bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gastrointestinal manifestations in systemic lupus erythematosus: data from an Indian multi-institutional inception (INSPIRE) cohort
Authors: Mehta Pankti , Aggarwal Amita , Rajasekhar Liza , Shobha Vineeta , Mathew Ashish J , Kavadichanda Chengappa , Ghosh Parasar , Das Bidyut , Rathi Manish , Srivastava Akansha , Gupta Ranjan , Jain Avinash 
Published: December 2023

Abstract

Objectives
To study the prevalence, correlates, and outcomes of GI manifestations in a prospectively enrolled nationwide cohort of SLE in India (INSPIRE).

Methods
It is an observational cohort study with analysis of the baseline database of the INSPIRE cohort with early outcomes assessed till 10 April 2023. Cases with GI manifestations as per the BILAG index were selected, pertinent clinical and laboratory data were retrieved for analysis. Patients with GI manifestations were compared with the rest of the cohort and factors associated with death were determined.

Results
Of the 2503 patients with SLE enrolled in the INSPIRE cohort, 243 (9.7%) had GI manifestations observed early in the disease course (1, 0–3 months). Ascites (162, 6.5%), followed by enteritis (41,1.6%), pancreatitis (35, 1.4%) and hepatitis (24, 0.9%) were the most prevalent manifestations. All patients received immunosuppressive therapy, and four patients required surgery. Twenty-nine patients died (11.9%), with uncontrolled disease activity (17, 58.6%) and infection (6, 20.7%) accounting for the majority of deaths. Low socioeconomic class [lower Hazard Ratio (95% confidence intervals, CI) 2.8 (1.1–7.9); upper lower 7.5 (2–27.7); reference as upper class] and SLEDAI 2K [1.06 (1.02–1.11)] were associated with death in the GI group. GI manifestations were significantly associated with age [odds ratio and 95% CI 0.97 (0.96–0.99)], pleural effusion [4.9 (3.6–6.7)], thrombocytopenia [1.7 (1.2–2.4)], myositis [1.7 (1.1–2.7)], albumin [0.7 (0.5–0.8)], alkaline phosphatase (ALP) [1.01 (1.0–1.002)], low C3 [1.9 (1.3–2.5)], total bilirubin [1.2 (1.03–1.3)], alopecia [0.62 (0.5–0.96], elevated anti-dsDNA [0.5 (0.4–0.8)], and anti-U1RNP antibody [0.8 (0.5–0.7)] in model one; and age [0.97 (0.96–0.99)], creatinine [1.2 (1.03–1.4)], total bilirubin [1.2 (1.03–1.3)], ALP [1.01 (1.0–1.002)], albumin [0.6 (0.5–0.7)], andanti-U1RNP antibody [0.6 (0.5–0.8)] in model two in multivariate analysis compared with patients without GI features. The mortality was higher in the GI group (11.9% and 6.6%, P = 0.01) as compared with controls.

Conclusion
GI manifestations were observed in 9.7% of the cohort and were always associated with systemic disease activity and had higher mortality.
IL-2 produced by HBV-specific T cells as a biomarker of viral control and predictor of response to PD-1 therapy across clinical phases of chronic hepatitis B
Authors: Chua Conan , Salimzadeh Loghman , Ma Ann T. , Adeyi Oyedele A. , Seo Hobin , Boukhaled Giselle M. , Mehrotra Aman , Patel Anjali , Ferrando-Martinez Sara , Robbins Scott H. , La Danie , Wong David , Janssen Harry L.A. , Brooks David G. , Feld Jordan J. , Gehring Adam J. 
Published: December 2023

Background:
There are no immunological biomarkers that predict control of chronic hepatitis B (CHB). The lack of immune biomarkers raises concerns for therapies targeting PD-1/PD-L1 because they have the potential for immune-related adverse events. Defining specific immune functions associated with control of HBV replication could identify patients likely to respond to anti-PD-1/PD-L1 therapies and achieve a durable functional cure.

Methods:
We enrolled immunotolerant, HBeAg+ immune-active (IA+), HBeAg− immune-active (IA−), inactive carriers, and functionally cured patients to test ex vivo PD-1 blockade on HBV-specific T cell functionality. Peripheral blood mononuclear cells were stimulated with overlapping peptides covering HBV proteins +/−α-PD-1 blockade. Functional T cells were measured using a 2-color FluoroSpot assay for interferon-γ and IL-2. Ex vivo functional restoration was compared to the interferon response capacity assay, which predicts overall survival in cancer patients receiving checkpoint inhibitors.

