bluuebunny/crossref_metadata_2025_split huggingface dataset:
SERPINA11related novel Serpinopathy- a perinatal lethal disorder
Authors: Aggarwal Shagun , Vineeth Venugopal Satidevi , Padwal Shrutika S. , Bhat Sameer Ahmed , Singh Arpita , Kulkarni Aditya , Patil Mallikarjun , Tallapaka Karthik , Pasumarthi Divya , Venkatapuram Vijayasree , Dalal Ashwin , Bhandari Rashna 
Published: October 2023

SummarySERPINA11is a hitherto poorly characterised gene belonging to Clade A of the SERPIN superfamily. The exact functional significance and expression pattern of this gene remains unknown. Here we report a perinatal lethal phenotype associated with biallelic loss of function variants inSERPINA11, and characterised by gross and histopathological features of extracellular matrix disruption. We found SERPINA11 protein expression in multiple mouse tissues and human fetal lungs. Immunofluorescence of the affected fetal lung revealed markedly reduced expression of SERPINA11 protein compared with healthy, gestation matched human fetal lung. Protein expression data from HEK293T cell lines following site directed mutagenesis is also presented to support the loss of function nature of the variant. This novel serpinopathy appears to be a consequence of loss of inhibition of serine proteases involved in extracellular matrix remodelling, revealing SERPINA11 as a protease inhibitor critical for embryonic development.
Evaluating the Human Safety Net: Observational study of Physician Responses to Unsafe AI Recommendations in high-fidelity Simulation
Authors: Festor Paul , Nagendran Myura , Gordon Anthony C. , Faisal A. Aldo , Komorowski Matthieu 
Published: October 2023

ABSTRACTIn the context of Artificial Intelligence (AI)-driven decision support systems for high-stakes environments, particularly in healthcare, ensuring the safety of human-AI interactions is paramount, given the potential risks associated with erroneous AI outputs. To address this, we conducted a prospective observational study involving 38 intensivists in a simulated medical setting.Physicians wore eye-tracking glasses and received AI-generated treatment recommendations, including unsafe ones. Most clinicians promptly rejected unsafe AI recommendations, with many seeking senior assistance. Intriguingly, physicians paid increased attention to unsafe AI recommendations, as indicated by eye-tracking data. However, they did not rely on traditional clinical sources for validation post-AI interaction, suggesting limited “debugging.”Our study emphasises the importance of human oversight in critical domains and highlights the value of eye-tracking in evaluating human-AI dynamics. Additionally, we observed human-human interactions, where an experimenter played the role of a bedside nurse, influencing a few physicians to accept unsafe AI recommendations. This underscores the complexity of trying to predict behavioural dynamics between humans and AI in high-stakes settings.
Wake and non-rapid eye movement sleep dysfunction is associated with colonic neuropathology in Parkinson’s disease
Authors: Sadoc Mathilde , Clairembault Thomas , Coron Emmanuel , Berthomier Christian , Le Dily Séverine , Vavasseur Fabienne , Pavageau Albane , St. Louis Erik K. , Péréon Yann , Neunlist Michel , Derkinderen Pascal , Leclair-Visonneau Laurène 
Published: October 2023

