bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling the transmission of antibiotic-resistant Enterobacterales in the community: a systematic review
Authors: Rahbé Eve , Glaser Philippe , Opatowski Lulla 
Published: January 2024

AbstractBackgroundInfections by antibiotic-resistant Enterobacterales are a public health threat worldwide. While dissemination of these opportunistic pathogens has been largely studied in hospitals, less is known about their acquisition and spread in the community. Here, we aim to characterize mechanistic hypotheses and scientific contributions of mathematical modeling studies focusing on antibiotic-resistant Enterobacterales in the community.MethodsWe conducted a systematic review of mathematical modeling studies indexed in PubMed and focusing on the transmission of antibiotic-resistant Enterobacterales in the community (i.e., excluding models only specific to hospitals). For each study, we extracted model features (host population, setting), formalism (compartmental, individual-based), biological hypotheses (transmission, infection, antibiotic use impact, resistant strain specificities) and main findings. We discussed additional mechanisms to be considered, open scientific questions, and most pressing data needs to further improve upon existing epidemiological modeling.ResultsWe identified 18 modeling studies focusing on the human transmission of antibiotic-resistant Enterobacterales in the community (n=11) or in both community and hospital (n=7). Models aimed at: (i) understanding mechanisms driving resistance dynamics; (ii) identifying and quantifying transmission routes; or (iii) evaluating public health interventions to reduce resistance. Studies highlighted that community transmission, compared to hospital transmission, play a significant role in the overall acquisition of antibiotic-resistantEscherichia coli. Predictions across models regarding the success of public health interventions to reduce resistance rates depended on pathogens, settings, and antibiotic resistance mechanisms. ForE. coli, lowered person-to-person transmission led to greater reduction in antibiotic resistance rates compared to lowered antibiotic use in the community (n=2). ForKlebsiella pneumoniaelowered antibiotic use in the hospital led to greater reduction compared to lowered use in the community (n=2). Finally, we reported a moderate number of modeling studies inferring parameters from empirical data (n=9), probably due to a critical lack of available data for antibiotic resistance rates in the community.ConclusionsWe found a limited number of modeling studies addressing the transmission of antibiotic-resistant Enterobacterales in the community, highlighting a need for model development and extensive community-based data collection. Such modeling will be critical to better understand the spread of antibiotic-resistant Enterobacterales in the community and design public health interventions specific to this setting.
Establishment of a novel amyotrophic lateral sclerosis patient-derived blood-brain barrier model: Investigating barrier dysfunction and immune cell interaction
Authors: Matsuo Kinya , Nagata Kazuhiro , Umeda Ryusei , Shiota Takaya , Morimoto Satoru , Suzuki Naoki , Aoki Masashi , Okano Hideyuki , Nakamori Masayuki , Nishihara Hideaki 
Published: January 2024

AbstractAmyotrophic lateral sclerosis (ALS) is a major neurodegenerative disease for which there is currently no effective treatment. The main feature of the disease is the loss of motor neurons in the central nervous system (CNS), but other CNS components and the immune system also appear to be involved in the pathogenesis of the disease. The blood-brain barrier (BBB) is formed by specialized brain microvascular endothelial cells (BMECs) and plays a crucial role in maintaining homeostasis within the central nervous system (CNS). Autopsy studies have reported BBB abnormalities in ALS patients, and studies in animal models suggest that BBB breakdown may precede neurodegeneration. However, the difficulty of obtaining patient samples has hampered further studies. We used the method of differentiating BMEC-like cells from human induced pluripotent stem cells (hiPSCs), which have robust barrier functions and express adhesion molecules necessary for immune cell adhesion, to investigate BBB functions in ALS patients. We also established a method using automated analysis techniques to analyze immune cell adhesion to the BBB in multiple samples simultaneously and with minimal bias. BMEC-like cells derived from ALS patients carryingTARDBPN345K/WTmutations exhibited increased permeability to small molecules due to loss of tight junction, as well as increased expression of cell surface adhesion molecules, leading to enhanced immune cell adhesion. BMEC-like cells derived from hiPSCs with other types ofTARDBPgene mutations (TARDBPK263E/K263EandTARDBPG295S/G295S) introduced by genome editing technology did not show such BBB dysfunction compared to the isogenic control. These results indicate that our model can recapitulate BBB abnormalities reported in ALS patients using patient (TARDBPN345K/WT) -derived hiPSCs and that two types of missense mutation,TARDBPK263E/K263EandTARDBPG295S/G295S, do not contribute to the BBB dysfunction. This novel ALS patient-derived BBB model is useful for the challenging analysis of the involvement of BBB dysfunction in the pathogenesis and to promote therapeutic drug discovery.
Global view of domain-specific O-linked mannose glycosylation in glycoengineered cells
Authors: Povolo Lorenzo , Tian Weihua , Vakhrushev Sergey Y. , Halim Adnan 
Published: January 2024

