bluuebunny/crossref_metadata_2025 huggingface dataset:
Achilles tenotomy during Ponseti’s clubfoot treatment: better early than late
Authors: Ghanem Ismat , Ghanem Diane , Rassi Joe , Saliba Ibrahim
Published: March 2024

To evaluate the outcome of Achilles tenotomy at first cast in neonates with stiff clubfoot undergoing Ponseti’s method of treatment. One hundred forty stiff clubfeet (Dimeglio grades III and IV) scheduled for Ponseti’s method were prospectively randomized into two groups of 70 each: (1) early, tenotomy at first cast; (2) late, tenotomy at fourth to sixth casts (conventional). The procedure was performed under local lidocaine spray in an office setting using a needle. The results were assessed at an average follow-up of 12.4 years. Technical difficulties and short and long-term complications were recorded. At last follow-up, the results were rated excellent, good, fair, and poor in 70, 18, 9, and 3% of patients in the late group, respectively, and 82, 13, 4, and 1% in the early group (P = 0.048). Technical difficulties were encountered in 38% of the late group and 3% in the early group (P < 0.0001). Flattening of the talar dome of mild to moderate severity was found in 16% of the late group and 4% in the early group (P < 0.001). Early Achilles tenotomy seems to give better results than the conventional late tenotomy, with less short and long-term complications. This may be explained by the greater ease to palpate the Achilles tendon on a previously untreated foot, and the less amount of compressive forces across the tibiotalar and subtalar joints produced by early release of the posterior tether.
Association of Previous Antibiotics Use and Kawasaki Disease: A Cohort Study of 106,908 Patients
Authors: Kim Tae-Hwan , Shin Ji Seong , Kim Sin Young , Kim Jihye
Published: March 2024

Background:

Microbial imbalance in the gut from antibiotic use may be an etiologic factor of Kawasaki disease (KD). We aimed to identify the association between the use of antibiotics and the development of KD, considering various antibiotic profiles.

Methods:

A population-based, case-control study was performed using data from the Health Insurance Review and Assessment Service database. Children <5 years of age, who were diagnosed with KD between 2016 and 2019, were identified. Propensity score-matched controls were selected from the general population in a 1:5 ratio. Four separate study cohorts were created according to different periods of antibiotic use: (1) within 28 days and (2) 12 months after birth and (3) within 6 months and (4) 12 months from the index date. Profiles regarding antibiotic use were compared between patients with KD and matched controls.

Results:

We included 17,818 patients with KD and 89,090 matched controls. Use of antibiotics within 6 months [odds ratio (OR): 1.18; 95% confidence interval (CI): 1.12–1.26] and 12 months (OR: 1.23; 95% CI: 1.14–1.32) from the index date were associated with the development of KD. The association between antibiotic use and KD was most prominent in patients who had received 3 or more types of antibiotics within 12 months from the index date (OR: 1.26; 95% CI: 1.17–1.37).

Conclusions:

Antibiotic use within the preceding 6 or 12 months was associated with KD. Alteration in gut microbiota due to antibiotic usage might play a role in the development of KD.
Identifying drivers of cost in pediatric liver transplantation
Authors: Sabapathy Divya G. , Hosek Kathleen , Lam Fong W. , Desai Moreshwar S. , Williams Eric A. , Goss John , Raphael Jean L. , Lopez Michelle A.
Published: March 2024

Understanding the economics of pediatric liver transplantation (LT) is central to high-value care initiatives. We examined cost and resource utilization in pediatric LT nationally to identify drivers of cost and hospital factors associated with greater total cost of care. We reviewed 3295 children (<21 y) receiving an LT from 2010 to 2020 in the Pediatric Health Information System to study cost, both per LT and service line, and associated mortality, complications, and resource utilization. To facilitate comparisons, patients were stratified into high-cost, intermediate-cost, or low-cost tertiles based on LT cost. The median cost per LT was $150,836 [IQR $104,481–$250,129], with marked variance in cost within and between hospital tertiles. High-cost hospitals (HCHs) cared for more patients with the highest severity of illness and mortality risk levels (67% and 29%, respectively), compared to intermediate-cost (60%, 21%; p<0.001) and low-cost (51%, 16%; p<0.001) hospitals. Patients at HCHs experienced a higher prevalence of mechanical ventilation, total parental nutrition use, renal comorbidities, and surgical complications than other tertiles. Clinical (27.5%), laboratory (15.1%), and pharmacy (11.9%) service lines contributed most to the total cost. Renal comorbidities ($69,563) and total parental nutrition use ($33,192) were large, independent contributors to total cost, irrespective of the cost tertile (p<0.001). There exists a significant variation in pediatric LT cost, with HCHs caring for more patients with higher illness acuity and resource needs. Studies are needed to examine drivers of cost and associated outcomes more granularly, with the goal of defining value and standardizing care. Such efforts may uniquely benefit the sicker patients requiring the strategic resources located within HCHs to achieve the best outcomes.
Desialylation by neuraminidases in platelets, kiss of death or bittersweet?
Authors: Butta Nora , van der Wal Dianne E.
Published: March 2024

Purpose of review

Loss of surface sialic acid by neuraminidases is known as ‘desialylation’. Platelets are desialylated in bacterial or viral infections, during storage, senescence, various mutations, platelet auto antibodies, hemostasis and shear stress. In this review the recent literature on the different sialic acid capped glycan structures will be covered as well as platelet desialylation in inherited glycan disorders and induced by external neuraminidases.

