bluuebunny/crossref_metadata_2025_split huggingface dataset:
An anti-virulence drug targeting the evolvability protein Mfd protects against infections with antimicrobial resistant ESKAPE pathogens
Authors: Tran SL. , Lebreuilly L. , Cormontagne D. , Samson S. , Tô TB. , Dervyn R. , Grießhammer A. , de la Cuesta-Zuluaga J. , Maier L. , Naas T. , Mura S. , Nicolas J. , Rognan D. , André G. , Ramarao N. 
Published: January 2024

AbstractThe increased incidence of antibiotic resistance and declining discovery of new antibiotics have created a global health crisis, especially for the treatment of infections caused by Gram-negative bacteria. Here, we identify and characterize a molecule, NM102, that displays antimicrobial activity exclusively in the context of infection. NM102 inhibits the activity of the non-essential Mutation Frequency Decline (Mfd) protein by competing with ATP binding to its active site. Inhibition of Mfd by NM102 sensitizes pathogenic bacteria to the host immune response and blocks infections with clinically- relevantKlebsiella pneumoniaeandPseudomonas aeruginosa, without inducing host toxicity. Finally, NM102 inhibits the function of Mfd as a mutation and evolvability factor, thus reducing the bacterial capacity to develop antimicrobial resistance. These data provide a potential roadmap to expand the arsenal of drugs to combat antimicrobial resistance.HighlightNM102 is a “first in class” molecule specifically targeting the active site of the bacterial Mfd proteinNM102 has a new mode of action: it inhibits Mfd function during immune stress responseNM102 also inhibits Mfd evolvability function and thereby decreases bacterial resistance to known antibioticsNM102 effectively treats Gram-negative infections in animal modelsNM102 is efficient against clinically relevant resistant bacteria and provides an increased efficacy in combination with the β-lactam meropenem
Antigen-specific age-related memory CD8 T cells induce and track Alzheimer’s-like neurodegeneration
Authors: Panwar Akanksha , Rentsendorj Altan , Jhun Michelle , Cohen Robert M. , Cordner Ryan , Gull Nicole , Pechnick Robert N. , Duvall Gretchen , Mardiros Armen , Golchian David , Schubloom Hannah , Jin Lee-Way , Van Dam Debby , Vermeiren Yannick , De Reu Hans , De Deyn Peter Paul , Raskatov Jevgenij A. , Black Keith L. , Irvin Dwain K. , Williams Brian A. , Wheeler Christopher J. 
Published: January 2024

AbstractCerebral (Aβ) plaque and (pTau) tangle deposition are hallmarks of Alzheimer’s disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of Aβ/pTau in AD remain unknown, but their identification could enable earlier diagnosis and more effective treatments. T cell abnormalities are emerging AD hallmarks, and CD8 T cells were recently found to mediate neurodegeneration downstream of tangle deposition in hereditary neurodegeneration models. The precise impact of T cells downstream of Aβ/fibrillar pTau, however, appears to vary depending on the animal model used. Our prior work suggested that antigen-specific memory CD8 T (“hiT”) cells act upstream of Aβ/pTau after brain injury. Here we examine whetherhiT cells influence sporadic AD-like pathophysiology upstream of Aβ/pTau. Examining neuropathology, gene expression, and behavior in ourhiT mouse model we show that CD8 T cells induce plaque and tangle-like deposition, modulate AD-related genes, and ultimately result in progressive neurodegeneration with both gross and fine features of sporadic human AD. T cells required Perforin to initiate this pathophysiology, and IFNγ for most gene expression changes and progression to more widespread neurodegenerative disease. Analogous antigen-specific memory CD8 T cells were significantly elevated in the brains of human AD patients, and their loss from blood corresponded to sporadic AD and related cognitive decline better than plasma pTau-217, a promising AD biomarker candidate. Our work is the first to identify an age-related factor acting upstream of Aβ/pTau to initiate AD-like pathophysiology, the mechanisms promoting its pathogenicity, and its relevance to human sporadic AD.Significance StatementThis study changes our view of Alzheimer’s Disease (AD) initiation and progression. Mutations promoting cerebral beta-amyloid (Aβ) deposition guarantee rare genetic forms of AD. Thus, the prevailing hypothesis has been that Aβ is central to initiation and progression of all AD, despite contrary animal and patient evidence. We show that age-related T cells generate neurodegeneration with compelling features of AD in mice, with distinct T cell functions required for pathological initiation and neurodegenerative progression. Knowledge from these mice was applied to successfully predict previously unknown features of human AD and generate novel tools for its clinical management.
FicD Sensitizes Cellular Response to Glucose Fluctuations in Mouse Embryonic Fibroblasts
Authors: Gulen Burak , Kinch Lisa N. , Servage Kelly A. , Blevins Aubrie , Stewart Nathan M. , Gray Hillery F. , Casey Amanda K. , Orth Kim 
Published: January 2024

