bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide association study in chondrocalcinosis reveals ENPP1 as a candidate therapeutic target in calcium pyrophosphate deposition disease
Authors: Takei Riku , Rosenthal Ann , Pascart Tristan , Reynolds Richard J. , Tedeschi Sara K. , Merriman Tony R.
Published: October 2024

Objective

The genetic basis of calcium pyrophosphate deposition (CPPD) disease is largely unknown. This limits the development of therapeutic strategies. We aimed to analyze a genome-wide association study (GWAS) on a large administrative database to identify new candidate causal genes for CPPD disease.

Methods

We used publicly available GWAS summary statistics for chondrocalcinosis and for crystal arthropathy from the Veterans Affairs Million Veteran Program in people of African (AFR) and European (EUR) ancestry. Included were 3,004 (536 AFR and 2,468 EUR) cases for chondrocalcinosis and 3,766 (700 AFR and 3,066 EUR) cases for crystal arthropathy. Our primary analysis was in chondrocalcinosis with secondary analysis in crystal arthropathy. We tested for colocalization of chondrocalcinosis genetic association signals with genetic control of gene expression.

Results

There were two genome-wide significant loci for chondrocalcinosis in both AFR and EUR, both on chromosome 6 (signals within theENPP1andRNF144Bgenes). Findings were supported by analysis of the crystal arthropathy cohort. Colocalization analysis of chondrocalcinosis genetic association signals with genetic control of gene expression and alternative splicing further supportedENPP1andRNF144Bas candidate casual genes. AtENPP1the allele that increases the risk for chondrocalcinosis associated with increasedENPP1expression.

Conclusion

ENPP1encodes ectonucleotide pyrophosphatase / phosphodiesterase family member 1 that produces AMP and pyrophosphate, potentially contributing to the formation of calcium pyrophosphate crystals. Selective ENPP1 inhibitors developed for infectious disease and cancer could be repurposed for the treatment of chondrocalcinosis and CPPD disease.
Multiplex PCR detection of enteric pathogens in a community-based birth cohort in Ecuador: comparison of xTAG-GPP and TaqMan array card assays
Authors: Ayala Stuart Torres , Vivanco Lesly Simbaña , Walas Nikolina , Jesser Kelsey , Zhou Nicolette A. , Fagnant-Sperati Christine S. , Burroughs Hadley R. , Lee Gwenyth O. , Eisenberg Joseph N.S. , Trueba Gabriel , Levy Karen , Arnold Benjamin F.
Published: October 2024

We compared the performance of two multiplex platforms, Luminex xTAG Gastrointestinal Pathogen Panel®and TaqMan Array Card, against a panel of 14 enteric pathogen targets in a community-based birth cohort in Ecuador. We found high levels of agreement and similar prevalence estimates across most pathogens.
Medication use patterns among older patients in temporary stays in Denmark
Authors: Harbi Hanin , Lundby Carina , Jensen Peter Bjødstrup , Larsen Søren Post , Rørbæk Linda Grouleff , Ravn-Nielsen Lene Vestergaard , Ryg Jesper , Reilev Mette , Edwards Kasper , Pottegård Anton
Published: October 2024

Background

Patients in temporary stays are typically older individuals with frailty and multimorbidity. However, limited knowledge exists about their medication use. This study aimed to describe prescription drug use among patients in temporary stays in Denmark.

Methods

We conducted a drug utilisation study on 11,424 patients in public healthcare-operated temporary stay units across 14 Danish municipalities between 2016 to 2023 (median age 81 years; 54% women). Prescription data were sourced from the Danish National Prescription Registry.

Results

Patients used a median of 6 drug classes (interquartile range [IQR] 4-10) in the four months before moving into a temporary stay facility; 68% used ≥ 5 drug classes, and 26% used ≥ 10. The most commonly used drug classes were paracetamol (49%), statins (30%), and proton pump inhibitors (29%). The monthly rate of new drug use increased from 23/100 patients six months before move-in to a peak of 262/100 patients in the first month after move-in, driven primarily by laxatives, analgesics, and antibiotics. High-risk drug use increased from 70% to 83% following move-in, with 49% of patients initiating at least one new high-risk drug, most commonly opioids (28%), potassium (17%), and anticoagulants (15%). General practitioners initiated 60%-70% of treatments and maintained 80%-90%. Hospital physician prescriptions increased around move-in, peaking at 55% for initiation and 25% for maintenance in the first month after move-in.