AbstractStudy ObjectivesThe body-first Parkinson’s disease (PD) hypothesis suggests initial gut Lewy body pathology that propagates to the pons before reaching the substantia nigra, and subsequently progresses to the diencephalic and cortical levels. This disease course may also be the most likely in PD with rapid eye movement sleep behavior disorder (RBD).ObjectivesWe aimed to explore the potential association between colonic phosphorylated alpha-synuclein histopathology (PASH) and diencephalic or cortical dysfunction evidenced by non-rapid eye movement (NREM) sleep and wakefulness polysomnographic markers.MethodsIn a study involving 43 patients with PD who underwent clinical examination, rectosigmoidoscopy, and polysomnography, we detected PASH on colonic biopsies using whole-mount immunostaining. We performed a visual semi-quantitative and automated quantification of spindle and slow wave features of NREM sleep, and the wake dominant frequency, and then determined Braak and Arizona stage classifications for PD severity based on sleep and wake electroencephalographic features.ResultsThe visual analysis aligned with the automated quantified spindle characteristics and the wake dominant frequency. Altered NREM sleep and wake parameters correlated with markers of PD severity, colonic PASH, and RBD diagnosis. Colonic PASH frequency also increased in parallel to presumed PD Braak and Arizona stage classifications.ConclusionsColonic PASH in PD is strongly associated with widespread brain sleep and wake dysfunction, pointing toward likely extensive diffusion of the pathological process in the presumptive body-first PD phenotype. Visual and automated analyses of polysomnography signals provide useful markers to gauge covert brain dysfunction in PD.Statement of SignificanceThe presence of gut synucleinopathy in Parkinson’s disease can be linked to the body-first hypothesis in its pathophysiology. This study, performed in a cohort of 43 patients with Parkinson’s disease that underwent clinical assessment, rectosigmoidoscopy and polysomnography, provides evidence that colonic neuropathology in Parkinson’s disease is associated with widespread brain dysfunction, as evaluated by wake and non-rapid eye movement sleep polysomnographic markers. Our results support the assumption of an extensive diffusion of the pathological process to diencephalic and neocortical structures in the presumptive body-first phenotype. They also suggest the use of routine polysomnography in phenotyping patients with Parkinson’s disease. Future studies should investigate the brain diffusion pattern and its sleep markers in the hypothesized brain-first phenotype of Parkinson’s disease.
Diet order affects energy balance in randomized crossover feeding studies that vary in macronutrients but not ultra-processing
Authors: Sciarrillo Christina M. , Guo Juen , Hengist Aaron , Darcey Valerie L. , Hall Kevin D. 
Published: October 2023

BACKGROUNDCrossover studies can induce order effects, especially when they lack a wash-out period.OBJECTIVETo explore diet order effects on energy balance and food intake between randomized diet order groups in two inpatient crossover studies originally designed to compare within-subject differences inad libitumenergy intake between either minimally processed low carbohydrate (LC) versus low fat (LF) diets or macronutrient-matched diets composed of mostly minimally processed food (MPF) or ultra-processed food (UPF).METHODSDiet order group comparisons of changes in body weight, body composition, and differences in energy expenditure, and food intake were assessed over four weeks in 20 adults randomized to either the LC followed immediately by the LF diet (LC→LF) or the opposite order (LF→LC) as well as 20 adults randomized to either the MPF followed by UPF (MPF→UPF) diets or the opposite order (UPF→MPF).RESULTSSubjects randomized to LC→LF lost 2.9 ± 1.1 kg more body weight (p< 0.001) and 1.5 ± 0.6 kg more body fat (p= 0.03) than the LF→LC group likely because the LC→LF group consumed 922 ± 304 kcal/d less than the LFàLC group (p= 0.0024). Reduced energy intake in LC→LFvsLFàLC was driven by the last two weeks (−1610 ± 306 kcal/d;p<0.00001) perhaps due to carryover effects of gut adaptations over the first two weeks arising from large differences in the mass of food (1295 ± 209 g/d;p<0.00001) and fiber intake (58 ± 5 g/d;p<0.00001). There were no diet order effects onad libitumenergy intake, body weight, or body composition change between UPF→MPF versus MPF→UPF groups.CONCLUSIONSDiet order influences dailyad libitumenergy intake, body weight change, and fat change within the context of a 4-week crossover inpatient diet study varying in macronutrients, but not varying in extent and purpose of processing.Funding sourcesIntramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of HealthClinical Trial RegistrationNCT03407053 andNCT03878108
Longitudinal Associations of Dietary Fructose and Psychological Stress with Vascular Aging Index and Incident Cardiovascular Disease in the CARDIA Cohort
Authors: Osborne Meaghan , Bernard Alexa , Falkowski Emily , Peterson Deni , Vavilikolanu Anusha , Komnenov Dragana 
Published: October 2023

