bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lack of complete biochemical response in autoimmune hepatitis leads to adverse outcome: First report of the IAIHG retrospective registry
Authors: Slooter Charlotte D. , van den Brand Floris F. , Lleo Ana , Colapietro Francesca , Lenzi Marco , Muratori Paolo , Kerkar Nanda , Dalekos George N. , Zachou Kalliopi , Lucena M. Isabel , Robles-Díaz Mercedes , Di Zeo-Sánchez Daniel E. , Andrade Raúl J. , Montano-Loza Aldo J. , Lytvyak Ellina , Lissenberg-Witte Birgit I. , Maisonneuve Patrick , Bouma Gerd ,   Dutch AIH Study Group, Macedo Guilherme , Liberal Rodrigo , de Boer Ynto S. ,   on behalf of the International Autoimmune Hepatitis Group
Published: September 2023

Background and Aims:
The International Autoimmune Hepatitis Group retrospective registry (IAIHG-RR) is a web-based platform with subjects enrolled with a clinical diagnosis of autoimmune hepatitis (AIH). As prognostic factor studies with enough power are scarce, this study aimed to ascertain data quality and identify prognostic factors in the IAIHG-RR cohort.

Methods:
This retrospective, observational, multicenter study included all patients with a clinical diagnosis of AIH from the IAIHG-RR. The quality assessment consisted of external validation of completeness and consistency for 29 predefined variables. Cox regression was used to identify risk factors for liver-related death and liver transplantation (LT).

Results:
This analysis included 2559 patients across 7 countries. In 1700 patients, follow-up was available, with a completeness of individual data of 90% (range: 30–100). During a median follow-up period of 10 (range: 0–49) years, there were 229 deaths, of which 116 were liver-related, and 143 patients underwent LT. Non-White ethnicity (HR 4.1 95% CI: 2.3–7.1), cirrhosis (HR 3.5 95% CI: 2.3–5.5), variant syndrome with primary sclerosing cholangitis (PSC) (HR 3.1 95% CI: 1.6–6.2), and lack of complete biochemical response within 6 months (HR 5.7 95% CI: 3.4–9.6) were independent prognostic factors.

Conclusions:
The IAIHG-RR represents the world’s largest AIH cohort with moderate-to-good data quality and a relevant number of liver-related events. The registry is a suitable platform for patient selection in future studies. Lack of complete biochemical response to treatment, non-White ethnicity, cirrhosis, and PSC-AIH were associated with liver-related death and LT.
Myocilin Mutation N480K Leads to Early Onset Juvenile and Adult-onset Primary Open Angle Glaucoma in a Six Generation Family
Authors: Kader Mohideen Abdul , Devarajan Bharanidharan , Vijayan Saravanan , Ramakrishnan Rengappa , Sundaresan Periasamy , Uduman Mohammed Sithiq , Krishnadas Subbiah R. , Kuppamuthu Dharmalingam 
Published: September 2023

Précis:
A pathogenic autosomal dominant MYOC mutation N480K detected in 6 generations of an Indian family is primarily responsible for juvenile open angle glaucoma (JOAG) and adult-onset primary open angle glaucoma (POAG), emphasizing the importance of screening this mutation at a younger age.

Purpose:
To screen myocilin mutations in a large South Indian family with early-onset JOAG and adult-onset POAG

Methods:
In a large South Indian family with 20 members, 8 members diagnosed as JOAG, 7 members as POAG, 4 members as JOAG suspect, and 1 member as POAG suspect were screened for myocilin (MYOC) mutations using Sanger sequencing. Whole exome sequencing was performed on clinically suspected JOAG/POAG individuals.

Results:
Myocilin gene mutation N480K (c.1440C>G) was detected in 20 family members, including proband, of whom 8 were JOAG and 7 were POAG patients, 3 were JOAG suspects, and 2 were unaffected. Among the unaffected carriers, 1 was less than 5 years old, and another was 25 years old. The earliest to develop the disease was a 10-year-old child. The penetrance of the mutation was 95% over 10 years of age. This family had JOAG/POAG suspects with no N480K MYOC mutation, and they were further screened for other mutations using whole-exome sequencing. Polymorphisms CYP1B1 L432V and MYOC R76K were detected in 3 JOAG/POAG suspects, and among these 3, one had another CYP1B1 polymorphic variant R368H. The presence of the CYP1B1 polymorphism along with an MYOC polymorphic variant among the JOAG/POAG suspects needs additional studies to explore their combined role in the onset of glaucoma.