AbstractDuring homeostasis, the endoplasmic reticulum (ER) maintains productive transmembrane and secretory protein folding that is vital for proper cellular function. The ER-resident HSP70 chaperone, BiP, plays a pivotal role in sensing ER stress to activate the unfolded protein response (UPR). BiP function is regulated by the bifunctional enzyme FicD that mediates AMPylation and deAMPylation of BiP in response to changes in ER stress. AMPylated BiP acts as a molecular rheostat to regulate UPR signaling, yet little is known about the molecular consequences of FicD loss. In this study, we investigate the role of FicD in mouse embryonic fibroblast (MEF) response to pharmacologically and metabolically induced ER stress. We find differential BiP AMPylation signatures when comparing robust chemical ER stress inducers to physiological glucose starvation stress and recovery. Wildtype MEFs respond to pharmacological ER stress by downregulating BiP AMPylation. Conversely, BiP AMPylation in wildtype MEFs increases upon metabolic stress induced by glucose starvation. Deletion of FicD results in widespread gene expression changes under baseline growth conditions. In addition, FicD null MEFs exhibit dampened UPR signaling, altered cell stress recovery response, and unconstrained protein secretion. Taken together, our findings indicate that FicD is important for tampering UPR signaling, stress recovery, and the maintenance of secretory protein homeostasis.Significance StatementThe chaperone BiP plays a key quality control role in the endoplasmic reticulum, the cellular location for the production, folding, and transport of secreted proteins. The enzyme FicD regulates BiP’s activity through AMPylation and deAMPylation. Our study unveils the importance of FicD in regulating BiP and the unfolded protein response (UPR) during stress. We identify distinct BiP AMPylation signatures for different stressors, highlighting FicD’s nuanced control. Deletion of FicD causes widespread gene expression changes, disrupts UPR signaling, alters stress recovery, and perturbs protein secretion in cells. These observations underscore the pivotal contribution of FicD for preserving secretory protein homeostasis. Our findings deepen the understanding of FicD’s role in maintaining cellular resilience and open avenues for therapeutic strategies targeting UPR-associated diseases.
The cost and payout of age on germline regeneration and sexual maturation inPlatynereis dumerilii
Authors: Metzger Bria , Özpolat B. Duygu 
Published: January 2024

ABSTRACTRegeneration, regrowing lost and injured body parts, is an ability that generally declines with age or developmental transitions (i.e. metamorphosis, sexual maturation) in many organisms. Regeneration is also energetically a costly process, and trade-offs occur between regeneration and other costly processes such as somatic growth, or sexual reproduction. Here we investigate the interplay of regeneration, reproduction, and age in the segmented wormPlatynereis dumerilii.P. dumeriliican regenerate its whole posterior body axis, along with its reproductive cells, thereby having to carry out the two costly processes (somatic and germ cell regeneration) after injury. We specifically examine how age affects the success of germ cell regeneration and sexual maturation in developmentally young versus old organisms. We hypothesized that developmentally younger individuals (i.e. lower investment state, with gametes in early mitotic stages) will have higher regeneration success and reach sexual maturation faster than the individuals at developmentally older stages (i.e. higher investment state, with gametes in the process of maturation). Surprisingly, older amputated worms grew faster and matured earlier than younger amputees, even though they had to regenerate more segments and recuperate the more costly germ cells which were already starting to undergo gametogenesis. To analyze germ cell regeneration across stages, we used Hybridization Chain Reaction for the germline markervasa. We found that regenerated worms start repopulating new segments with germ cell clusters as early as 14 days post amputation. In addition,vasaexpression is observed in a wide region of newly-regenerated segments, which appears different from expression patterns during normal growth or regeneration in worms before gonial cluster expansion. Future studies will focus on determining the exact sources of gonial clusters in regeneration.FundingNIGMS 1R35GM138008-01, Hibbitt Fellowship, WashU Startup funds
JAK/STAT signaling promotes the emergence of unique cell states in ulcerative colitis
Authors: Maciag Grzegorz , Hansen Stine Lind , Krizic Kata , Kellermann Lauge , Ulyanchenko Svetlana , Maimets Martti , Baattrup Astrid Møller , Riis Lene Buhl , Khodosevich Konstantin , Sato Toshiro , Nielsen Ole Haagen , Jensen Kim B. 
Published: January 2024