Recent findings

Neuraminidases are released from platelet intracellular stores and translocated to the platelet surface. Apart from clearance, loss of surface sialic acid by neuraminidases (‘desialylation’) affects platelet signaling including ligand binding and their procoagulant function. Platelets are also desialylated in infections, various mutations, presence of platelet auto antibodies.

Since platelet desialylation occurs in various healthy and pathological conditions, measuring desialylation might be a new diagnostic tool.
How safe are proprotein convertase subtilisinekexin type 9 inhibitors in diabetes?
Authors: Chen Tian , Liu Naifeng
Published: March 2024

Purpose of review

To examine the safety of proprotein convertase subtilisinekexin type 9 (PCSK9) inhibitors in patients with diabetes, specifically focusing on their impact on glucose metabolism.

Recent findings

Patients with diabetes often require intensified lipid-lowering therapy. PCSK9 inhibitors can reduce low-density lipoprotein cholesterol (LDL-C) concentrations by approximately 60%, and significantly reduce cardiovascular risk when added to statin therapy. Some studies have suggested an association between low LDL-C levels and an increased risk of new-onset diabetes, and genetics has almost consistently shown an increased glucose concentration and risk of diabetes. Most clinical trials have not demonstrated a deterioration in glycaemic control in patients with diabetes after the use of PCSK9 inhibitors, and they do not lead to other significant treatment-emergent adverse events.

Although the majority of patients with diabetes are undergoing background statin therapy, which may mask potential adverse effects of PCSK9 inhibitors on glycaemic control, current data suggest that the benefits outweigh the risks for diabetic patients using PCSK9 inhibitors. Considering the different nature of genetic studies and of clinical trials, close monitoring of glucose parameters is necessary, especially in individuals with prediabetes.
Mixed Connective Tissue Disease Presenting With Psychosis—A Case Report
Authors: Tondehal Nikhil , Sengupta Arnab , Mohankumar Kavya , Trivedi Chintan , Mansuri Zeeshan , Jain Shailesh
Published: March 2024

Mixed connective tissue disease (MCTD) is a systemic autoimmune disease with features overlapping multiple autoimmune disorders. One study found that over 55% of patients with MCTD experienced neuropsychiatric symptoms, the most common of which was an “aseptic meningitis-like syndrome.” We present a case of a 17-year-old adolescent girl presenting with abnormal speech and behavior, auditory hallucinations, and paranoid delusions after an isolated episode of fever. She was treated for her psychotic symptoms but later developed symptoms resembling neuroleptic malignant syndrome. An antibody screen revealed elevated anti-U1-ribonucleoprotein antibodies with a possible diagnosis of MCTD. She finally responded to steroid therapy. To our knowledge, this is the first reported case of MCTD initially presenting with psychosis. A diagnosis of autoimmune disorders should be kept in the differential of similar clinical presentations including connective tissue disorders and autoimmune thyroid conditions.
Are rehabilitation professionals familiar with visual impairments? A survey of professional orders in Quebec, Canada
Authors: Nemargut Joseph P. , Boucher-Costi Geneviève , Ta Angel , St-Amant Laurie
Published: March 2024

Significance

The number of patients with mild to moderate visual impairments (MVIs) is increasing as the average age of the population increases. Thus, it is important to understand the training and resources available for rehabilitation practitioners to provide adequate care to these patients within their scope of practice.

Purpose

This study explores rehabilitation professionals' perceptions of their competence in screening and treating patients with MVI, and identifying the tools and resources needed to increase these professionals' comfort level in managing these patients.

Methods

Data collection was carried via an online questionnaire to Quebec rehabilitation professionals and student-trainees who are members of their respective professional orders. The questionnaire consisted of 29 to 30 questions (open- and close-ended) related to demographics, service provision to MVI patients, education in MVI and future training, and future service delivery to MVI patients.

Results

Data were collected from 96 professionals, with 52 fully completing the questionnaire, with all the responses included in the analysis. Most respondents had little or no confidence in adequately screening or treating patients with MVI and mentioned that they knew little or nothing about the range of services offered by vision rehabilitation centers in Quebec (81%), whereas 55% at least occasionally offer services to these patients. The majority felt that their profession would benefit from continuing education on MVI (73%), with a marked interest in online training.