Results:

Ex vivo interferon-γ+ responses did not differ across clinical phases. IL-2+ responses were significantly higher in patients with better viral control and preferentially restored with PD-1 blockade. Inactive carrier patients displayed the greatest increase in IL-2 production, which was dominated by CD4 T cell and response to the HBcAg. The interferon response capacity assay significantly correlated with the degree of HBV-specific T cell restoration.

Conclusions:
IL-2 production was associated with better HBV control and superior to interferon-γ as a marker of T cell restoration following ex vivo PD-1 blockade. Our study suggests that responsiveness to ex vivo PD-1 blockade, or the interferon response capacity assay, may support stratification for α-PD-1 therapies.
Mild Traumatic Brain Injury in the Maturing Brain: An Investigation of Symptoms and Cognitive Performance in Soldiers Returning From Afghanistan and Iraq
Authors: Ivins Brian , Risling Mårten , Wisén Niclas , Schwab Karen , Rostami Elham 
Published: December 2023

Objective:
The majority of traumatic brain injuries (TBIs) are classified as mild and occur in young individuals. The course of recovery varies but can result in chronic or troubling outcomes. The impact of age on TBI outcomes in young adults before complete brain maturation is not well studied.

Methods:
In this study, we compared the effects of mild TBI on cognitive performance and self-reported TBI symptoms and posttraumatic stress disorder (PTSD) in 903 soldiers in 3 different age groups: 24 years or younger, 25 to 27 years, and 28 to 40 years. The soldiers had returned from war zones in Iraq and were screened for TBI within a few days of return. Cognitive performance was measured with the Automated Neuropsychological Assessment Metrics of Military TBI Version 4 (ANAM4). Symptoms associated with mild TBI were self-reported on the Neurobehavioral Symptom Inventory, and the PTSD Checklist—Civilian Version (PCL-C).

Results:
Soldiers with TBI in every age group had significantly higher prevalence of most symptoms than those with no TBI. Soldiers with TBI also reported more chronic pain sites, regardless of age. Soldiers aged 28 to 40 years with TBI had the lowest cognitive performance scores (ANAM) across several subtests, both unadjusted and adjusted. The Global Deficit Score was significantly higher for soldiers aged 28 to 40 years and 25 to 27 years with TBI than for soldiers younger than 24 years with no TBI. After adjusting for PTSD symptoms, education, and number of lifetime TBIs, the overall test battery mean for soldiers aged 28 to 40 years with TBI was significantly lower than for soldiers younger than 24 years with no TBI.

Conclusion:
Soldiers with mild TBI in the younger age group show more symptoms associated to frontal lobe function while soldiers in the older group suffer more cognitive impairment. This may warrant further study as it may indicate a propensity to later cognitive decline among soldiers who were older at the time of injury.
Development of adaptive anoikis resistance promotes metastasis that can be overcome by CDK8/19 Mediator kinase inhibition
Authors: Monavarian Mehri , Page Emily Faith , Rajkarnikar Resha , Kumari Asha , Macias Liz Quintero , Massicano Felipe , Lee Nam Y , Sahoo Sarthak , Hempel Nadine , Jolly Mohit Kumar , Ianov Lara , Worthey Elizabeth , Singh Abhyudai , Broude Eugenia V , Mythreye Karthikeyan 
Published: December 2023