Conclusion

Patients in temporary stays in Denmark demonstrate high medication use, including high-risk drugs, with a notable increase in treatment initiations around the time of move-in.
Parity and cumulative incidence rates of breast cancer in the Norwegian Woman and Cancer Study (NOWAC)
Authors: Krum-Hansen Sanda , Wiik Arne Bastian , Olsen Karina Standahl , Lukic Marko , Paulssen Ruth H. , Lund Eiliv
Published: October 2024

Background

The reduced risk of breast cancer (BC) following increasing parity has been known for decades. Most prospective studies have presented the relative risk as the percentage decrease for each child during follow-up. Since the risk reduction is up to ten percent for each child, the overall lifelong BC risk reduction could be under communicated. In this study we use cumulative incidence rates (CIR) to calculate and describe the lifelong risk of BC in relation to parity.

Methods

NOWAC is a prospective cohort study with 172,000 women recruited between 1991 and 2007 with follow-up through questionnaires and national registers of cancer and death. For the present analyses, we included 165 238 women with follow-up from 01.01.2000 until 31.12. 2018. We calculated CIR of BC by parity, stratified by other established BC risk factors (maternal age at first birth, breastfeeding, body mass index (BMI), smoking and alcohol consumption).

Results

After 17.3 years of average follow-up, 8120 women aged 35-84 years developed breast cancer. Age-specific incidence rates increased for each age group up to 60-64 years, decreased for the age group 75-79 years, and increased again among the oldest women aged 80-84. CIR for all participants up to 84 years was 11 700 per 100 000 person years (PY). In analyses stratified by parity, the CIR of BC for nullipara was 12 600 per 100 000 PY, for 1-2 children: 12 100, 3-4 children: 10 200, and 5-6 children: 8 700 per 100 000 PY. The parity-specific CIR of BC had the same pattern of decrease in analyses stratified for other BC risk factors.

Conclusion

Cumulative incidence rates showed a consistent decrease in BC risk for each additional child. The decrease was consistent in strata of other established BC risk factors.
Capturing Trial-by-Trial Variability in Behaviour: People with Parkinson’s Disease Exhibit a Greater Rate of Short-Term Fluctuations in Response Times
Authors: MacDonald Hayley J. , Fasmer Ole Bernt , Jønsi Olav T. , Sørensen Lin
Published: October 2024

Average response time is frequently used to reflect executive function. Less often studied is intra-individual variability in response times (IIVRT) which reflects within-person consistency. Higher IIVRT in Parkinson’s disease (PD) has been associated with poor executive function but almost exclusively studied using standard deviations. Such linear measures cannot capture rapid and spontaneous changes in biological systems such as dopaminergic bursting activity. Therefore, nonlinear measures may provide important complementary insights into dopamine-related neurocognition. Our primary aim was to investigate nonlinear IIVRT measures in PD using graph theory, constituting the first use of this approach on RT data. As hypothesized, PD was associated with a greater rate of trial-by-trial IIVRT compared to healthy older adults. These novel results indicate that a similarity graph algorithm may be a useful tool to capture the more rapidly varying and spontaneous changes in RT behavior that result from the dysfunctional dopamine bursting dynamics present in PD.
Accelerated Biological Aging in Familial Pulmonary Fibrosis
Authors: Serezani Ana P.M. , Mitchell Daphne B. , Cogan Joy D. , Malabanan M. Merced U. , Markin Cheryl R. , Garnett Errine T. , Douglas Katrina , Fadely Tisra H. , Kropski Jonathan A. , Salisbury Margaret L. , Blackwell Timothy S.
Published: October 2024

Since Familial Pulmonary Fibrosis (FPF) manifests in older adults and telomere attrition is common in FPF and sporadic Idiopathic Pulmonary Fibrosis (IPF), we postulated that accelerated aging, as determined by epigenetic clock (DNA methylation) measurements, could occur in FPF. We measured DNAge from blood of patients with FPF and a group of first-degree relatives of FPF patients without disease (termed “at-risk” for FPF) with or without genetic rare variants (RVs) in telomerase pathway genes. We observed accelerated epigenetic aging with increased DNAge compared to chronological age in individuals at-risk for FPF and FPF patients compared to healthy controls. We found that increased DNAge manifests independently of the presence of RVs in telomerase pathway genes or telomere length in peripheral blood cells. These findings suggest that increased DNAge could be an independent risk factor for the development of FPF.
Association of Bleeding Risk With Recurrent Cardiovascular Events in Asian Patients with Acute Coronary Syndrome: A Nationwide Population-Based Cohort Study
Authors: Chen Chih-Wei , Lin Yi-Cheng , Lin Donna Shu-Han , Chang Chia-Li , Huang Chun-Yao , Chen Jaw-Wen , Lin Shing-Jong , Shao Yu-Hsuan , Hsu Chien-Yi
Published: October 2024