ABSTRACTBackgroundCardiovascular disease (CVD) risk increases exponentially with age, largely due to vascular aging. We explored how dietary behaviors (sucrose, fructose, sodium, and potassium consumption) and endured psychological stress in young adult males and females impact the vascular aging index (VAI) and CVD risk by mid-life.MethodsData were obtained from the Coronary Artery Risk Development in Young Adults Study, an ongoing longitudinal study. Included participants (n=2,656) had undergone carotid artery ultrasound Doppler scans at year 20 allowing VAIs to be calculated. Demographics, dietary data and depression scale scores were obtained at the initial visit. Regression analyses were used to assess the predictors of VAI 20 years later. Cox regression analyses were conducted to assess the risk of fatal and non-fatal CVD, hypertensive CVD, and stroke.ResultsPredictors of vascular aging were found to be sex-specific. In females, CES-D scores at baseline were positively associated with VAI (B-weight=0.063, p=0.015). In males, sodium intake at year 20 positively predicted VAI (B-weight=0.145, p=0.003) and potassium intake inversely predicted VAI (B-weight=-0.160, p<0.001). On Cox regression analyses, BMI significantly predicted CVD, stroke, and death. In addition, fructose consumption at year 20 was a significant predictor of CVD risk while having blood pressure above 130/80 mmHg at baseline was significantly associated with stroke risk.ConclusionOur findings support the promotion of nutrient-specific behavior changes (specifically, limiting fructose consumption) to prevent vascular aging in early adulthood and CVD risk in mid-life.
Transposon mutagenesis reveals differential essential pathways in modelSalmonellaTyphimurium strains SL1344 and SL3261
Authors: Rooke Jessica L. , Goodall Emily C. A. , Pullela Karthik , Costa Rochelle Da , Martinelli Nicole , Henderson Ian R. 
Published: October 2023

AbstractSalmonella entericais a globally disseminated pathogen that is the cause of over 100 million infections per year. The resulting diseases caused byS. entericaare dependent upon host susceptibility and the infecting serovar. For example, Typhoid fever is a human exclusive disease caused byS. entericaserovar Typhi. AsS. entericaserovar Typhimurium induces a typhoid like disease in mice, this model has been used extensively to illuminate various aspects ofSalmonellainfection and host responses. However, the infection is so severe that even one infectious bacterium injected intravenously will cause mortality in 100% of animals within one week of infection. Due to this severity, researchers often use strains of mice resistant to infection or attenuatedSalmonellastrains to understand adaptive immunity and infection dynamics. Despite decades of research, many aspects ofSalmonellainfection and fundamental biology remain poorly understood. Here, we use a Transposon Insertion Sequencing (TIS) technique to interrogate the essential genomes of widely used isogenic wild-type and attenuatedS. Typhimurium strains. We reveal differential essential pathways between strains, provide a direct link between iron starvation, DNA synthesis and bacterial membrane integrity, and showS.Typhi andS.Typhimurium have similar requirements for iron.
Investigation of H9N2 avian influenza immune escape mutant that lacks haemagglutination activity
Authors: Karunarathna Thusitha K. , Sadeyen Jean-Remy , Bhat Sushant , Chang Pengxiang , Yang Jiayun , Qureshi Mehnaz , Sealy Joshua E. , Daines Rebecca , Iqbal Munir 
Published: October 2023