Conclusions

Rehabilitation professionals in Quebec are not confident in identifying or treating patients presenting MVI but express an interest in attending continuing education courses given by optometrists, low vision professionals, or a member of their own profession. Numerous barriers account for this problem, including a lack of experience and competence in the assessment and treatment options for MVI, as well as a lack of informational and human resources available in their workplaces.
Spinal Muscular Atrophy Mortality Despite Novel Medications
Authors: Bach John R. , Conceição Nayara , Goncalves Miguel R.
Published: March 2024

Despite new effective medications, patients with spinal muscular atrophy types 1–3 can continue to have inadequate cough flows to prevent episodes of acute respiratory failure. Ventilator unweanable intubated patients are thought to require tracheostomy tubes. As a result, potentially beneficial medications may be discontinued and patients die despite receiving these medications. Three cases are presented of medically treated, physically strengthening children, with spinal muscular atrophy type 1. All three subsequently died or underwent tracheotomy. However, there is no evidence of extubation attempts to noninvasive ventilatory support settings or optimal mechanical insufflation-exsufflation despite this option being described to be over 98% successful for extubating unweanable medically untreated children with spinal muscular atrophy 1.
Interprofessional Collaboration and Patient/Family Engagement on Rounds in a Comprehensive Stroke Center: A Mixed-Methods Study
Authors: Xie Anping , Barany E. Alexandra , Tanner Elizabeth K. , Blakeney Erin Abu-Rish , Bahouth Mona N. , Hanson Ginger C. , Hansen Bryan R. , McDonald Kathryn M. , Salas Rachel Marie E. , Shakes Tenise , Watson Heather , Zink Elizabeth K. , Hairston Dorna P.
Published: March 2024

Background and Objectives:

Daily rounds provide an opportunity for interprofessional collaboration and patient/family engagement, which are critical to stroke care. As part of a quality improvement program, we conducted a baseline assessment to examine interprofessional collaboration and patient/family engagement during the current rounding process in a 12-bed comprehensive stroke center. Findings from the baseline assessment will be used to inform the development, implementation, and evaluation of a new rounding model.

Methods:

The baseline assessment used a mixed-methods approach with a convergent parallel design. Although observations of the current rounding process were conducted to quantitatively assess interprofessional collaboration and patient/family engagement on rounds, qualitative interviews were conducted with different stakeholders to identify strengths and weaknesses of the current rounding process, as well as suggestions for facilitating interprofessional collaboration and patient/family engagement.

Results:

We observed 103 table rounds and 99 bedside rounds and conducted 30 interviews with patients, families, and clinicians. Although the current process was perceived to facilitate interprofessional collaboration, the participation of nurses and other health care professionals on rounds was inconsistent due to competing clinical duties. Good practices for engaging patients and families during bedside rounds were also performed inconsistently.

Conclusions:

These findings lead to recommendations for revising the rounding process with poststroke patients, utilizing a more interprofessional collaborative approach with focus on patient/family engagement.
Positive 18F-FDG and Negative 68Ga-FAPI-04 Findings in a Patient With Gallbladder Adenocarcinoma
Authors: Qi Na , Chen Xing , Zhou Zirong , Yuan Zengbei , Zhao Jun
Published: March 2024

Radiolabeled fibroblast activation protein inhibitor (FAPI) is considered as a potential alternative agent to 18F-FDG for tumor-specific imaging. We report 18F-FDG and 68Ga-FAPI-04 PET/MR findings in a 67-year-old woman with gallbladder adenocarcinoma. The lesions showed intense 18F-FDG uptake but limited 68Ga-FAPI-04 uptake in PET/MR. This case emphasizes the necessity for nuclear clinicians to exercise caution when assessing gallbladder lesions with limited 68Ga-FAPI-04 uptake, underscoring the continued relevance of 18F-FDG in this diagnostic domain.
The state of art on the use of patient reported outcomes in migraine
Authors: Alpuente Alicia , Torres-Ferrus Marta , Caronna Edoardo , Pozo-Rosich Patricia
Published: March 2024

Purpose of review

This review aims to explore the use of patient-reported outcome measures (PROMs) in migraine. Traditionally assessed through specific features, recent adoption of PROMs allows for a more objective and quantifiable evaluation. PROMs, which are standardized questionnaires collecting health information directly from a patients’ perspective, cover various aspects, including migraine specific aspects. The review focuses on delineating the applications and interpretation of commonly used PROMs in migraine research, with an emphasis on their integration in clinical care.

Recent findings

Generic and migraine-specific PROMs play a crucial role in clinical research, particularly in assessing health-related quality of life, disability, impact, and associated comorbidities. Some of these measures are strongly recommended to be used by the International Guidelines and are, in fact, mandated by the FDA for product labeling. Recently, there has been an expansion in the use of PROMs to assess migraine in diverse populations, in particular pediatric patients. However, the application of these measures in clinical care shows considerable heterogeneity, and some have not been validated specifically for migraine. The existing multitude of PROMs, coupled with ongoing development of new ones to better capture patient concerns, creates complexity in their research and clinical application. To address these challenges, it becomes imperative to streamline their use, focusing on those that are more validated and better aligned with the patients’ perspective including different populations’ needs.