AbstractProtein O-linked mannose (O-Man) glycosylation is an evolutionary conserved post-translational modification (PTM) that fulfills important biological roles during embryonic development. Three non-redundant enzyme families, POMT1/POMT2, TMTC1-4 and TMEM260, selectively coordinate the initiation of protein O-Man glycosylation on distinct classes of transmembrane proteins, including α-dystroglycan, cadherins and plexin receptors. However, a systematic investigation of their substrate specificities is lacking, in part due to the ubiquitous expression of O-Man glycosyltransferases in cells, which precludes analysis of pathway-specific O-Man glycosylation on a proteome-wide scale. Here, we apply a targeted workflow for membrane glycoproteomics across five human cell lines to extensively map O-Man substrates and genetically deconstruct O-Man initiation by individual and combinatorial knock-out (KO) of O-Man glycosyltransferase genes. We established a human cell library for analysis of substrate specificities of individual O-Man initiation pathways by quantitative glycoproteomics. Our results identify 180 O-Man glycoproteins, demonstrate new protein targets for the POMT1/POMT2 pathway and show that TMTC1-4 and TMEM260 pathways widely target distinct Ig-like protein domains of plasma membrane proteins involved in cell-cell and cell-extracellular matrix interactions. The identification of O-Man on Ig-like folds adds further knowledge on the emerging concept of domain-specific O-Man glycosylation which opens for functional studies of O-Man glycosylated adhesion molecules and receptors.
Direct Measurement of 8OGsyn-antiFlips in Mutagenic 8OG•A and Long-Range Damage-Dependent Hoogsteen Breathing Dynamics Using1H CEST NMR
Authors: Gu Stephanie , Al-Hashimi Hashim M. 
Published: January 2024

ABSTRACTElucidating how damage impacts DNA dynamics is essential for understanding the mechanisms of damage recognition and repair. Many DNA lesions alter the propensities to form lowly-populated and short-lived conformational states. However, NMR methods to measure these dynamics require isotopic enrichment, which is difficult for damaged nucleotides. Here, we demonstrate the utility of the1H chemical exchange saturation transfer (CEST) NMR experiment in measuring the dynamics of oxidatively damaged 8-oxoguanine (8OG) in the mutagenic 8OGsyn•Aantimismatch. Using 8OG-H7 as an NMR probe of the damaged base, we directly measured 8OGsyn-antiflips to form a lowly-populated (pop. ∼ 5%) and short-lived (lifetime ∼ 50 ms) non-mutagenic 8OGanti•Aanti. These exchange parameters were in quantitative agreement with values from13C off-resonanceR1ρand CEST on a labeled partner adenine. The Watson-Crick-like 8OGsyn•Aantimismatch also rescued the kinetics of Hoogsteen motions at distance A-T base pairs, which the G•A mismatch had slowed down. The results lend further support for 8OGanti•Aantias a minor conformational state of 8OG•A, reveal that 8OG damage can impact Hoogsteen dynamics at a distance, and demonstrate the utility of1H CEST for measuring damage-dependent dynamics in unlabeled DNA.
Translational validation of shotgun proteomics findings in cerebrospinal fluid of sporadic cerebral amyloid angiopathy patients
Authors: Vervuurt Marc , de Kort Anna M. , Kersten Iris , Rens Astrid van , Klijn Catharina J. M. , Schreuder Floris H. B. M. , Lefeber Dirk J. , Kuiperij H. Bea , Verbeek Marcel M. 
Published: January 2024