ABSTRACTH9N2 avian influenza viruses pose a global threat to animal and human health. While vaccination is essential for mitigating disease impact, these viruses evolve to evade vaccine immunity through changes in the haemagglutinin (HA) glycoprotein. In this study, we identified immune escape mutation in an H9N2 virus resulting from pressure exerted by homologous chicken antisera. The immune-escape variant acquired an amino acid substitution, replacing glycine (G) with glutamic acid (E) at position 149 in the HA protein. The G149E mutant virus lost the ability to agglutinate chicken erythrocytes, while still maintaining replication comparable to the wild-type virus in chicken embryos and cells. This led to the hypothesis that the G149E substitution, leading to a shift from a neutral to a negative charge polarity at HA position 149, might be crucial for the optimal interaction between the virus and receptors on erythrocytes. Investigation indicated that agglutination could be restored by substituting E to positively charged amino acids histidine (H), arginine (R) or lysine (K). These findings suggest that the H9N2 virus may be likely acquire the G149E mutation under immune pressure in nature. This mutation poses challenges to vaccination and surveillance efforts as it partially evades immune protection and is not easily detectable by conventional haemagglutination assays. This underscores the intricate interplay between antigenic variation and viral traits, emphasising the critical need for ongoing surveillance and research to effectively mitigate the risks associated with avian influenza H9N2 viruses.IMPORTANCEUnderstanding how avian influenza viruses evolve to persist in nature is crucial for enhancing disease mitigation tools such as vaccines, diagnostics, and risk assessment. In this study, we identified an H9N2 virus antibody escape mutant with G149E mutation in the haemagglutinin that had lost the ability to agglutinate chicken erythrocytes, while retaining infectivity and replication fitness. The lack of haemagglutination activity potentially negatively impacts routine surveillance and commonly used diagnostics such as haemagglutination assay or haemagglutination inhibition assay. Therefore, it is urgent to develop and adopt alternative methods for viral detection. Difficult to detect variants potentially that are not compatible with common surveillance techniques could circulate remain silent while reassort with other influenza viruses, which posing unpredictable risks to animal and human health. This research helps us better understand avian influenza, leading to improved disease control, diagnostics, and risk assessment to protect both animals and humans.
Interfacial water confers transcription factors with dinucleotide specificity
Authors: Morgunova Ekaterina , Yin Yimeng , Zhu Fangjie , Xiao Tianyi , Sokolov Ilya , Popov Alexander , Laughton Charles , Taipale Jussi 
Published: October 2023

AbstractTranscription factors bind to DNA by recognizing specific bases within their binding motifs. Binding to each DNA mononucleotide within the motif often contributes independently to total binding energy. However, some transcription factors (TFs) can bind to DNA more specifically than predicted by this model, by directly recognizing DNA dinucleotides. To understand this process, we have solved the structures of the basic helix-loop-helix protein MYF5, and the homeodomain protein BARHL2 together with DNA containing a set of dinucleotides that have different affinities to the proteins at high resolution (< 1 Å). We observe that dinucleotides can be recognized either enthalpically by an extensive water network that connects the adjacent bases to the TF, or entropically by formation of a hydrophobic patch that maintains water mobility at the protein-DNA interface. The two distinct thermodynamic signatures of the two equally optimal sites also confer differential temperature sensitivity to the optimal sites, with implications for thermal regulation of gene expression. Our results uncover the enigma of how TFs can recognize more complex local features than mononucleotides, and demonstrate that water-mediated recognition is important in predicting affinities of macromolecules from their sequence.
Viral-mediated expression of Erk2 in the nucleus accumbens regulates responses to rewarding and aversive stimuli
Authors: Parise Lyonna F. , Iñiguez Sergio D. , Warren Brandon L. , Parise Eric M. , Bachtell Ryan K. , Dietz David , Nestler Eric J. , Bolaños-Guzmán Carlos A. 
Published: October 2023

AbstractSecond-messenger signaling within the mesolimbic reward circuit is involved in both the long-lived effects of stress and in the underlying mechanisms that promote drug abuse liability. To determine the direct role of kinase signaling within the nucleus accumbens, specifically mitogen-activated protein kinase 1 (ERK2), in mood- and drug-related behavior, we used a herpes-simplex virus to up- or down-regulate ERK2 in adult male rats. We then exposed rats to a battery of behavioral tasks including the elevated plus-maze, open field test, forced-swim test, conditioned place preference, and finally cocaine self-administration. Herein, we show that viral overexpression or knockdown of ERK2 in the nucleus accumbens induces distinct behavioral phenotypes. Specifically, over expression of ERK2 facilitated depression- and anxiety-like behavior while also increasing sensitivity to cocaine. Conversely, down-regulation of ERK2 attenuated behavioral deficits, while blunting sensitivity to cocaine. Taken together, these data implicate ERK2 signaling, within the nucleus accumbens, in the regulation of affective behaviors and modulating sensitivity to the rewarding properties of cocaine.
Therapeutic Targeting of TIM-4-L With Engineered T Cells for Acute Myeloid Leukemia
Authors: Cieniewicz Brandon , Oliveira Edson , Saxton Mike , Torabi Damoun , Bhatta Ankit , Kukutla Phanidhar , Arballo Alexander , Yang Zhou , Yu Bi , Fate Maria , Ning Hongxiu , Corey Lawrence , Maiti Abhishek , Corey Daniel 
Published: October 2023