Background

Acute coronary syndrome (ACS) carries significant risks of recurrent cardiovascular (CV) events and bleeding complications. In particular, Asian patients have higher rates of bleeding complications due to genetic and physiological factors. Bleeding complications are associated with an increased risk of subsequent thrombotic events, and the impact of such complications on long-term outcomes must therefore be investigated. This study compared long-term outcomes and clinical characteristics between ACS patients who experienced a single ACS event and those who experienced multiple CV events.

Methods

Utilizing data from Taiwan’s National Health Insurance Research Database, this retrospective cohort study categorized patients into single-event and multiple-event groups based on the occurrence of major adverse CV events within 2 years after the index ACS event. In this cohort study, 28,535 patients were included. After matching by age, sex, and the interval between the first and second CV events at a 1:2 ratio, 8,720 patients were included in the multiple-event group and 17,368 in the single-event group.

Results

The multiple-event group had higher rates of comorbidities, including hypertension, prior coronary artery disease, heart failure, stroke, and chronic kidney disease. Over a 5-year period, the multiple-event group exhibited higher all-cause mortality (34.1% vs. 24.6%, p < 0.0001) and CV mortality (11.4% vs. 6.2%, p < 0.0001) than the single-event group. The rates of major bleeding events (7.8% vs. 1.6%, p < 0.0001) and minor bleeding events (34.4% vs. 7.2%, p < 0.0001) were also higher in the multiple-event group than in the single-event group. Compared with the single-event group, which showed a significant reduction in major bleeding events 1 month after the index ACS event, the multiple-event group continued to have a higher rate of major bleeding events within 3 months following the index ACS event. In the multiple-event group, patients who experienced a major bleeding event had an earlier onset of subsequent CV events than patients who did not experience a major bleeding event. Specifically, every 1-day earlier occurrence of major bleeding was associated with a 1.0044-day earlier occurrence of a subsequent CV event.

Conclusion

ACS patients with multiple CV events have higher rates of all-cause mortality, CV mortality, and major bleeding than ACS patients with a single CV event. However, major bleeding may be associated with the risk of subsequent CV events, highlighting the importance of implementing a tailored antiplatelet strategy in Asian populations.
Weight loss with different types of fasting in patients with type two diabetes and hypertension: a randomized clinical trial
Authors: Oshakbayev Kuat , Idrissov Alisher , Nabiyev Altay , Manekenova Kenzhekyz , Bedelbayeva Gulnara , Durmanova Aigul , Kuttymuratov Gani , Bikhanov Nurzhan , Dukenbayeva Bibazhar
Published: October 2024

Background

The coexistence of type two diabetes (T2D) and cardiovascular diseases (CVD) in patients with overweight increases the risk of macro-vascular complications. Some studies are controversial of the results of Ramadan fasting (RF) in patients T2D+CVD.

Objective

To compare different RF (antique and modern) on anthropometric, glycemic, blood pressure (BP), lipids, heel bone mineral density (HBMD), and ejection fraction (EF) in patients with T2D+CVD.

Methods

An open, 60-day, controlled, single-center, randomized clinical trial included 51 patients (29 women) with T2D+CVD: 26 in Main (antique RF); 25 in Controls (modern RF).Primary endpoints:weight loss, fasting blood glucose and, blood insulin, BP.Secondary endpoints:blood lipids, HBMD, and EF.

Results

Patients in Main lost weight –8.02 kg (P<0.0001), in Controls lost weight –2.67 kg (P<0.025); BMI in Main significantly decreased (P<0.0001), but in Controls did not significantly decrease (P>0.025). During a 30-day follow-up, Main did not regain weight and WC; but Controls regained weight and WC.