Conclusions:
This study reveals that MYOC mutation is primarily responsible for JOAG and adult-onset POAG in a family, emphasizing the importance of screening for this mutation at a younger age for early treatment.
Participant Experience Using Novel Perimetry Tests to Monitor Glaucoma Progression
Authors: Freeman Sandra E. , De Arrigunaga Sofia , Kang Joyce , Zhao Yan , Roldán Ana M. , Lin Michael M. , Elze Tobias , Liebman Daniel , Chang Dolly S. , Friedman David S. 
Published: September 2023

Précis:
Participant surveys taken after using tablet-based and smart visual function analyzer (SVFA) perimetry tests suggest that patients may prefer novel perimetry tests over traditional visual field machines.

Purpose:
Compare patient experience using the IMOvifa SVFA and the tablet-based Melbourne Rapid Fields visual field (VF) tests to the Humphrey Field 24-2 Swedish Interactive Threshold Algorithm Standard.

Patients and Methods:
Prospective observational cohort study on adult participants with diagnoses of glaucoma suspect, ocular hypertension, or glaucoma. Participants attended 2 study visits ~3 months apart. During the first visit, participants were trained to use the 2 novel perimeters, took 1 test on both new devices and the Humphrey Field Analyzer, then were surveyed. Participants received tablets and performed weekly tablet VF tests at home between study visits. At the final study visit, participants re-took the VF tests and completed the same surveys.

Results:
Eighty-one participants were surveyed twice. At the baseline survey, participants preferred the SVFA (71.7%) and tablet tests (69.2%) over the Humphrey VF. Most were willing to perform weekly monitoring at home on the SVFA (69.1%) and tablet (75.4%). Participants generally had a “very good” overall experience when testing on the SVFA (71.6%) and tablet (90.1%). At the final visit, fewer participants were willing to test on the tablet daily (23.5% to 9.9%; P = 0.02 for change) and more were willing to test monthly (18.5% to 33.3%; P = 0.03 for change).

Conclusion:
Users reported a preference for novel VF devices. Overall participant experience using these devices was positive, supporting the feasibility of home monitoring of VFs from an experience perspective.
Reliability of Intraocular Pressure Measurements in a Low-Contact Drive-Through Setting
Authors: Sun Lynn W. , Zhou Yunshu , Stein Joshua D. , Weizer Jennifer S. 
Published: September 2023

Précis:
Drive-through intraocular pressure (IOP) measurement using iCare tonometry is a promising method of low-contact, high-throughput IOP monitoring. However, owing to its vulnerability to variable measurement technique and local air currents, the iCare may overestimate IOPs.

Purpose:
During the COVID-19 pandemic, a drive-through IOP measurement protocol using the iCare tonometer was established to facilitate low-contact monitoring of select glaucoma patients. As the iCare may be prone to error due to variable measurement technique and local air currents, we endeavored to assess the reliability of drive-through IOP measurements by comparing them with recent measurements taken in clinic settings.

Methods:
Inclusion criteria were patients with drive-through IOP measurements performed from April 28 to October 11, 2020; exclusion criteria were pre-drive-through IOPs >21 mmHg. Drive-through IOP measurements were compared with the closest previous and/or subsequent in-clinic IOP measurements. Data were gathered using the Sight Outcomes Research Collaborative (SOURCE) data repository.

Results:
The post-exclusion study group consisted of 314 patients receiving a total of 868 drive-through IOP measurements, all of whom had prior in-clinic measurements, and 56.8% of whom had subsequent in-clinic measurements. Drive-through IOPs were, on average, +2.4 mmHg (+14.5%; SD 4.9) higher than in-clinic IOPs. Further sub-analysis of the data showed a difference of +2.1 mmHg OD and +2.6 mmHg OS. Compared with the closest previous in-clinic visit, the difference was +2.4 mmHg OU (+2.1 mmHg OD, +2.7 mmHg OS); compared with the closest subsequent in-clinic visit, the difference was +2.3 mmHg OU (+2.1 mmHg OD, +2.5 mmHg OS). 68.6% of all drive-through IOPs were higher than corresponding in-clinic IOPs; 21.1% were lower. 25.9% of drive-through IOPs were higher by more than 5 mmHg, whereas 3.9% of drive-through IOPs were lower by more than 5 mmHg.

Discussion:
As teleophthalmology becomes an ever more important tool in glaucoma patient care, drive-through or walk-through IOP monitoring methods are likely to play an increasing role. However, our data reveals potential inaccuracies in drive-through iCare IOP measurements which tended to overestimate IOP. It is advisable to confirm large changes in IOP with in-clinic measurement before making management decisions.

