, with White individuals as reference group.

Results

Of all COVID-related deaths in U.S. prisons through October 2020, 23.35% (272 of 1165) were captured in our analyses. The average age at COVID-19 mortality was 63 years (SD=10 years) and was significantly lower among Black (60 years, SD=11 years) compared to White adults (66 years, SD=10 years; p<0.001). In age-standardized analysis, COVID-19 mortality rates were significantly higher among Black (RR=1.93, 95% CI: 1.25-2.99), Hispanic (RR=1.81, 95% CI: 1.10-2.96) and those of Other racial and ethnic groups (RR=2.60, 95% CI: 1.01-6.67) when compared to White individuals.

Conclusions

Age-standardized mortality rates were higher among incarcerated Black, Hispanic and those of Other RE groups compared to their White counterparts. Greater data transparency from all carceral systems is needed to better understand populations at disproportionate risk of COVID-19 morbidity and mortality.
Neuronal identity defines α-synuclein and tau toxicity
Authors: Praschberger Roman , Kuenen Sabine , Schoovaerts Nils , Kaempf Natalie , Janssens Jasper , Swerts Jef , Nachman Eliana , Calatayud Carles , Aerts Stein , Poovathingal Suresh , Verstreken Patrik
Published: June 2022

Pathogenic α-synuclein and tau are critical drivers of neurodegeneration and their mutations cause neuronal loss in patients. Whether the underlying preferential neuronal vulnerability is a cell-type intrinsic property or a consequence of increased expression levels is an open question. Here, we explore cell-type specific α-synuclein and tau expression in human brain datasets and use deep phenotyping as well as brain-wide single-cell RNA sequencing of >200 live neuron types in fruit flies to ask which cellular environments react most to α-synuclein or tau toxicity. We detect phenotypic and transcriptomic evidence of differential neuronal vulnerability independent of α-synuclein or tau expression levels. Comparing vulnerable with resilient neurons enabled us to identify molecular signatures associated with these differential responses. We used these to verify, and then predict resilient and vulnerable neuron subtypes in human brains. This confirms substantia nigra dopaminergic neurons to be sensitive to α-synuclein, and we predict pathogenic tau vulnerable and protected cortical neuron subtypes. Our work indicates that cellular determinants confer selective vulnerability to specific types of amyloid toxicity, thus paving the way to leverage neuronal identity to uncover modifiers of neurodegeneration-associated toxic proteins.