In Main BP, all glycemic parameters (fasting glucose, immunoassay insulin, HOMA-IR), lipids (cholesterol, triglyceride, HDL), HBMD, and EF in patients with and without heart failure (HF) were significantly normalized at 30-day RF (P<0.0001). In Controls BP and all glycemic parameters significantly improved but they did not achieve normal (P>0.025). In Controls HBMD and EF in patients with HF did not change (P>0.025). At 30-day follow-up, glycemic, BP, lipids, HBMD, and EF parameters did not significantly change in Main; but in Controls they worsened as weight regained.

Conclusion

Both the RF methods allowed weight loss, but antique RF led to markedly weight loss and significant positive change in glycemic, BP, lipids, bone mineralization, and EF in patients with T2D+CVD; the antique RF allowed patients to stop taking medications. The duration of the positive results depended on the maintenance of the achieved weight loss on RF.

Trial Registration

ClinicalTrials.govNCT06410352(05/08/2024):https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000EG8K&selectaction=Edit&uid=U0006MBT&ts=139&cx=bhsvd1
Cost-utility Analysis of Different Treatment Modalities in Patients Undergoing Percutaneous Coronary Intervention: Thai PCI Registry
Authors: Pattanaprateep Oraluck , Limpijankit Thosaphol , Anothaisintawee Thunyarat , Siriyotha Sukanya , Sansanayudh Nakarin , Thakkinstian Ammarin
Published: October 2024

Background

Cost-utility analyses of percutaneous coronary interventions (PCIs) provide valuable insights into the economic value of these procedures. This analysis aimed to compare the cost-utility of different treatment modalities used for PCI patients within a Thai PCI registry.

Methods

Clinical and quality-of-life data from 39 hospitals spread throughout Thailand were used in this analysis. Three treatment modalities for PCI procedures were compared: a) radial vs. femoral access, b) partial vs. complete revascularization for multivessel coronary artery disease, and c) use vs. non-use of device-guided PCIs (intracoronary ultrasound, optical coherence tomography or fractional flow reserve). Cost data were obtained from each patient’s bill for their hospital stay. Utility scores were measured using the Thai EQ-5D-5L at admission, discharge, and one-year post-procedure. The incremental cost-effectiveness ratio (ICER) was then estimated and used for each comparison.

Results

Of 19,701 patients enrolled in 2018-19, approximately one-third (n=7,332) had hospital cost data available for analysis. At discharge, the mean costs associated with radial access and partial revascularization were $986 and $391, respectively, less than the costs for device-guided PCIs, which increased by a mean of $2004. The delta utility gains for these approaches were 2.97, 1.60, and 1.07 at discharge and 1.08, 1.06, and 0.29 at one year, respectively. The estimated ICERs at one year were -$894, -$359, and $7041 per unit of utility gained, respectively.

Conclusion

Radial access and partial revascularization demonstrated cost-effectiveness, while device-guided PCI incurred high costs for the achieved utility scores. Identifying the factors that influence these outcomes may assist clinicians in tailoring interventions to optimize a patient’s quality of life after PCI.
Computational Microbiome Pharmacology Analysis Elucidates the Anti-Cancer Potential of Vaginal Microbes and Metabolites
Authors: Lawore Damilola C. , Jena Smrutiti , Berard Alicia R , Birse Kenzie , Lamont Alana , Mackelprang Romel D. , Noel-Romas Laura , Perner Michelle , Hou Xuanlin , Irungu Elizabeth , Mugo Nelly , Knodel Samantha , Muwonge Timothy R. , Katabira Elly , Hughes Sean M , Levy Claire , Calienes Fernanda L. , Hladik Florian , Lingappa Jairam R. , Burgener Adam D , Green Leopold N , Brubaker Douglas K.
Published: October 2024