Conclusion:
With better optimization of accuracy and reliability of measurements, drive-through tonometry is a promising, high-throughput, low-contact method of measuring IOP.
Diode Laser Transscleral Cyclophotocoagulation With a Novel Low-Cost Torchlight Method of Trans-Corneal Transillumination in Refractory Pediatric Glaucoma
Authors: Choudhary Sandeep , Snehi Sagarika , Singh Ashok , Thattaruthody Faisal , Pandav Surinder Singh , Kaushik Sushmita 
Published: September 2023

Précis:
Trans-corneal transillumination (TI) aided transscleral cyclophotocoagulation (TSCPC) for intraocular pressure control of refractory pediatric glaucoma was found to be effective at 1 year.

Purpose:
To study 1-year outcomes of diode laser TSCPC with trans-corneal TI using a novel low-cost torchlight method in refractory pediatric glaucoma.

Methods:
This prospective interventional study included children with refractory glaucoma who underwent TSCPC with the Oculight laser system (IRIS Medical Instruments) with trans-corneal TI (TSCPC-TI) using a novel low-cost torchlight method. Children completing a minimum 1-year follow-up were analyzed. They were compared with a historical control group of children who underwent TSCPC without TI (TSCPC-No-TI) at the 1-year follow-up period. We analyzed the mean laser energy delivered, post-laser intraocular pressure reduction, number of antiglaucoma medications (AGM), the requirement of retreatment and complications of the procedure in both groups.

Results:
Forty-two eyes of 35 patients comprised the TSCPC-TI group and were compared with 31 eyes of 21 patients in the TSCPC-No-TI group. The TSCPC-TI group required lower energy than the TSCPC-No-TI group (24.7±7.8 J vs. 47.2±10.9 J, P<0.0001). Mean topical antiglaucoma drug requirement decreased from 2.9±0.08 before treatment to 0.66±0.8 at the end of 1 year in TSCPC-TI and from 2.6±1.0 before treatment to 0.6±0.77 in the TSCPC-No-TI groups, respectively (P=0.15). There was a significantly reduced dependence of oral acetazolamide in the TSCPC-TI group at 1-year follow-up [5.7% vs. 61.9%, respectively (P<0.001%)]. No adverse event of hypotony or choroidal detachment was noted in any group.

Conclusions:
TSCPC aided by TI with a low-cost torchlight for pediatric refractory glaucoma was found to be effective at 1 year in reducing intraocular pressure and the burden of medication.
Supporting CIF Format of Biomolecular Structures in GROMACS
Authors: Wang Hengyue , Zhang Zhiyong 
Published: September 2023

AbstractIn the Protein Data Bank (PDB), the PDB format stands as the major file format for protein structures. However, there are certain intrinsic limitations in the PDB format, such as the storage of structural information in a fixed-width format that would be an issue for very large protein complexes. Therefore, the CIF (crystallographic information framework) format has been proposed, which is characterized by superior expansibility. GROMACS, a widely used software suite for molecular dynamics simulations, currently supports only the PDB format. In this study, we modified the source code of GROMACS, which enables it to support the CIF format structure files as input and subsequently generate molecular topology files. This work simplifies the preprocessing of large protein complexes for MD simulations.Program summaryProgram title: GROMACS-CIFGitHub link to program files:https://github.com/zyzhangGroup/Gromacs-CIFLicensing provisions: GPL-3.0 licenseProgramming language: C++Nature of problem: GROMACS currently supports only the PDB format but does not support the CIF format of protein structures. For a very large protein complex, the PDB format is not suitable, and only a CIF file is available in the protein data bank. However, the latter cannot be used as a direct input of GROMACS.Solution method: Source codes of the program “pdb2gmx” in GROMACS have been modified by adding several CIF analysis functions parallel to the PDB analysis functions.
Enhancing Neurocognitive Outcome Prediction in Congenital Heart Disease Patients: The Role of Brain Age Biomarkers and Beyond
Authors: Hussain Mohammad Arafat , Grant Ellen , Ou Yangming 
Published: September 2023