AbstractBackgroundPrior research conducted in model rats of CAA Type 1 (rTg-DI) identified a range of cerebrospinal fluid biomarker candidates associated with sCAA pathology. This list of potential biomarkers includes the lysosomal proteases cathepsins B and S (CTSB/CTSS) and hexosaminidase B (HEXB). It is yet unknown if these findings obtained in rTg-DI rats translate to differential protein levels and/or enzyme activities in cerebrospinal fluid (CSF) of sCAA patients. In this study, we attempted to validate CTSB, CTSS and HEXB in CSF as potential biomarkers for sCAA in a human population.Materials and methodsWe have included sCAA patients (n = 34) and control participants (n = 27) from our BIONIC/CAFE cohort. We analysed the CSF of these participants with ELISA for protein levels of CTSB and CTSS. Additionally, we used in-house enzyme assays to determine activity levels of total hexosaminidase and hexosaminidase A (HEXA) in CSF. The proportion of HEXA activity to total HEX activity was used as a proxy for HEXB activity.ResultsCSF CTSB and CTSS protein levels were not significantly different between sCAA and controls (p = 0.21 and p = 0.34). Total HEX activity was unaltered as well (p = 0.11), whereas a significant decrease was observed in HEXA activity levels (p = 0.05). HEXA / total HEX activity levels (as a proxy for HEXB activity) were unaltered between sCAA patients and controls (p = 0.19). Additionally, CTSB and CTSS protein levels positively associated with total HEX activity (rsp= 0.37, p = 0.005; rsp= 0.40, p = 0.003).ConclusionThe contrasting results between biomarker discovery in rats and validation in human participants highlight the challenges and complexities of biomarker research. These findings offer valuable insights into the nuances of disease and the difficulties in translating laboratory findings using animal models to clinical practice. Understanding these discrepancies is essential for improving the precision of biomarker translation, ensuring clinical relevance, and developing comprehensive biomarker panels for CAA and related conditions.
Projection-Targeted Photopharmacology Reveals Distinct Anxiolytic Roles for Presynaptic mGluR2 in Prefrontal- and Insula-Amygdala Synapses
Authors: Munguba Hermany , Gutzeit Vanessa A. , Srivastava Ipsit , Kristt Melanie , Singh Ashna , Vijay Akshara , Arefin Anisul , Thukral Sonal , Broichhagen Johannes , Stujenske Joseph M. , Liston Conor , Levitz Joshua 
Published: January 2024

AbstractDissecting how membrane receptors regulate neural circuit function is critical for deciphering basic principles of neuromodulation and mechanisms of therapeutic drug action. Classical pharmacological and genetic approaches are not well-equipped to untangle the roles of specific receptor populations, especially in long-range projections which coordinate communication between brain regions. Here we use viral tracing, electrophysiological, optogenetic, and photopharmacological approaches to determine how presynaptic metabotropic glutamate receptor 2 (mGluR2) activation in the basolateral amygdala (BLA) alters anxiety-related behavior. We find that mGluR2-expressing neurons from the ventromedial prefrontal cortex (vmPFC) and posterior insular cortex (pIC) preferentially target distinct cell types and subregions of the BLA to regulate different forms of avoidant behavior. Using projection-specific photopharmacological activation, we find that mGluR2-mediated presynaptic inhibition of vmPFC-BLA, but not pIC-BLA, connections can produce long-lasting decreases in spatial avoidance. In contrast, presynaptic inhibition of pIC-BLA connections decreased social avoidance, novelty-induced hypophagia, and increased exploratory behavior without impairing working memory, establishing this projection as a novel target for the treatment of anxiety disorders. Overall, this work reveals new aspects of BLA neuromodulation with therapeutic implications while establishing a powerful approach for optical mapping of drug action via photopharmacology.Highlights- Basolateral amygdala is a key site for anxiolytic action of mGluR2 agonism- BLA receives dense Grm2+inputs from ventromedial prefrontal cortex and posterior insular cortex- Photoactivation of mGluR2 has distinct anxiolytic effects in vmPFC-BLA and pIC-BLA synapses- Grm2+vmPFC and pIC projections target medial and lateral BLA subregions, respectively
Superiority of chromosomal compared to plasmid-encoded compensatory mutations
Authors: Wright Rosanna C.T. , Wood A. Jamie , Bottery Michael J. , Muddiman Katie J. , Paterson Steve , Harrison Ellie , Brockhurst Michael A. , Hall James P.J. 
Published: January 2024