AbstractDisruption of the lipid asymmetric bilayer is a common feature observed in cancer cells. We utilized the natural immune receptor TIM-4 to interrogate for loss of plasma membrane phospholipid polarity in primary acute myelogenous leukemia (AML) samples. We performed FACs analysis in 33 patients and correlated TIM-4-L expression frequency and intensity with molecular disease characteristics. In normal tissues, TIM-4-L is confined to the internal leaflet of the plasma membrane. By contrast, 86% of untreated AML blasts in our analysis displayed upregulation of cell surface TIM-4-L. These observations were agnostic to AML genetic classification, as samples with mutations inTP53, ASXL1, andRUNX1, also displayed TIM-4-L upregulation similar to that seen in favorable and intermediate subtypes. This TIM-4-L dysregulation was also stably present in both Kasumi-1 and MV-4-11 AML cell lines. To evaluate the potential of upregulated TIM-4-L to serve as a target for adoptive T cell therapy (ACT), we constructed TIM-4-L-directed engineered T cells, which demonstrated potent anti-leukemic effects, effectively eliminating AML cell lines both in vitro and in vivo. This approach led to the eradication of AML cells across a range of endogenous TIM-4-L expression levels. These results highlight TIM-4-L as a highly prevalent and novel target for T cell-based therapy in AML. Further investigations into the role of TIM-4-L in AML pathogenesis and its potential as an anti-leukemic target for clinical development are warranted.
Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis
Authors: Alecki Célia , Rizwan Javeria , Le Phuong , Jacob-Tomas Suleima , Fernandez-Comaduran Mario , Verbrugghe Morgane , Xu Jia Ming Stella , Minotti Sandra , Lynch James , Wu Tad , Durham Heather , Yeo Gene W. , Vera Maria 
Published: October 2023

ABSTRACTProteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. However, this is challenging in neuronal projections because of their polarized morphology and constant synaptic proteome remodeling. Using high-resolution fluorescence microscopy, we discovered that hippocampal and spinal cord motor neurons of mouse and human origin localize a subset of chaperone mRNAs to their dendrites and use microtubule-based transport to increase this asymmetric localization following proteotoxic stress. The most abundant dendritic chaperone mRNA encodes a constitutive heat shock protein 70 family member (HSPA8). Proteotoxic stress also enhancedHSPA8mRNA translation efficiency in dendrites. Stress-mediatedHSPA8mRNA localization to the dendrites was impaired by depleting fused in sarcoma—an amyotrophic lateral sclerosis-related protein—in cultured spinal cord mouse motor neurons or by expressing a pathogenic variant of heterogenous nuclear ribonucleoprotein A2/B1 in neurons derived from human induced pluripotent stem cells. These results reveal a crucial and unexpected neuronal stress response in which RNA-binding proteins increase the dendritic localization ofHSPA8mRNA to maintain proteostasis and prevent neurodegeneration.
Firm's life cycle and cash flow classification: evidence from Indian firms
Authors: Mulchandani Kalyani , Mulchandani Ketan , Jain Megha 
Published: October 2023

PurposeThe study examines the influence of a firm's life cycle on the cash flow classification of Indian firms.Design/methodology/approachThe study employs Dickinson's (2011) cash flow patterns to classify firm years under various life-cycle stages. Cash flow classification is employed to measure a firm's classification shifting (CS) practices. The study includes Indian firms listed on the Bombay Stock Exchange during 2012–2020, an ordinary least squares regression model, a fixed-effect model and a panel corrected with standard error regression method.FindingsFirms face different opportunities and challenges at different stages of the firm's life cycle and therefore adopt cash flow CS. The results show that firms adopt cash flow CS during introduction, growth and decline stage of life cycle either to boost or to reduce operating cash flows.Originality/valueThis study is one of its kind to study the influence of a firm's life cycle on the cash flow classification of Indian firms.