ABSTRACTAnoikis resistance or evasion of cell death triggered by cell detachment into suspension is a hallmark of cancer that is concurrent with cell survival and metastasis. The effects of frequent matrix detachment encounters on the development of anoikis resistance in cancer remains poorly defined. Here we show using a panel of ovarian cancer models, that repeated exposure to suspension stress in vitro followed by attached recovery growth leads to the development of anoikis resistance paralleling in vivo development of anoikis resistance in ovarian cancer ascites. This resistance is concurrent with enhanced invasion, chemoresistance and the ability of anoikis adapted cells to metastasize to distant sites. Adapted anoikis resistant cells show a heightened dependency on oxidative phosphorylation and can also evade immune surveillance. We find that such acquired anoikis resistance is not genetic, as acquired resistance persists for a finite duration in the absence of suspension stress. Transcriptional reprogramming is however essential to this process, as acquisition of adaptive anoikis resistance in vitro and in vivo is exquisitely sensitive to inhibition of CDK8/19 Mediator kinase, a pleiotropic regulator of transcriptional reprogramming. Our data demonstrate that growth after recovery from repeated exposure to suspension stress is a direct contributor to metastasis and that inhibition of CDK8/19 Mediator kinase during such adaptation provides a therapeutic opportunity to prevent both local and distant metastasis in cancer.
Three-dimensional assessments are necessary to determine the true, spatially-resolved composition of tissues
Authors: Forjaz André , Vaz Eduarda , Romero Valentina Matos , Joshi Saurabh , Braxton Alicia M. , Jiang Ann C. , Fujikura Kohei , Cornish Toby , Hong Seung-Mo , Hruban Ralph H. , Wu Pei-Hsun , Wood Laura D. , Kiemen Ashley L. , Wirtz Denis 
Published: December 2023

ABSTRACTMethods for spatially resolved cellular profiling using thinly cut sections have enabled in-depth quantitative tissue mapping to study inter-sample and intra-sample differences in normal human anatomy and disease onset and progression. These methods often profile extremely limited regions, which may impact the evaluation of heterogeneity due to tissue sub-sampling. Here, we applied CODA, a deep learning-based tissue mapping platform, to reconstruct the three-dimensional (3D) microanatomy of grossly normal and cancer-containing human pancreas biospecimens obtained from individuals who underwent pancreatic resection. To compare inter-and intra-sample heterogeneity, we assessed bulk and spatially resolved tissue composition in a cohort of two-dimensional (2D) whole slide images (WSIs) and a cohort of thick slabs of pancreas tissue that were digitally reconstructed in 3D from serial sections. To demonstrate the marked under sampling of 2D assessments, we simulated the number of WSIs and tissue microarrays (TMAs) necessary to represent the compositional heterogeneity of 3D data within 10% error to reveal that tens of WSIs and hundreds of TMA cores are sometimes needed. We show that spatial correlation of different pancreatic structures decay significantly within a span of microns, demonstrating that 2D histological sections may not be representative of their neighboring tissues. In sum, we demonstrate that 3D assessments are necessary to accurately assess tissue composition in normal and abnormal specimens and in order to accurately determine neoplastic content. These results emphasize the importance of intra-sample heterogeneity in tissue mapping efforts.
Normalization of RNA-Seq Data using Adaptive Trimmed Mean with Multi-reference
Authors: Singh Vikas , Kirtipal Nikhil , Song Byong-Sop , Lee Sunjae 
Published: December 2023

AbstractThe normalization of RNA sequencing data is a primary step for downstream analysis. The most popular method used for the normalization is the trimmed mean of M values (TMM) and DESeq. The TMM tries to trim away extreme log fold changes of the data to normalize the raw read counts based on the remaining non-deferentially expressed genes. However, the major problem with the TMM is that the values of trimming factor M are heuristic. This paper tries to estimate the adaptive value of M in TMM based on Jaeckel’s Estimator, and each sample acts as a reference to find the scale factor of each sample. The presented approach is validated on SEQC, MAQC2, MAQC3, PICKRELL, and two simulated datasets with two groups and three groups conditions by varying the percentage of differential expression and the number of replicates. The performance of the present approach is compared, and it shows better in terms of area under the receiver operating characteristic curve (AUC) and differential expression. The implementation of the present approach is available on the GitHub platform:https://github.com/vikkyak/Normalization-of-Bulk-RNA-seq.
“The impact of the Little Orange Book on how parents/carers manage symptoms of illness in children: A mixed methods study”
Authors: Johnson Amy , Carruthers Kathryn , Breckons Matthew , Shotton Lynette Harland 
Published: December 2023