ABSTRACTThis paper aimed to investigate the predictive power of combining demographic, socioeconomic, and genetic factors with a brain MRI-based quantified measure of accelerated brain aging (referred to asdeltaAGE) for neurocognitive outcomes in adolescents and young adults with Congenital Heart Disease (CHD). Our hypothesis posited that including the brain age biomarker (deltaAGE) would enhance neurocognitive outcome predictions compared to models excluding it. We conducted comprehensive analyses, including leave-one-subject-out and leave-one-group-out cross-validation techniques. Our results demonstrated that the inclusion ofdeltaAGEconsistently improved prediction performance when considering the Pearson correlation coefficient, a preferable metric for this study. Notably, thedeltaAGE-augmented models consistently outperformed those withoutdeltaAGEacross all cross-validation setups, and these correlations were statistically significant (p-value < 0.05). Therefore, our hypothesis that incorporating the brain-age biomarker alongside demographic, socioeconomic, and genetic factors enhances neurocognitive outcome predictions in adolescents and young adults with CHD is supported by the findings.
A Cholinergic Signaling Pathway underlying Cortical Circuit Regulation of Lateral Ventricle Quiescent Neural Stem Cells
Authors: Naffaa Moawiah M , Yin Henry H. 
Published: September 2023

AbstractNeurogenesis and proliferation of neural stem cells (NSCs) in the subventricular zone (SVZ) are controlled by both intrinsic molecular pathways and extrinsic signaling cues, including neural circuits. One such circuit, the ACC-subep-ChAT+circuit, has been identified as a regulator of ventral SVZ neurogenesis by modulating the proliferation of LV NSCs. However, the specific neural signals that promote the proliferation activity of LV NSCs have remained largely unknown. In this study, we uncover a molecular mechanism underlying the cellular activation and proliferation of quiescent NSCs (qNSCs) in the lateral ventricle SVZ (LV-SVZ) mediated by the cortical circuit. Our findings demonstrate that postnatal and adult LV qNSCs are triggered by the cortical circuit through ChAT+neuron stimulation, consequently resulting in the activation of muscarinic 3 receptors (M3) expressed on LV qNSCs. This, in turn, triggers inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) activation, causing intracellular calcium release. Subsequently, the proliferation of LV qNSCs occurs through the downstream regulation of the calcium/calmodulin dependent protein kinase II delta (CAMK2D) and the MAPK10 signaling pathway. These findings shed light on the molecular regulatory mechanisms that govern LV qNSCs and emphasize the significant role of the cortical circuit in promoting their proliferative activation within the ventral LV-SVZ.
Multi-omics profiling reveals phenotypic and functional heterogeneity of neutrophils in COVID-19
Authors: Zhang Lin , Nishi Hafumi , Kinoshita Kengo 
Published: September 2023

AbstractBackgroundAccumulating evidence has revealed unexpected phenotypic heterogeneity and diverse functions of neutrophils in several diseases. Coronavirus disease (COVID-19) can alter the leukocyte phenotype based on disease severity, including neutrophil activation in severe cases. However, the plasticity of neutrophil phenotypes and their relative impact on COVID-19 pathogenesis has not been well addressed. This study aimed to identify and validate the heterogeneity of neutrophils in COVID-19 and evaluate the phenotypic alterations for each subpopulation.MethodsWe analyzed public single-cell RNA-seq, bulk RNA-seq, and human plasma proteome data from healthy donors and patients with COVID-19 to investigate neutrophil subpopulations and their response to disease pathogenesis.ResultsWe identified eight neutrophil subtypes, namely C1–C8, and found that they exhibited distinct features, including activation signatures and multiple enriched pathways. The neutrophil subtype C4 (DEFA1/1B/3+) associated with severe and fatal disease. Bulk RNA-seq and proteome dataset analyses using a cellular deconvolution approach validated the relative abundances of neutrophil subtypes and the expansion of C4 (DEFA1/1B/3+) in severe COVID-19 patients. Cell– cell communication analysis revealed representative ligand-receptor interactions among the identified neutrophil subtypes. Notably, the C4 (DEFA1/1B/3+) fraction showed transmembrane receptor expression of CD45 and CAP1 as well as the secretion of pro-platelet basic protein (PPBP). We further demonstrated the clinical potential of PPBP as a novel diagnostic biomarker for severe COVID-19.ConclusionOur work has great value in terms of both clinical and public health as it furthers our understanding of the phenotypic and functional heterogeneity of neutrophils and other cell populations in multiple diseases.
TPX2 expression promotes sensitivity to dasatinib in breast cancer by activating the YAP transcriptional signaling
Authors: Marugán Carlos , Ortigosa Beatriz , Sanz-Gómez Natalia , Monfort-Vengut Ana , Bertinetti Cristina , Teijo Ana , González Marta , Alonso de la Vega Alicia , Lallena María José , Moreno-Bueno Gema , de Cárcer Guillermo 
Published: September 2023