The utilization of PROMs in evaluating migraine enables a more holistic assessment, helps quantify the impact of the disease facilitating change measurement, improves communication between healthcare providers and patients and, guides treatment decisions for improved outcomes. However, the increasing number of PROMs questionnaires, underscores the importance of validating these tools for migraine and, the dynamic nature of the disease makes it relevant to decide with whom, why and when these should be used.
PMMA bone cement with
L
-arginine/nano fish bone nanocomplex for apatite formation
Authors: Khoman Gessica Aurel , Kalijaga Muhammad Harza Arbaha , Aisah Nuning , Fidyaningsih Riastuti , Raharjo Jarot , Arjasa Oka P. , Prajatelistia Ekavianty
Published: March 2024

Bone cement is one of the materials used in orthopaedics that serves various functions, such as binding bone implants, replacing damaged bones and filling spaces within bones. Various materials have been used to synthesize bone cement, and one promising material for further research is fish bone waste-based bone cement. This study investigates the potential of fish bone waste-based bone cement by incorporating nano fish bone (NFB) and
L
-arginine (
L
-Arg) protein into polymethyl methacrylate (PMMA) to examine apatite growth. NFB derived from the
Salmo salar
fish positively influences osteoblast cell proliferation and differentiation, while L-Arg enhances biocompatibility and antibiotic properties. The NFB/L-Arg combination holds promise in accelerating new bone formation and cell growth, both of which are crucial for fracture healing and bone remodelling. Tensile strength tests reveal the superior performance of BC-PMMA-1-NFB/L-Arg (36.11 MPa) compared with commercial PMMA (32 MPa). Immersion tests with simulated body fluid (SBF) solution for 7 days reveal accelerated apatite layer formation, emphasizing the potential benefits of NFB/
L
-Arg in bone cement applications.
Trends and antibiotic susceptibility patterns of diarrhoeal pathogens - an experience of fourteen years in Southern India
Authors: Mohanty Ankita , Lakra Nayannika , Mandal Jharna
Published: March 2024

INTRODUCTION:
Enteric pathogens contribute largely to morbidity in a developing country like India. Early and prompt diagnosis of diarrhoeal diseases can reduce the mortality rate, particularly in children.  The pattern of sensitivity to antimicrobials for the common pathogens can vary from time to time. The present study was conducted to study the pathogen distribution and antimicrobial susceptibility pattern during the study period (January 2010 to December 2023).
HYPOTHESIS/GAP STATEMENT: Studying the changing trend in the antimicrobial sensitivity pattern of diarrhoeal pathogens over a decade can help to plan future treatment options.
AIM: This study was undertaken to provide insight into the changing pattern of pathogen distribution and antimicrobial susceptibility of enteric pathogens over 14 years.
METHODS: A retrospective observational cohort analysis was conducted on all the stool pathogens isolated from the samples received in the Microbiology department of a tertiary care hospital from the year 2010 to 2023. The demographic details, stool microscopy, culture reports, and antimicrobial susceptibility patterns were noted.
RESULTS:  18336 stool specimens were received in the Microbiology laboratory between January 2010 to December 2023. A total of 591 Salmonella, 471 Shigella,181 Vibrio, and 80 Aeromonas species were isolated. 93% of Salmonella species, 89% of Shigella species, and 95 % of Vibrio species were susceptible to Ceftriaxone.91% of Aeromonas isolates were susceptible to Chloramphenicol. Some major parasites were also observed on microscopy.
CONCLUSION: Timely diagnosis of diarrhoeal pathogens can be life-saving for patients belonging to extremes of age. Pathogens can exhibit a changing susceptibility pattern to antibiotics which should be regularly observed to plan future therapy.
Root foraging response to gradients of calcium and magnesium, essential bivalent cations with low mobility in the soil
Authors: Skálová Hana , Pánková Karolína , Stiblíková Pavlína , Křivohlavý Filip , Hadincová Věroslava , Tylová Edita , Herben Tomáš
Published: March 2024

Plants forage for nutrients by root proliferation in nutrient-rich patches. While foraging for nitrogen and phosphorus has been repeatedly confirmed, foraging for calcium and magnesium, which are essential for plant growth and form much more stable patches in the soil, has never been examined.

We examined preferential root placement into dolomite-limestone-rich patches in a pot experiment with 17 species, and compared it with foraging for a nitrogen, phosphorus and potassium mixture (NPK). About one half of the species showed root proliferation in dolomite-rich patches. It was less pronounced than foraging for NPK and did not show any relationship to species field preferences to soil reaction, or dicots-grass difference, but it showed clear negative relationship to species-specific Ca+Mg tissue concentrations.

While foraging for NPK shows the potential of species to change their root systems by proliferation, only some species use this potential to respond to the Ca+Mg gradient. The negative correlation of this response to Ca+Mg tissue concentrations implies that nonresponding species compensate for it by physiological mechanisms. The response to Ca+Mg also implies that in contrast to nitrogen, which never shows stable patches in the soil, Ca+Mg-rich patches, which are much more stable, can be exploited by root proliferation.
Functional Diversity of Memory CD8 T Cells is Spatiotemporally Imprinted
Authors: Reina-Campos Miguel , Monell Alexander , Ferry Amir , Luna Vida , Cheung Kitty P. , Galletti Giovanni , Scharping Nicole E. , Takehara Kennidy K. , Quon Sara , Boland Brigid , Lin Yun Hsuan , Wong William H. , Indralingam Cynthia S. , Yeo Gene W. , Chang John T. , Heeg Maximilian , Goldrath Ananda W.
Published: March 2024