SummaryThe intestinal epithelium forms a barrier to the lumen and ensures uptake of vital nutrients. During inflammatory diseases, such as ulcerative colitis (UC), this barrier is compromised. Here, we perform single-cell RNA sequencing (scRNA-seq) of epithelial cells and outline patterns of cell fate decisions in healthy individuals and patients with UC. We demonstrate that lineage biased progenitors are major sources of normal tissue replenishment, and that patterns of cell behavior are profoundly altered in UC. We furthermore identify unique regenerative cell states linked to JAK/STAT activation extending into the non-inflamed areas of the colon. In organoid models, this can be mimicked by cytokine mediated activation of JAK/STAT leading to the emergence of cell populations with regenerative potential. These findings have profound implications for our understanding of tissue regeneration and illustrates how cytokine signaling influences cell fate decisions. This suggests widespread consequences in patients with chronic ulcerative conditions.
Randomizing the human genome by engineering recombination between repeat elements
Authors: Koeppel Jonas , Ferreira Raphael , Vanderstichele Thomas , Riedmayr Lisa M. , Peets Elin Madli , Girling Gareth , Weller Juliane , Liberante Fabio Giuseppe , Ellis Tom , Church George M. , Parts Leopold 
Published: January 2024

AbstractWhile protein-coding genes are characterized increasingly well, 99% of the human genome is non-coding and poorly understood. This gap is due to a lack of tools for engineering variants that affect sequence to the necessary extent. To bridge this gap, we have developed a toolbox to create deletions, inversions, translocations, and extrachromosomal circular DNA at scale by highly multiplexed insertion of recombinase recognition sites into repetitive sequences with CRISPR prime editing. Using this strategy, we derived stable human cell lines with several thousand clonal insertions, the highest number of novel sequences inserted into single human genomes. Subsequent recombinase induction generated an average of more than one hundred megabase-sized rearrangements per cell, and thousands across the whole population. The ability to detect rearrangements as they are generated and to track their abundance over time allowed us to measure the selection pressures acting on different types of structural changes. We observed a consolidation towards shorter variants that preferentially delete growth-inhibiting genes and a depletion of translocations. We isolated and characterized 21 clones with multiple recombinase-induced rearrangements. These included viable haploid clones with deletions that span hundreds of kilobases as well as triploid HEK293T clones with aneuploidies and fold back chromosomes. We mapped the impact of these genetic changes on gene expression to decipher how structural variants affect gene regulation. The genome scrambling strategy developed here makes it possible to delete megabases of sequence, move sequences between and within chromosomes, and implant regulatory elements into new contexts which will shed light on the genome organization principles of humans and other species.
Genetic polymorphism and evidence of signatures of selection in thePlasmodium falciparumcircumsporozoite protein gene in Tanzanian regions with different malaria endemicity
Authors: Lyimo Beatus M. , Bakari Catherine , Popkin-Hall Zachary R. , Giesbrecht David J. , Seth Misago D. , Pereus Dativa , Moshi Ramadhan , Boniface Ruth , Mandara Celine I. , Madebe Rashid , Juliano Jonathan J. , Bailey Jeffrey A. , Ishengoma Deus S. 
Published: January 2024