The vaginal microbiome’s role in risk, progression, and treatment of female cancers has been widely explored. Yet, there remains a need to develop methods to understand the interaction of microbiome factors with host cells and to characterize their potential therapeutic functions. To address this challenge, we developed a systems biology framework we term the Pharmacobiome for microbiome pharmacology analysis. The Pharmacobiome framework evaluates similarities between microbes and microbial byproducts and known drugs based on their impact on host transcriptomic cellular signatures. Here, we apply our framework to characterization of the Anti-Gynecologic Cancer Vaginal Pharmacobiome. Using published vaginal microbiome multi-omics data from the Partners PrEP clinical trial, we constructed vaginal epithelial gene signatures associated with each profiled vaginal microbe and metabolite. We compared these microbiome-associated host gene signatures to post-drug perturbation host gene signatures associated with 35 FDA-approved anti-cancer drugs from the Library of Integrated Network-based Cellular Signatures database to identify vaginal microbes and metabolites with high statistical and functional similarity to these drugs. We found thatLactobacilliand their metabolites can regulate host gene expression in ways similar to many anti-cancer drugs. Additionally, we experimentally tested our model prediction that taurine, a metabolite produced byL. crispatus,kills cancerous breast and endometrial cancer cells. Our study shows that the Pharmacobiome is a powerful framework for characterizing the anti-cancer therapeutic potential of vaginal microbiome factors with generalizability to other cancers, microbiomes, and diseases.
The small GTPase Ran defines Nuclear Pore Complex Asymmetry
Authors: Sachweh Jenny , Börmel Mandy , Klumpe Sven , Becker Anja , Taniguchi Reiya , Kubańska Marta Anna , Pintschovius Verena , Kaindl Eva , Plitzko Jürgen M. , Wilfling Florian , Beck Martin , Hampoelz Bernhard
Published: October 2024

Nuclear pore complexes (NPCs) bridge across the nuclear envelope and mediate nucleocytoplasmic exchange. They consist of hundreds of nucleoporin building blocks and exemplify the structural complexity of macromolecular assemblies. To ensure transport directionality, different nucleoporin complexes are attached to the cytosolic and nuclear face of the NPC. How those asymmetric structures are faithfully assembled onto the symmetric scaffold architecture that exposes the same interaction surfaces to either side, remained enigmatic. Here we combine cryo-electron tomography, subtomogram averaging, and template matching with live cell imaging to address this question in budding yeast andDrosophila melanogaster. We genetically induce ectopic nuclear pores and show that pores outside the nuclear envelope are symmetric. We furthermore demonstrate that the peripheral NPC configuration depends on the nucleotide state of the small GTPase Ran. Our findings indicate that the nuclear transport system is self-regulatory, namely the same molecular mechanism controls both transport and transport channel composition.
Cardiolipin deficiency disrupts CoQ-complex III interface in steatohepatitis
Authors: Brothwell Marisa J. , Cao Guoshen , Maschek J. Alan , Poss Annelise M. , Peterlin Alek D. , Wang Liping , Baker Talia B. , Shahtout Justin L. , Siripoksup Piyarat , Pearce Quentinn J. , Johnson Jordan M. , Finger Fabian M. , Prola Alexandre , Pellizzari Sarah A. , Hale Gillian L. , Manuel Allison M. , Watanabe Shinya , Miranda Edwin R. , Affolter Kajsa E. , Tippetts Trevor S. , Nikolova Linda S. , Choi Ran Hee , Decker Stephen T. , Patil Mallikarjun , Catrow J. Leon , Holland William L. , Nowinski Sara M. , Lark Daniel S. , Fisher-Wellman Kelsey H. , Mimche Patrice N. , Evason Kimberley J. , Cox James E. , Summers Scott A. , Gerhart-Hines Zach , Funai Katsuhiko
Published: October 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to steatohepatitis (MASH). A key feature of the transition to MASH involves oxidative stress resulting from defects in mitochondrial oxidative phosphorylation (OXPHOS). Here, we show that pathological alterations in the lipid composition of the inner mitochondrial membrane (IMM) directly instigate electron transfer inefficiency to promote oxidative stress. Specifically, mitochondrial cardiolipin (CL) was downregulated with MASLD/MASH in mice and in humans. Hepatocyte-specific CL synthase knockout (CLS-LKO) led to spontaneous and robust MASH with extensive steatotic and fibrotic phenotype. Loss of CL paradoxically increased mitochondrial respiratory capacity but also reduced the formation of I+III2+IV1respiratory supercomplex and interfered with the ability of coenzyme Q (CoQ) to transfer electrons to complex III. In turn, the bottleneck at complex III promoted electron leak primarily at site IIIQ0as well as other upstream sites in the electron transport chain. Thus, reduction in mitochondrial CL promotes oxidative stress and contributes to pathogenesis of MASH.
Functional Impact of Nth-like DNA glycosylase on Mitochondrial Dynamics
Authors: Hubers Lisa , Sjetne Alexander Myr , Luna Luisa , Wågbø Ane Marit , Lefol Yohan , Galindo Francisco Jose Naranjo , Berg-Eriksen Anders Knoph , Visnes Torkild , Nilsen Hilde , Montaldo Nicola P.
Published: October 2024