AbstractBackgroundParental decision-making regarding children’s healthcare represents a complex and difficult process. While there is general agreement that information and education may play a key role in supporting self-care and the use of health services, there is potential for information to increase, as well as reduce anxiety.ObjectivesThis article summarises the key recommendations of an applied evaluation of a paediatric health resource, The Little Orange Book.MethodsA mixed-methods approach was used to collect data regarding parental perceptions on the health resource. Parents and carers in the North-East of England were invited to participate in an online survey and qualitative interviews. Qualitative data were analysed using thematic analysis and quantitative data analysed using descriptive statistical analytical methods.ResultsOne-hundred-and-twenty-eight parents completed the online survey and 16 took part in interviews. Three themes were identified within the data:Increasing parental empowerment in managing their child’s health, Equality of Access to Health-based LiteratureandBarriers and Facilitators to using the Little Orange Book.ConclusionsThe Little Orange Book has the potential to be a useful form of information to support parents and carers in healthcare decisions. Further development should ensure inclusivity, widen access and view provision of the information as an opportunity for healthcare professionals to engage with parents.
State Adoption of Paid Sick Leave and Cardiovascular Disease Mortality Among Adults Aged 15-64 in the United States, 2008 to 2019
Authors: Swift Sam , O’Donnell Lexi , Horn Brady , Kezios Katrina , Elfassy Tali , Reagan Julie , Zeki Al Hazzouri Adina , Collins Tracie 
Published: December 2023

ABSTRACTBackgroundCardiovascular Disease (CVD) is the leading cause of death in the United States and may be prevented through improved working conditions. The United States is one of the few high-income nations that does not guarantee paid sick leave (PSL) at the federal level. Our objective was to examine the relationship between state-level PSL policies and CVD mortality.MethodsWe used quasi-experimental event study methods to examine the relationship between implementing a mandatory PSL policy for all employees at the state-level and county-level CVD mortality rates using National Center for Health Statistics data among working-age adults aged 15 to 64 over time from 2008 to 2019. During this time, 11 states implemented PSL policies. We examined the annual CVD mortality rates (2008-2019) in 1054 counties from all 50 states and Washington D.C., accounting for approximately 88% of the United States population in this analysis.ResultsWe found that in the Northeastern region of the United States, there were drops in the CVD mortality rate for persons ages 15-64 for all years after PSL was implemented, ranging from 7.1 fewer deaths per 100,000 persons (β=-7.1, 95% CI = -9.7, -4.4) seven years post-treatment to 2.7 fewer deaths two years post-treatment (β=-2.7, 95% CI= -5.1, -0.3).ConclusionOur results support the use of state-level PSL policies to reduce county-level CVD mortality rates, especially in the Northeastern United States.
Towards explainable interaction prediction: Embedding biological hierarchies into hyperbolic interaction space
Authors: Pogány Domonkos , Antal Péter 
Published: December 2023

AbstractGiven the prolonged timelines and high costs associated with traditional approaches, accelerating drug development is crucial. Computational methods, particularly drug-target interaction prediction, have emerged as efficient tools, yet the explainability of machine learning models remains a challenge. Our work aims to provide more interpretable interaction prediction models using similarity-based prediction in a latent space aligned to biological hierarchies. We investigated integrating drug and protein hierarchies into a joint-embedding drug-target latent space via embedding regularization by conducting a comparative analysis between models employing traditional flat Euclidean vector spaces and those utilizing hyperbolic embeddings. Besides, we provided a latent space analysis as an example to show how we can gain visual insights into the trained model with the help of dimensionality reduction. Our results demonstrate that hierarchy regularization improves interpretability without compromising predictive performance. Furthermore, integrating hyperbolic embeddings, coupled with regularization, enhances the quality of the embedded hierarchy trees. Our approach enables a more informed and insightful application of interaction prediction models in drug discovery by constructing an interpretable hyperbolic latent space, simultaneously incorporating drug and target hierarchies and pairing them with available interaction information. Moreover, compatible with pairwise methods, the approach allows for additional transparency through existing explainable AI solutions.
Disease progression modelling reveals heterogeneity in trajectories of Lewy-type α-synuclein pathology
Authors: Mastenbroek Sophie E. , Vogel Jacob W. , Collij Lyduine E. , Serrano Geidy E. , Tremblay Cecilia , Young Alexandra L. , Arce Richard A. , Shill Holly A. , Driver-Dunckley Erika D. , Mehta Shyamal H. , Belden Christine M. , Atri Alireza , Choudhury Parichita , Barkhof Frederik , Adler Charles H. , Ossenkoppele Rik , Beach Thomas G. , Hansson Oskar 
Published: December 2023