Tissue-resident memory CD8 T cells (TRM) kill infected cells and recruit additional immune cells to limit pathogen invasion at barrier sites. Small intestinal (SI) TRMcells consist of distinct subpopulations with higher expression of effector molecules or greater memory potential. We hypothesized that occupancy of diverse anatomical niches imprints these distinct TRMtranscriptional programs. We leveraged human samples and a murine model of acute systemic viral infection to profile the location and transcriptome of pathogen-specific TRMcell differentiation at single-transcript resolution. We developed computational approaches to capture cellular locations along three anatomical axes of the small intestine and to visualize the spatiotemporal distribution of cell types and gene expression. TRMpopulations were spatially segregated: with more effector- and memory-like TRMpreferentially localized at the villus tip or crypt, respectively. Modeling ligand-receptor activity revealed patterns of key cellular interactions and cytokine signaling pathways that initiate and maintain TRMdifferentiation and functional diversity, including different TGFβ sources. Alterations in the cellular networks induced by loss of TGFβRII expression revealed a model consistent with TGFβ promoting progressive TRMmaturation towards the villus tip. Ultimately, we have developed a framework for the study of immune cell interactions with the spectrum of tissue cell types, revealing that T cell location and functional state are fundamentally intertwined.
Cortical evidence accumulation for perceptual experience occurs irrespective of reports
Authors: Stockart François , Msheik Ramla , Robin Alexis , Jurkovičová Lenka , Goueytes Dorian , Rouy Martin , Mareček Radek , Hoffmann Dominique , Mudrik Liad , Roman Robert , Brázdil Milan , Minotti Lorella , Kahane Philippe , Pereira Michael , Faivre Nathan
Published: March 2024

Perceptual experience is a multi-faceted, dynamical process, tackled empirically through measures of stimulus detectability and confidence. To assess if stimulus detection and confidence can be explained by evidence accumulation, a form of sequential sampling of sensory evidence, we analyzed high-gamma activity from stereo-electroencephalographic data of 29 participants partaking in 3 pre-registered experiments. In an immediate-response experiment, individual channels and decoded multivariate latent variables in the visual, inferior frontal, and anterior insular cortices displayed functional markers of evidence accumulation. In two further experiments, this signal in the ventral visual cortex differentiated between (1) seen and unseen stimuli in delayed detection, (2) high and low intensity stimuli during passive viewing, and (3) levels of confidence when stimuli were seen. A computational model of leaky evidence accumulation successfully reproduced both behavioral and neural data. Overall, these results indicate that evidence accumulation explains key aspects of perceptual experience, encompassing both conscious access and monitoring.
Adaptation optimizes sensory encoding of future stimuli
Authors: Mao Jiang , Rothkopf Constantin , Stocker Alan A.
Published: March 2024

Sensory neurons continually adapt their response characteristics according to recent sensory input. However, it is unclear how such a reactive process shaped by sensory history can benefit the organism going forward. Here, we test the hypothesis that adaptation indeed acts proactively in the sense that it optimally adjusts sensory encoding for the future, i.e. for the next expected sensory input. We first quantified adaptation induced changes in sensory encoding by psychophysically measuring discrimination thresholds for visual orientation under different adaptation conditions. Using an information theoretic analysis, we found that adaptation consistently reallocates coding resources such that encoding accuracy peaks at the adaptor orientation while total coding capacity remains constant. We then asked whether this characteristic change in encoding accuracy is predicted by the temporal statistics of natural visual input. By analyzing the retinal input of freely behaving human subjects in natural environments, we found that the distribution of local visual orientations in the retinal input stream at any moment in time is also peaked at the mean orientation computed over a short input history leading up to that moment. We further tested our hypothesis with a recurrent neural network trained to predict the next frame of natural scene videos (PredNet). We simulated our human adaptation experiment with PredNet while analyzing its internal sensory representation. We found that the network exhibited the same change in encoding accuracy as observed in human subjects, and as predicted by the natural input statistics. Taken together, our results suggest that adaptation induced changes in encoding accuracy are an attempt of the visual systems to be best possibly prepared for future sensory input.
VaccineDesigner: A Web-based Tool for Streamlined Multi-epitope Vaccine Design
Authors: Trygoniaris Dimitrios , Korda Anna , Paraskeva Anastasia , Dushku Esmeralda , Tzimagiorgis Georgios , Yiangou Minas , Kotzamanidis Charalampos , Malousi Andigoni
Published: March 2024

Background

Multi-epitope vaccines have become the preferred strategy for protection against infectious diseases by integrating multiple MHC-restricted T-cell and B-cell epitopes that elicit both humoral and cellular immune responses against pathogens. Computational methods address various aspects independently, yet their orchestration is technically challenging as most bioinformatics tools are accessible through heterogeneous interfaces and lack interoperability features. The present work proposes a novel framework for rationalized multi-epitope vaccine design that streamlines end-to-end analyses through an integrated Web-based environment.