AbstractChromosomal instability (CIN) is a hallmark of cancer aggressiveness, providing genetic plasticity and tumor heterogeneity that allows the tumor to evolve and adapt to stress conditions. CIN is considered a cancer therapeutic biomarker because healthy cells do not exhibit CIN. Despite recent efforts to identify therapeutic strategies related to CIN, the results obtained have been very limited. CIN is characterized by a genetic signature where a collection of genes, mostly mitotic regulators, are overexpressed in CIN-positive tumors, providing aggressiveness and poor prognosis. We attempted to identify new therapeutic strategies related to CIN genes by performing a drug screen, using cells that individually express CIN-associated genes in an inducible manner. We find that the overexpression of TPX2 enhances sensitivity to the SRC inhibitor dasatinib due to activation of the YAP pathway. Furthermore, using breast cancer data from the TCGA and a cohort of cancer-derived patient samples, we find that both TPX2 expression and YAP activation are present in a significant percentage of cancer tumor samples, providing poor prognosis, being therefore putative biomarkers for dasatinib therapy.
Mechanistic implications of the ternary complex structural models for the photoenzyme protochlorophyllide oxidoreductase
Authors: Taylor Aoife , Zhang Shaowei , Johannissen Linus O. , Sakuma Michiyo , Phillips Robert S. , Green Anthony P. , Hay Sam , Heyes Derren J. , Scrutton Nigel S. 
Published: September 2023

ABSTRACTThe photoenzyme protochlorophyliide oxidoreductase (POR) is an important enzyme for understanding biological H-transfer mechanisms. It uses light to catalyse the reduction of protochlorophyllide (Pchlide) to chlorophyllide, a key step in chlorophyll biosynthesis. Although a wealth of spectroscopic data have provided crucial mechanistic insight about the light-driven reaction chemistry, a structural rationale for POR photocatalysis has proved more challenging and remains hotly debated. Recent structural models of the ternary enzyme-substrate complex, derived from crystal and electron microscopy data, show differences in the orientation of the Pchlide substrate and the architecture of the POR active site that have significant implications for the catalytic mechanism of Pchlide reduction. Here, we have used a combination of computational and experimental approaches to investigate the compatibility of each of these structural models with the hypothesised reaction mechanisms and propose an alternative structural model for the cyanobacterial POR-Pchlide-NADPH ternary complex based on these findings. Through detailed site-directed mutagenesis studies we show that a strictly conserved Tyr residue, which has previously been proposed to act as the proton donor in POR photocatalysis, is not likely to be involved in this step of the reaction but is crucial for Pchlide binding. Instead, an active site Cys residue is important for both hydride and proton transfer reactions in POR and is proposed to act as the proton donor, either directly or through a water-mediated network. Moreover, a conserved Gln residue is found to be important for Pchlide binding and ensuring efficient photochemistry by tuning its electronic properties, likely by interacting with the central Mg atom of the substrate. This optimal ‘binding pose’ for the POR ternary enzyme-substrate complex illustrates how light energy can be harnessed to facilitate enzyme catalysis by this unique enzyme.
Cell of origin epigenetic priming determines susceptibility toTet2mutation
Authors: Schiroli Giulia , Kartha Vinay , Duarte Fabiana M. , Kristiansen Trine A. , Mayerhofer Christina , Shrestha Rojesh , Earl Andrew , Hu Yan , Tay Tristan , Rhee Catherine , Buenrostro Jason D. , Scadden David T. 
Published: September 2023

AbstractHematopoietic stem cell mutations can result in clonal hematopoiesis (CH) but the clinical outcomes are heterogeneous. The nature of the founder mutation and secondary mutations likely drive emergent neoplastic disease. We investigated how the state of the cell of origin where theTet2mutation occurs affects susceptibility to that commonly occurring CH mutation. Here, we provide evidence that risk is written in the epigenome of the cell of origin. By characterizing cell states that underlie myeloid differentiation and linking this information to an inducible system to assess myeloid progenitor clones, we provide evidence that epigenetic markers of the cell whereTet2mutation occurs stratifies clonal behaviors. Specifically, Sox4 fosters a global cell state of high sensitization towardsTet2KO. Using GMP and primary HSC models, we show that Sox4 promotes cell dedifferentiation, alters cell metabolism and increases the in vivo clonal output of mutant cells. Our results validate the hypothesis that epigenetic features can predispose specific clones for dominance and explain why an identical mutation can result in different outcomes.