AbstractPlasmids are important vectors of horizontal gene transfer in microbial communities but can impose a burden on the bacteria that carry them. Such plasmid fitness costs are thought to arise principally from conflicts between chromosomal- and plasmid-encoded molecular machineries, and thus can be ameliorated by compensatory mutations (CMs) that reduce or resolve the underlying causes. CMs can arise on plasmids (i.e. plaCM) or on chromosomes (i.e. chrCM), with contrasting predicted effects upon plasmid success and subsequent gene transfer because plaCM can also reduce fitness costs in plasmid recipients, whereas chrCM can potentially ameliorate multiple distinct plasmids. Here, we develop theory and a novel experimental system to directly compare the ecological effects of plaCM and chrCM that arose during evolution experiments betweenPseudomonas fluorescensSBW25 and its sympatric mercury resistance megaplasmid pQBR57. We show that while plaCM was predicted to succeed under a broader range of parameters in mathematical models, experimentally chrCM dominated under all conditions, including those with numerous recipients, due to a more efficacious mechanism of compensation, and advantages arising from transmission of costly plasmids to competitors (plasmid ‘weaponisation’). We show analytically the presence of a mixed Rock-Paper-Scissors regime for plaCM, driven by trade-offs with horizontal transmission, that explains the observed failure of plaCM to dominate even in competition against an uncompensated plasmid. Our results reveal broader implications of plasmid-bacterial evolution for plasmid ecology, demonstrating the importance of compensatory mutations for resistance gene spread. One consequence of the superiority of chrCM over plaCM is the likely emergence in microbial communities of compensated bacteria that can act as ‘hubs’ for plasmid accumulation and dissemination.
Loss of primary cilia and dopaminergic neuroprotection in pathogenic LRRK2-driven and idiopathic Parkinson’s disease
Authors: Khan Shahzad S. , Jaimon Ebsy , Lin Yu-En , Nikoloff Jonas , Tonelli Francesca , Alessi Dario R. , Pfeffer Suzanne R. 
Published: January 2024

AbstractActivating LRRK2 mutations cause Parkinson’s disease. Previously, we showed that cholinergic interneurons and astrocytes but not medium spiny neurons of the dorsal striatum lose primary cilia in LRRK2 mutant mice. Single nucleus RNA sequencing shows that cilia loss in cholinergic interneurons correlates with higher LRRK2 expression and decreased glial derived neurotrophic factor transcription. Nevertheless, much higher LRRK2 expression is seen in medium spiny neurons that have normal cilia in mice and humans. In parallel with decreased striatal dopaminergic neurite density, LRRK2 G2019S neurons show increased autism-linked CNTN5 adhesion protein expression; glial cells show significant loss of ferritin heavy chain. Human striatal tissue from LRRK2 pathway mutation carriers and idiopathic Parkinson’s disease show similar cilia loss in cholinergic interneurons and astrocytes and overall loss of such neurons. These data strongly suggest that loss of cilia in specific striatal cell types decreases neuroprotection for dopamine neurons in mice and human Parkinson’s disease.TeaserCilia loss in Parkinson’s disease decreases dopaminergic neuroprotection due to inability to sense Hedgehog signals
Gene editing of pigs to control influenza A virus infections
Authors: Kwon Taeyong , Artiaga Bianca L. , McDowell Chester D. , Whitworth Kristin M. , Wells Kevin D. , Prather Randall S. , Delhon Gustavo , Cigan Mark , White Stephen N. , Retallick Jamie , Gaudreault Natasha N. , Morozov Igor , Richt Juergen A. 
Published: January 2024