Nth-like DNA glycosylase (NTHL1) is a base excision repair enzyme, with a crucial role both in nuclear and mitochondrial genomic maintenance. In this study, we demonstrate a key function of NTHL1 on mitochondrial DNA (mtDNA) maintenance and mitochondrial dynamics. Our results reveal significant accumulation of mitochondrial transcripts and increased mtDNA levels in NTHL1-deficient cells, accompanied by an accumulation of mtDNA lesions. These findings underscore the essential role of NTHL1 in protecting against mitochondrial genomic damage. In addition to increased OXPHOS mRNA and protein levels, Seahorse analyzer measurements further demonstrated enhanced mitochondrial respiratory capacity and elevated oxygen consumption rates. Furthermore, NTHL1 deficiency was associated with increased mitochondrial size and elevated protein levels of the mitochondrial fusion protein Dynamin-like GTPase OPA1, mitochondrial, long form (L-OPA1). Notably, NTHL1 knockout cells showed resistance to 1-methyl-4-phenylpyridinium (MPP+)-induced mitochondrial stress, indicating that the loss of NTHL1 promotes mitochondrial resilience and an adaptive response to oxidative stress. Combined, these findings indicate a complex phenotype where in NTHL1 plays a multifaceted role in mitochondrial maintenance and its loss leads to mild mitochondrial dysfunction that activates mitohormesis. This study thus extends the known functions of NTHL1 beyond nuclear DNA repair, highlighting its critical role in mitochondrial health and regulation of cellular resilience to oxidative stress.
Mgat4b mediated selectiveN-glycosylation regulates melanocyte development and melanoma progression
Authors: Sharma Babita , Aswin Keerthic , Jain Tanya , Nasreen Ayesha , Aggarwal Ayush , Subramaniam Yogaspoorthi , Rengaraju Jeyashri , Agrawal Srashti Jyoti , Bhatt Mayank , Paul Bhaskar , Chandrasekaran Koushika , Yadav Aanchal , Soni Jyoti , Ujjainiya Rajat , Akhter Md Quasid , Gupta Shantanu Sen , Pandey Rajesh , Suresh Shruthy , Sampathkumar Srinivasa-Gopalan , Natarajan Vivek T
Published: October 2024

Melanocyte development involves key pathways that are often recapitulated during melanoma initiation, highlighting the importance of understanding the regulators that control these early processes and also contribute to cancer onset. Our study identifiesmgat4b, a glycosyl transferase involved in selectiveN-glycan branching enriched in pigment progenitors, as a key regulator of directional melanocyte migration and establishment of melanocyte stem cell (McSC) pool during early development. Single cell RNA (scRNA) sequencing analysis in zebrafish upon targeted disruption ofmgat4breveals, that migratory melanocyte progenitors marked by galectin expression fail to persist. Lectin affinity proteomic analysis reveals the glycosylation of key melanocyte proteins GPNMB, KIT, and TYRP1 to be under the control of MGAT4B in melanocytic cells. Additionally, mislocalization of Junctional plakoglobin (JUP) explains the observed defects in cell adhesion and migration to be regulated by MGAT4B but not its isozyme MGAT4A. Our meta-analysis further reveals that melanoma patients with both the BRAFV600Emutation and elevated MGAT4B levels have significantly worse survival outcomes compared to those with only the BRAFV600Emutation. By leveraging the MAZERATI platform to model BRAFV600Edriver mutationin vivo, we show thatmgat4bmutant cells fail to aggregate and initiate tumors. RNA profiling of the transformed melanocytes revealed cell-cell junction, adhesion and ECM binding to be probable contributing factors that resulted in the failure of tumor onset. Using a small-molecule inhibitor we demonstrate the inhibitory role of this complexN-glycosylation in the progression of early-stage melanoma. Our study underscores the importance of selectiveN-glycan branching in both melanocyte development and melanoma initiation, suggesting MGAT4B as a promising therapeutic target for melanoma treatment.
Dissecting compounded hepatocyte injury in a model of MASLD progression from human induced pluripotent stem cells
Authors: Weihs Julian , Baldo Fatima , Cardinali Alessandra , Youssef Gehad , Ludwik Katarzyna , Stachelscheid Harald , Haep Nils , Tang Peter , Sauer Igor , Kumar Pavitra , Engelmann Cornelius , Quach Susanna , Bufler Philip , Han Namshik , Rezvani Milad
Published: October 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex, multifactorial condition influenced by genetic predisposition, inter-organ signaling, and immune cell infiltration. The difficulty of modeling the complex nature of the disease makes it increasingly challenging to identify treatments that intercept its progression. Here, we show the suitability of cumulative injury modeling toward steatohepatitis from hepatocyte-like cells (HLCs) generated from human induced pluripotent stem cells (iPSCs). These include insults such as free fatty acid excess, soluble extra-hepatic signaling, pro-inflammatory immune cell co-culture and genomic modifiers (PNPLA3-I148M variant). We harness this model to elucidate the molecular and functional consequences of hepatocellular injury progression and identify suitable points of therapeutic interception. Both healthy and PNPLA3-I148M iPSC-donor derived HLCs developed high-level generic steatosis response, yet the PNPLA3-I148M line was more susceptible to mitochondrial injury by the adipokine resistin and the myokine myostatin. Co-culture with peripheral blood mononuclear cells (PBMCs) compounded the previous multi-hit injury. Further, transcriptomic data revealed inflammatory HLC reprogramming and loss of genomically encoded mitochondrial metabolism along injury progression. We demonstrate a nuanced spectral metabolic injury model, mirroring clinical MASLD progression, suitable for testing stage and donor-specific disease interceptions.
Deep mutational scanning identifies variants of Cas1 and Cas2 that increase spacer acquisition in type II-A CRISPR-Cas systems
Authors: Hofmann Raphael , Herman Calvin , Mo Charlie Y. , Mathai Jacob , Marraffini Luciano A.
Published: October 2024