AbstractBackgroundIn 2021 and 2023, the World Health Organization approved RTS,S/AS01 and R21/Matrix M malaria vaccines, respectively, for routine immunization of children in African countries with moderate to high transmission. These vaccines are made ofPlasmodium falciparumcircumsporozoite protein (Pfcsp)but polymorphisms in this gene raises concerns regarding strain-specific responses and the long-term efficacy of these vaccines. This study assessed thePfcspgenetic diversity, population structure and signatures of selection among parasites from areas of different malaria transmission in mainland Tanzania, to generate baseline data before the introduction of the malaria vaccines in the country.MethodsThe analysis involved 589 whole genome sequences generated by and as part of the MalariaGEN Community Project. The samples were collected between 2013 and January 2015 from five regions of mainland Tanzania: Morogoro and Tanga (Muheza) (moderate transmission areas), and Kagera (Muleba), Lindi (Nachingwea), and Kigoma (Ujiji) (high transmission areas). Wright’s inbreeding coefficient (Fws), Wright’s fixation index (FST), principal component analysis, nucleotide diversity, and Tajima’s D were used to assess within-host parasite diversity, population structure and natural selection.ResultsBased on Fws(< 0.95), there was high polyclonality (ranged from 69.23% in Nachingwea to 56.9% in Muheza). No population structure was detected in thePfcspgene in the five regions (mean FST= 0.0068). The average nucleotide diversity (π), nucleotide differentiation (K) and haplotype diversity (Hd) in the five regions were 4.19, 0.973 and 0.0035, respectively. The C-terminal region ofPfcspshowed high nucleotide diversity at Th2R and Th3R regions. Positive values for the Tajima’s D were observed in the Th2R and Th3R regions consistent with balancing selection. ThePfcspC-terminal sequences had 50 different haplotypes (H_1 to H_50) and only 2% of sequences matched the 3D7 strain haplotype (H_50).ConclusionsThe findings demonstrate high diversity of thePfcspgene with limited population differentiation. ThePfcspgene showed positive Tajima’s D values for parasite populations, consistent with balancing selection for variants within Th2R and Th3R regions. This data is consistent with other studies conducted across Africa and worldwide, which demonstrate low 3D7 haplotypes and little population structure. Therefore, additional research is warranted, incorporating other regions and more recent data to comprehensively assess trends in genetic diversity within this important gene. Such insights will inform the choice of alleles to be included in the future vaccines
Face-brain correlates as potential sex-specific biomarkers for schizophrenia and bipolar disorder
Authors: Hostalet Noemí , González Alejandro , Gonzàlez-Colom Rubèn , Salgado-Pineda Pilar , Canales-Rodríguez Erick J , Aguirre Candibel , Guerrero-Pedraza Amalia , Llanos-Torres María , Salvador Raymond , Pomarol-Clotet Edith , Sevillano Xavier , Martínez-Abadías Neus , Fatjó-Vilas Mar 
Published: January 2024

ABSTRACTGiven the shared ectodermal origin and integrated development of the face and the brain, facial biomarkers emerge as potential candidates to assess vulnerability for disorders in which neurodevelopment is compromised, such as Schizophrenia (SZ) and bipolar disorder (BD).The sample comprised 188 individuals (67 SZ patients, 46 BD patients and 75 healthy controls (HC)). Using a landmark-based approach on 3D facial reconstructions, we quantified global and local facial shape differences between SZ/BD patients and HC using geometric morphometrics. We assessed correlations between facial and brain cortical measures. The analyses were performed separately by sex.Diagnosis explained 4.1% - 5.9% of global facial shape variance in males and females with SZ, and 4.5% - 4.1% in BD. Regarding local facial shape, we detected 43.2% of significantly different distances in males and 47.4% in females with SZ compared to HC, whereas in BD the percentages decreased to 35.8% and 26.8%, respectively. We detected that brain area and volume significantly explained 2.2% and 2% of facial shape variance in the male SZ - HC sample.Our results support facial shape as a neurodevelopmental marker for SZ and BD and reveal sex- specific pathophysiological mechanisms modulating the interplay between the brain and the face.
Deep phenotyping of patient lived experience in functional bowel disorders
Authors: Ruffle James K. , Henderson Michelle , Ng Cho Ee , Liddle Trevor , Nelson Amy P. K. , Nachev Parashkev , Knowles Charles H , Yiannakou Yan 
Published: January 2024