AbstractProteolytic activation of the hemagglutinin (HA) glycoprotein by host cellular proteases is pivotal for influenza A virus (IAV) infectivity. Highly pathogenic avian influenza viruses possess the multibasic cleavage site of the HA which is cleaved by ubiquitous proteases, such as furin; in contrast, the monobasic HA motif is recognized and activated by trypsin-like proteases, such as the transmembrane serine protease 2 (TMPRSS2). Here, we aimed to determine the effects of TMPRSS2 on the replication of pandemic H1N1 and H3N2 subtype IAVs in the natural host, the pig. The use of the CRISPR/Cas 9 system led to the establishment of homozygous gene edited (GE)TMPRSS2knockout (KO) pigs. Delayed IAV replication was demonstrated in primary respiratory cells of KO pigsin vitro. IAV infectionin vivoresulted in significant reduction of virus shedding in the upper respiratory tract, and lower virus titers and pathological lesions in the lower respiratory tract ofTMPRSS2KO pigs as compared to WT pigs. Our findings could support the commercial use of GE pigs to minimize (i) the economic losses caused by IAV infection in pigs, and (ii) the emergence of novel IAVs with pandemic potential through genetic reassortment in the “mixing vessel”, the pig.
Invariant neural representation of parts of speech in the human brain
Authors: Misra Pranav , Shih Yen-Cheng , Yu Hsiang-Yu , Weisholtz Daniel , Madsen Joseph R , Sceillig Stone , Kreiman Gabriel 
Published: January 2024

AbstractElucidating the internal representation of language in the brain has major implications for cognitive science, brain disorders, and artificial intelligence. A pillar of linguistic studies is the notion that words have defined functions, often referred to as parts of speech. Here we recorded invasive neurophysiological responses from 1,801 electrodes in 20 patients with epilepsy while they were presented with two-word phrases consisting of an adjective and a noun. We observed neural signals that distinguished between these two parts of speech. The selective signals were circumscribed within a small region in the left lateral orbitofrontal cortex. The representation of parts of speech showed invariance across visual and auditory presentation modalities, robustness to word properties like length, order, frequency, and semantics, and even generalized across different languages. This selective, invariant, and localized representation of parts of speech for nouns versus adjectives provides elements for the compositional processes of language.
“You’ve actually got two patients, you haven’t got one”: parent-informed criteria for evaluating the autism assessment process
Authors: Burden Daisy Grace 
Published: January 2024

Purpose
Parents whose children have undergone an autism assessment often describe the process as extremely stressful. This affects how parents engage with services post-diagnosis, meaning less likelihood of using subsequent service support despite struggling to cope. Since parents already report many barriers to accessing services, e.g. long waiting lists, lack of co-ordination and limited resources (Sapiets et al. 2023), negative experiences during assessment should not pose another potential barrier to engagement. This study aimed to address how families’ needs can be better met during the assessment process.

Design/methodology/approach
In this qualitative study, the author conducted semi-structured interviews with 11 parents whose child had undergone an autism assessment in the last five years. Thematic analysis determined key themes.

Findings
The six themes were: clarity and communication, access to support and resources, aftercare, recognition of parent concerns, personalisation of the assessment process and concerns around the use of personal protective equipment/online assessments. These themes led to criteria to assess the quality of autism assessment services in line with parent perspectives.

Practical implications
These parent-informed criteria could facilitate the consideration of parents’ views into service evaluations of autism assessment services across the UK.

Originality/value
Previous research indicates that the autism assessment experience is often extremely stressful and overwhelming for families (Crane et al., 2016). Despite this, guidance to improve autism services rarely prioritises the opinions and experiences of service-users and their families. The criteria presented here were derived from themes identified by interviewing parents on their experiences of the autism assessment process, thus shifting the focus onto service-users.