Results

VaccineDesigner is a comprehensive Web-based framework that streamlines the design of protective epitope-based vaccines by seamlessly integrating computational methods for B-cell, CTL, and HTL epitope prediction. VaccineDesigner incorporates single epitope prediction and evaluation as well as additional analyses, such as multi-epitope vaccine generation, estimation of population coverage, molecular mimicry, and proteasome cleavage. The functionalities are transparently integrated into a modular architecture, providing a single access point for rationalized, multi-epitope vaccine generation, time and cost-effectively.

Conclusions

VaccineDesigner is a Web-based interface for developing multi-epitope vaccines. Given a protein sequence, VaccineDesigner identifies and evaluates candidate B-cell, CTL, and HTL epitopes and constructs a library of multi-epitope vaccines that combine strong immunogenic responses, safety, and broad population coverage. The source code is available under the academic license at:https://github.com/BiolApps/VaccineDesigner. VaccineDesigner is freely accessible at:http://bioinformatics.med.auth.gr/VaccineDesigner.
Relationship between weapon size and six key behavioural and physiological traits in males of the European earwig
Authors: Blackwell Samantha E.M. , Pasquier Laura , Dupont Simon , Devers Séverine , Lécureuil Charlotte , Meunier Joël
Published: March 2024

In many animals, male weapons are large and extravagant morphological structures that typically enhance fighting ability and reproductive success. It is generally assumed that growing and carrying large weapons is costly, thus only males in the best condition can afford it. In the European earwig, males carry weapons in the form of forceps-like cerci, which can vary widely in size within populations. While long forceps appear to increase male’s access to females, it is unknown whether it also correlates with other important male lifen-history traits. This information is important, however, in determining the potential reliability of forceps length as an indicator of male quality and the stability of this signalling system. Here, we tested whether forceps length is associated with six important behavioural and physiological traits in males of the European earwig. We sampled hundreds of males from two populations, selected 60 males with the longest and shortest forceps from each population, and then measured locomotor performance, boldness, aggregation behaviour, survival under harsh conditions, sperm storage, and survival after pathogen exposure. Contrary to our predictions, we detected no main association between forceps length and the traits measured. This lack of association was consistent between the two populations, although there were population-specific levels of boldness, aggregation and survival in harsh conditions (for long-forceps males only). Overall, these results challenge our current understanding of the function and quality signal of forceps length in this species and raise questions about the evolutionary drivers that could explain the maintenance of weapon size diversity within and between populations.
Chronic hypertension and perfusion deficits conjointly affect disease outcome after tPA treatment in a rodent model of thromboembolic stroke
Authors: Franx Bart AA , Tiebosch Ivo ACW , van der Toorn Annette , Dijkhuizen Rick M.
Published: March 2024

Futile recanalization hampers prognoses for ischemic stroke patients despite successful recanalization therapy. Allegedly, hypertension and reperfusion deficits contribute, but a better understanding is needed of how they interact and mediate disease outcome. We assessed data from spontaneously hypertensive and normotensive Wistar-Kyoto rats (male, n=6-7/group) that were subjected to two-hour embolic middle cerebral artery occlusion and thrombolysis in preclinical trials. Serial MRI allowed lesion monitoring and parcellation of regions-of-interest that represented infarcted (core) or recovered (perilesional) tissue. Imaging markers of hemodynamics and blood-brain barrier (BBB) status were related to tissue fate and neurological outcome. Despite comparable ischemic severity during occlusion between groups, hypertensive rats temporarily developed larger lesions after recanalization, with permanently aggravated vasogenic edema and BBB permeability. One day post-stroke, cerebral blood flow (CBF) was variably restored, but blood transit times were consistently prolonged in hypertensives. Compared to the core, perilesional CBF was normo-to- hyperperfused in both groups, yet this pattern reversed after seven days. Volumes of hypo- and hyperperfusion developed irrespective of strain, differentially associating with final infarct volume and behavioral outcome. Incomplete reperfusion and cerebral injury after thrombolysis were augmented in hypertensive rats. One day after thrombolysis, hypoperfusion associated with worsened outcomes, while regional hyperperfusion appeared beneficial or benign.
Neuroprotective Effects of Bioactive Molecules Derived from Tobacco as Potential Therapeutic Candidates for Alzheimer Disease
Authors: Liao Ceheng , Li Meng , Li Zhu , Wang Meixia , Peng Qiyuan , Zhu Zhouhai , Wang Hong-Hui , Guan Ying
Published: March 2024