A remarkable feature of CRISPR-Cas systems is their ability to acquire short sequences from invading viruses to create a molecular record of infection. These sequences, known as spacers, are inserted into the CRISPR locus by the Cas1-Cas2 integrase complex and mediate sequence- specific immunity in prokaryotes. Spacer acquisition has been used to develop unique biotechnological applications such as the immunization of industrially relevant bacteria against bacteriophage infection and the recording of biological signals into stable genetic information. These technologies, however, are constrained by the low efficiency of the spacer acquisition process. To overcome this limitation, we developed a genetic system that combined deep mutational scanning (DMS) ofcasgenes from theStreptococcus pyogenestype II-A CRISPR- Cas system with a method that selects bacteria that acquire new spacers. This procedure enabled the identification ofcasmutations that support up to a sevenfold increase in the levels of spacer acquisition and a significant enhancement of immunity against phage infection. In addition, our analysis revealed key interactions at the Cas1-Cas2 interface critical for spacer integration. Our findings provide insights into the molecular determinants of spacer acquisition and offer a platform to improve CRISPR-Cas-based applications.
Biosynthesis of glucosaminyl phosphatidylglycerol inPseudomonas aeruginosa
Authors: Khan Fabiha Zaheen , Palmer Kelli L. , Guan Ziqiang
Published: October 2024

Glucosaminyl phosphatidylglycerol (GlcN-PG) was first identified in bacteria in the 1960s and was recently reported inPseudomonas aeruginosa. Despite the important implications in altering membrane charge (by the modification of anionic PG with cationic glucosamine), the biosynthesis and functions of GlcN-PG have remained uncharacterized. Using bioinformatic and lipidomic analysis, we identified a 3-gene operon, renamed asgpgSDF, that is responsible for the biosynthesis and potential transport of GlcN-PG inP. aeruginosa:gpgSencodes a novel glycotransferase that is responsible for the modification of phosphatidylglycerol (PG) withN-acetylglucosamine (GlcNAc) to produce GlcNAc-PG, andgpgDencodes a novel deacetylase that removes the acetyl group from GlcNAc-PG to produce GlcN-PG. The third gene in the operon,gpgF, is predicated to encode a flippase whose activity remains to be experimentally verified. As expected, the heterologous expression of thegpgSDFoperon inEscherichia coliresulted in production of both GlcNAc-PG and GlcN-PG. The identification of the biosynthetic genes of GlcN-PG paves the way for the investigation of its biological and pathological functions, which has significant implications in our understanding of the unique membrane physiology, pathogenesis and antimicrobial resistance ofP. aeruginosa.
Plexin/Semaphorin Antagonism Orchestrates Collective Cell Migration, Gap Closure and Organ sculpting by Contact-Mesenchymalization
Authors: Bischoff Maik C. , Norton Jenevieve E. , Peifer Mark
Published: October 2024