AbstractClinical management relies on a diagnostic label as the primary guide to treatment. However, individual patients’ lived experiences vary more widely than standard diagnostic categories reflect. This is especially true for functional bowel disorders (FBDs), a heterogeneous and challenging group of gastrointestinal disorders where no definitive diagnostic tests, clinical biomarkers, or universally effective treatments exist. Characterising the link between disease and lived experience - in the face of marked patient heterogeneity - requires deep phenotyping of the interactions between multiple characteristics plausibly achievable only with complex modelling approaches. In a large patient cohort (n=1175), we developed a machine learning and Bayesian generative graph framework to better understand the lived experience of FBDs. Iterating through 59 factors available from routine clinical care, spanning patient demography, diagnosis, symptomatology, life impact, mental health indices, healthcare access requirements, COVID-19 impact, and treatment effectiveness, machine models were used to quantify the predictive fidelity of one feature from the remainder. Bayesian stochastic block models were used to delineate the network community structure underpinning the heterogeneous lived experience of FBDs. Machine models quantified patient personal health rating (R20.35), anxiety and depression severity (R20.54), employment status (balanced accuracy 96%), frequency of healthcare attendance (R20.71), and patient-reported treatment effectiveness variably (R2range 0.08-0.41). Contrary to the view of many healthcare professionals, the greatest determinants of patient-reported health and quality-of-life were life impact, mental well-being, employment status, and age, rather than diagnostic group and symptom severity. Patients responsive to one treatment were more likely to respond to another, leaving many others refractory to all. Clinical assessment of patients with FBDs should be less concerned with diagnostic classification than with the wider life impact of illness, including mental health and employment. The stratification of treatment response (and resistance) has implications for clinical practice and trial design, in need of further research.
Off-body Sleep Analysis for Predicting Adverse Behavior in Individuals with Autism Spectrum Disorder
Authors: Kiarashi Yashar , Suresha Pradyumna B , Rad Ali Bahrami , Reyna Matthew A , Anderson Conor , Foster Jenny , Lantz Johanna , Villavicencio Tania , Hamlin Theresa , Clifford Gari D 
Published: January 2024

AbstractPoor sleep quality in Autism Spectrum Disorder (ASD) individuals is linked to severe daytime behaviors. This study explores the relationship between a prior night’s sleep structure and its predictive power for next-day behavior in ASD individuals. The motion was extracted using a low-cost near-infrared camera in a privacy-preserving way. Over two years, we recorded overnight data from 14 individuals, spanning over 2,000 nights, and tracked challenging daytime behaviors, including aggression, self-injury, and disruption. We developed an ensemble machine learning algorithm to predict next-day behavior in the morning and the afternoon. Our findings indicate that sleep quality is a more reliable predictor of morning behavior than afternoon behavior the next day. The proposed model attained an accuracy of 74% and a F1 score of 0.74 in target-sensitive tasks and 67% accuracy and 0.69 F1 score in target-insensitive tasks. For 7 of the 14, better-than-chance balanced accuracy was obtained (p-value<0.05), with 3 showing significant trends (p-value<0.1). These results suggest off-body, privacy-preserving sleep monitoring as a viable method for predicting next-day adverse behavior in ASD individuals, with the potential for behavioral intervention and enhanced care in social and learning settings.
Prevalence and types of strabismus in cerebral palsy: A global and historical perspective based on a systematic review and meta-analysis
Authors: Herron Michael S. , Wang Lingchen , von Bartheld Christopher S. 
Published: January 2024

AbstractPurposeStrabismus is more frequent in cerebral palsy (CP) than in the normal population, but reports differ how much it is increased. We here examined the global prevalence and types of strabismus in CP, whether esotropia or exotropia is more frequent, and whether the prevalence differs between ethnicities and/or country income levels, and between generations.MethodsWe compiled in a systematic review and meta-analysis the results of 147 CP studies that report the prevalence of strabismus or the ratio of esotropia to exotropia, and we conducted subgroup analyses for region (income level) and ethnicity. We performed a pooled analysis for the CP strabismus prevalence, and estimated the global number of CP cases with strabismus.ResultsThe pooled prevalence of strabismus in CP is 49.8% in high-income countries and 39.8% in lower-income countries. We estimate the global number of strabismus cases in CP as 12.2 million, with 7.6 million males and 4.6 million females, based on current estimates of 29.6 million global CP cases. Esotropia is more frequent than exotropia in Caucasians, while exotropia is more frequent than esotropia in Hispanic and in some Asian and African populations. The strabismus prevalence in CP increases with increasing country income levels.ConclusionGenerational changes in strabismus prevalence appear to reflect a transition of CP types and an increase in prevalence as countries attain higher income and more effective maternal health care. The distribution of esotropia and exotropia in CP patients largely reflects the horizontal strabismus type that is predominant in the subject’s ethnicity.