Neurodegenerative diseases are significant global health challenges, particularly with an aging population. While tobacco is traditionally linked to health risks, recent studies suggest it may contain compounds beneficial for neurodegenerative conditions. Herein, we explore the potential of bioactive compounds in tobacco as neuroprotective agents for Alzheimer’s disease (AD). Using genetic engineering, we developed a novel approach with neural progenitor cells (NPCs) derived from embryonic stem cells, equipped with an NF-κB reporter system to screen tobacco extracts. Our screenings identified three compounds with significant inhibitory effects on NF-κB activation, a key mediator of neuroinflammation in AD. Among these, rutin exhibited profound neuroprotective effects in an NPC damage model induced by Amyloid-β25-35, reducing apoptotic cell death, enhancing cellular proliferation, and activating critical survival signaling pathways. This modulation underlies rutin’s anti-inflammatory and neuroprotective activities. Together, our findings support the potential of tobacco-derived compounds in AD therapy and lay the foundation for further exploration of their pharmaceutical value.
The oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling, and therapeutic implications
Authors: Iacoangeli Alfredo , Dilliott Allison A. , Al Khleifat Ahmad , Andersen Peter M , Başak Nazli A. , Cooper-Knock Johnathan , Corcia Philippe , Couratier Philippe , de Carvalho Mamede , Drory Vivian , Glass Jonathan D. , Gotkine Marc , Lerner Yossef , Hardiman Orla , Landers John E. , McLaughlin Russell , Mora Pardina Jesús S. , Morrison Karen E. , Pinto Susana , Povedano Monica , Shaw Christopher E. , Shaw Pamela J. , Silani Vincenzo , Ticozzi Nicola , Van Damme Philip , van den Berg Leonard H. , Vourc’h Patrick , Weber Markus , Veldink Jan H. ,   Project MinE ALS Sequencing Consortium, Dobson Richard JB , Rouleau Guy A. , Chalabi Ammar Al , Farhan Sali M.K.
Published: March 2024

Recently, large-scale case-control analyses have been prioritized in the study of ALS. Yet the same effort has not been put forward to investigate additive moderate phenotypic effects of genetic variants in genes driving ALS risk, despite case-level evidence suggesting a potential oligogenic risk model. Considering its direct clinical and therapeutic implications, a large-scale robust investigation of oligogenicity in ALS is greatly needed.

Here, we leveraged the Project MinE ALS Sequencing Consortium genome sequencing datasets of individuals with ALS (n = 6711) and controls (n = 2391) to identify signals of association between oligogenicity in known ALS genes (n=26) and disease risk, as well as clinical outcomes.

Applying regression models to a discovery and replication cohort, we observed that the risk imparted from carrying rare variants in multiple known ALS genes was significant and was greater than the risk associated with carrying only a single rare variant, both in the presence and absence of variants in the most well-established ALS genes, such asC9orf72. However, in contrast to risk, the relationships between oligogenicity and ALS clinical outcomes, such as age of onset and survival, might not follow the same pattern as we did not observe any associations.

Our findings represent the first large-scale, case-control assessment of oligogenic associations in ALS to date and confirm that oligogenic events involving known ALS risk genes are indeed relevant for the risk of disease in approximately 6% of ALS but not necessarily for disease onset and survival. This must be considered in genetic counselling and testing by ensuring the use of comprehensive gene panels even when a potential pathogenic variant has already been identified. Moreover, in the age of stratified medication and gene therapy, it supports the need of a complete genetic profile for the correct choice of therapy in all ALS patients.
Mutational scanning ofCRXclassifies clinical variants and reveals biochemical properties of the transcriptional effector domain
Authors: Shepherdson James L. , Granas David M. , Li Jie , Shariff Zara , Plassmeyer Stephen P. , Holehouse Alex S. , White Michael A. , Cohen Barak A.
Published: March 2024

Cone-Rod Homeobox, encoded byCRX, is a transcription factor (TF) essential for the terminal differentiation and maintenance of mammalian photoreceptors. Structurally, CRX comprises an ordered DNA-binding homeodomain and an intrinsically disordered transcriptional effector domain. Although a handful of human variants inCRXhave been shown to cause several different degenerative retinopathies with varying cone and rod predominance, as with most human disease genes the vast majority of observedCRXgenetic variants are uncharacterized variants of uncertain significance (VUS). We performed a deep mutational scan (DMS) of nearly all possible single amino acid substitution variants in CRX, using an engineered cell-based transcriptional reporter assay. We measured the ability of each CRX missense variant to transactivate a synthetic fluorescent reporter construct in a pooled fluorescence-activated cell sorting assay and compared the activation strength of each variant to that of wild-type CRX to compute an activity score, identifying thousands of variants with altered transcriptional activity. We calculated a statistical confidence for each activity score derived from multiple independent measurements of each variant marked by unique sequence barcodes, curating a high-confidence list of nearly 2,000 variants with significantly altered transcriptional activity compared to wild-type CRX. We evaluated the performance of the DMS assay as a clinical variant classification tool using gold-standard classified human variants from ClinVar, and determined that activity scores could be used to identify pathogenic variants with high specificity. That this performance could be achieved using a synthetic reporter assay in a foreign cell type, even for a highly cell type-specific TF like CRX, suggests that this approach shows promise for DMS of other TFs that function in cell types that are not easily accessible. Per-position average activity scores closely aligned to a predicted structure of the ordered homeodomain and demonstrated position-specific residue requirements. The intrinsically disordered transcriptional effector domain, by contrast, displayed a qualitatively different pattern of substitution effects, following compositional constraints without specific residue position requirements in the peptide chain. The observed compositional constraints of the effector domain were consistent with the acidic exposure model of transcriptional activation. Together, the results of theCRXDMS identify molecular features of the CRX effector domain and demonstrate clinical utility for variant classification.
Sub-cone visual resolution by active, adaptive sampling in the human foveola
Authors: Witten Jenny L. , Lukyanova Veronika , Harmening Wolf M.
Published: March 2024