ABSTRACTLewy body (LB) disorders, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. By applying data-driven disease progression modelling to regional neuropathological LB density scores from 814 brain donors, we describe three inferred trajectories of LB pathology that were characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) showed earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) exhibited the first abnormalities in brainstem regions. Early limbic pathology was associated with Alzheimer’s disease-associated characteristics. Meanwhile, brainstem-first pathology was associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in LBDs.
Ancestral neural circuits potentiate the origin of a female sexual behavior
Authors: Li Minhao , Chen Dawn S. , Junker Ian P. , Szorenyi Fabianna , Chen Guan Hao , Berger Arnold J. , Comeault Aaron A. , Matute Daniel R. , Ding Yun 
Published: December 2023

AbstractCourtship interactions are remarkably diverse in form and complexity among species. How neural circuits evolve to encode new behaviors that are functionally integrated into these dynamic social interactions is unknown. Here we report a recently originated female sexual behavior in the island endemicDrosophilaspeciesD. santomea, where females signal receptivity to male courtship songs by spreading their wings, which in turn promotes prolonged songs in courting males. Copulation success depends on this female signal and correlates with males’ ability to adjust his singing in such a social feedback loop. Functional comparison of sexual circuitry across species suggests that a pair of descending neurons, which integrates male song stimuli and female internal state to control a conserved female abdominal behavior, drives wing spreading inD. santomea. This co-option occurred through the refinement of a pre-existing, plastic circuit that can be optogenetically activated in an outgroup species. Combined, our results show that the ancestral potential of a socially-tuned key circuit node to engage the wing motor program facilitates the expression of a new female behavior in appropriate sensory and motivational contexts. More broadly, our work provides insights into the evolution of social behaviors, particularly female behaviors, and the underlying neural mechanisms.
Translation in Bacillus subtilis is spatially and temporally coordinated during sporulation
Authors: Iwańska Olga , Latoch Przemysław , Kopik Natalia , Kovalenko Mariia , Lichocka Małgorzata , Serwa Remigiusz , Starosta Agata L 
Published: December 2023

AbstractTranslational control during the intricate process of sporulation inBacillus subtilisas a response to nutrient limitation is still underexplored. Here, we employed a comprehensive approach including RNA-seq, ribosome profiling and fluorescence microscopy to dissect the translational landscape ofB. subtilisduring sporulation. We identified two events of translation silencing and described the spatiotemporal changes in the subcellular location of translational machinery during sporulation. Using a triple knock-out strain (3KO) of zinc-independents paralogs of three zinc-dependent ribosomal proteins L31, L33 and S14, we investigated the potential regulatory role of ribosome during sporulation. The 3KO strain exhibited delayed sporulation, reduced germination efficiency, and dysregulated translation including expression of key metabolic and sporulation-related genes as well as disruptions in translation silencing, particularly in late sporulation.
Structure and dynamics of the RF-amide QRFP receptor GPR103
Authors: Iwama Aika , Akasaka Hiroaki , Sano Fumiya K. , Oshima Hidetaka S. , Shihoya Wataru , Nureki Osamu 
Published: December 2023

AbstractPyroglutamylated RF amide peptide (QRFP) is a type of peptide hormone with a C-terminal RF-amide motif. QRFP selectively activates class-A categorized GPCR, GPR103 to exert various physiological functions such as energy metabolism and appetite regulation. Here, we report the cryo-electron microscopy structure of the QRFP-GPR103-Gqcomplex at 3.3 Å resolution. Unlike class-A GPCR, QRFP adopts an extended structure baring no secondary structure, with its N-terminal and C-terminal sides recognized by extracellular and transmembrane domains, respectively, of GPR103. The C-terminal heptapeptide of QRFP penetrates into the orthosteric pocket to act in receptor activation. Particularly, the residues that recognize the RF-amide are highly conserved in the RF-amide receptors. Notably, the unique N-terminal helix-loop-helix of the receptor traps the N-terminal side of QRFP with the pendulum-like motion to guide QRFP into the ligand-binding pocket. This movement, reminiscent of class B1 GPCRs except for orientation and structure of the ligand, is critical for the high affinity binding and receptor specificity of QRFP. Structural comparisons with closely related receptors, including RY-amide peptide-recognizing GPCRs, revealed conserved and diversified peptide recognition mechanisms, providing profound insights into the biological significance of RF-amide peptides. This study not only advances our understanding of GPCR-ligand interactions, but also paves the way for the development of novel therapeutics targeting metabolic and appetite disorders and emergency medical care.