The foveated architecture of the human retina and the eye’s mobility enable prime spatial vision, yet the interplay between photoreceptor cell topography and the constant motion of the eye during fixation remains unexplored. Within vivofoveal cone-resolved imaging and simultaneous microscopic photo stimulation, we examined visual acuity in both eyes of 16 participants while precisely recording the stimulus path on the retina. We find that resolution thresholds were correlated with the individual retina’s sampling capacity, and exceeded what static sampling limits would predict by 18 %, on average. The length and direction of fixational drift motion, previously thought to be primarily random, played a key role in achieving this sub-cone diameter resolution. The oculomotor system finely adjusts drift behavior towards retinal areas with higher cone densities within only a few hundred milliseconds to enhance retinal sampling.
Homeotic and non-homeotic patterns in the tetrapod vertebral formula
Authors: Cerbus Rory T. , Hiratani Ichiro , Kawaguchi Kyogo
Published: March 2024

Vertebrae can be differentiated into five categories along the body axis in tetrapods, with its numerical distribution known as the vertebral formula. The vertebral formula is a principal tool for connecting development and phylogeny [1]. This is largely due to its robust relationship with the conserved clusters ofHoxgenes [2], which exhibit expression boundaries coincident with vertebral divisions [3–11]. One avenue for variations in the vertebral formula is thus throughHox-mediated homeotic transformations, which manifest as a relatively fixed sum of adjacent vertebral counts. This expectation is borne out in the mammalian thoracolumbar count [12], but to date, no similar vertebral patterns have been found. Here we conduct a systematic search by generating a large dataset of complete vertebral formulae in a diverse range of tetrapod species and probing the variance of linear combinations of vertebrae. We uncover additional mammalian homeotic patterns, but also unexpected balances between distal vertebrae not comprehensible withHox-mediated regionalization. One distal pattern appears during the progression from theropods to birds, demonstrating its phylogenetic importance. We further show that several vertebral counts correlate with posterior intergenic distances in theHoxBgene cluster. By creating a vertebral formula database and mathematically defining patterns, our work establishes a quantitative approach for comparative genomics in morphology.
Traumatic injury causes selective degeneration and TDP-43 mislocalization in human iPSC-derivedC9orf72-associated ALS/FTD motor neurons
Authors: Martin Eric J. , Santacruz Citlally , Mitevska Angela , Jones Ian E. , Krishnan Gopinath , Gao Fen-Biao , Finan John D. , Kiskinis Evangelos
Published: March 2024

A hexanucleotide repeat expansion (HRE) inC9orf72is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, patients with the HRE exhibit a wide disparity in clinical presentation and age of symptom onset suggesting an interplay between genetic background and environmental stressors. Neurotrauma as a result of traumatic brain or spinal cord injury has been shown to increase the risk of ALS/FTD in epidemiological studies. Here, we combine patient-specific induced pluripotent stem cells (iPSCs) with a custom-built device to deliver biofidelic stretch trauma toC9orf72patient and isogenic control motor neurons (MNs)in vitro. We find that mutant but not control MNs exhibit selective degeneration after a single incident of severe trauma, which can be partially rescued by pretreatment with aC9orf72antisense oligonucleotide. A single incident of mild trauma does not cause degeneration but leads to cytoplasmic accumulation of TDP-43 inC9orf72MNs. This mislocalization, which only occurs briefly in isogenic controls, is eventually restored inC9orf72MNs after 6 days. Lastly, repeated mild trauma ablates the ability of patient MNs to recover. These findings highlight alterations in TDP-43 dynamics inC9orf72ALS/FTD patient MNs following traumatic injury and demonstrate that neurotrauma compounds neuropathology inC9orf72ALS/FTD. More broadly, our work establishes anin vitroplatform that can be used to interrogate the mechanistic interactions between ALS/FTD and neurotrauma.
A multi-tissuede novotranscriptome assembly and relative gene expression of the vulnerable freshwater salmonidThymallus ligericus
Authors: Secci-Petretto Giulia , Weiss Steven , Gomes-dos-Santos André , Persat Henri , Machado André M. , Vasconcelos Inês , C. Castro L. Filipe , Froufe Elsa
Published: March 2024

Freshwater ecosystems are among the most endangered worldwide. While numerous taxa are on the verge of extinction as a result of global changes and direct or indirect anthropogenic activity, genomic and transcriptomic resources are a key tool to comprehend species’ adaptability and serve as the foundation for conservation initiatives. The Loire grayling,Thymallus ligericus, is a freshwater European salmonid endemic to the upper Loire River basin. It comprises fragmented populations dispersed over a small area and has been identified as a vulnerable species. Here, we provide a multi-tissuede novotranscriptome assembly ofT. ligericus. The final assembly, with a contig N50 of 1,221 and Benchmarking Universal Single-Copy Orthologs (BUSCO) scores above 94%, is made accessible, along with structural and functional annotations and relative gene expression of five tissues. This is the first transcriptomic resource for this species, and it will serve as the foundation for future research on a species that is increasingly exposed to environmental stressors.