Cell behavior emerges from the intracellular distribution of properties like protrusion, contractility and adhesion. Thus, characteristic emergent rules of collective migration can arise from cell-cell contacts locally tweaking architecture – orchestrating self-regulation during development, wound healing, and cancer progression. The newDrosophilatestis-nascent-myotube-system allows dissection of contact-dependent migration in vivo at high resolution. Here, we describe a process driving gap-closure during migration: Contact-mesenchymalization via the axon guidance factor Plexin A. This is crucial for testis myotubes to migrate as a continuous sheet, allowing normal sculpting-morphogenesis. Cells must stay filopodial and dynamically ECM-tethered near cell-cell contacts to spread while collectively moving. Our data suggest Semaphorin 1B acts as a Plexin A antagonist, fine-tuning activation. Our data reveal a contact-dependent mechanism to maintain sheet-integrity during migration, driving organ-morphogenesis using a highly conserved pathway. This is relevant for understanding mesenchymal organ-sculpting and gap-closure in migratory contexts like angiogenesis.
A large reverse-genetic screen identifies numerous regulators of testis nascent myotube collective cell migration and collective organ sculpting
Authors: Bischoff Maik C. , Norton Jenevieve E. , Munguia Erika A. , Gurley Noah J. , Clark Sarah E. , Korankye Rebecca , Gyabaah Emmanuel Addai , Encarnacion Taino , Serody Christopher J. , Jones Corbin D. , Peifer Mark
Published: October 2024

Collective cell migration is critical for morphogenesis, homeostasis, and wound healing. During development migrating mesenchymal cells form tissues that shape some of the body’s organs. We have developed a powerful model for examining this, exploring how Drosophila testis nascent myotubes migrate onto the testis during pupal development, forming the muscles that ensheath it and also creating its characteristic spiral shape. To define genes that regulate this process, we have carried out RNAseq to define the genes expressed in myotubes during migration. Using this dataset, we curated a list of 131 ligands, receptors and cytoskeletal regulators, including all Rho-family GTPase GAPs and GEFs, as candidates. We then used the GAL4/UAS system to express 279 shRNAs targeting these genes, using the muscle specific driver dMef2>GAL4, and examined the adult testis. We identified 29 genes with diverse roles in testis morphogenesis. Some have phenotypes consistent with defects in collective cell migration, while others alter testis shape in different ways, revealing some of the underlying logic of testis morphogenesis. We followed up one of these genes in more detail—that encoding the Rho-family GEF dPix. dPix knockdown leads to a drastic reduction in migration and a substantial loss of muscle coverage. Our data suggest different isoforms of dPix play distinct roles in this process, reveal a role for its protein partner Git. We also explore whether cdc42 activity regulation or cell adhesion are among the dPix mechanisms of action. Together, our RNAseq dataset and genetic analysis will provide an important resource for the community to explore cell migration and organ morphogenesis.
Catabolism of extracellular glutathione supplies amino acids to support tumor growth
Authors: Hecht Fabio , Zocchi Marco , Tuttle Emily T. , Ward Nathan P. , Smith Bradley , Kang Yun Pyo , Cazarin Juliana , Soares Zamira G. , Ozgurses Mete Emir , Zhao Huiping , Sheehan Colin , Alimohammadi Fatemeh , Munger Lila D. , Trivedi Dhvani , Asantewaa Gloria , Blick-Nitko Sara K. , Zoeller Jason J. , Chen Ying , Vasiliou Vasilis , Turner Bradley M. , Muir Alexander , Coloff Jonathan L. , Munger Joshua , DeNicola Gina M. , Harris Isaac S.
Published: October 2024

Restricting amino acids from tumors is an emerging therapeutic strategy with significant promise. While typically considered an intracellular antioxidant with tumor-promoting capabilities, glutathione (GSH) is a tripeptide of cysteine, glutamate, and glycine that can be catabolized, yielding amino acids. The extent to which GSH-derived amino acids are essential to cancers is unclear. Here, we find that GSH catabolism promotes tumor growth. We show that depletion of intracellular GSH does not perturb tumor growth, and extracellular GSH is highly abundant in the tumor microenvironment, highlighting the potential importance of GSH outside of tumors. We find supplementation with GSH can rescue cancer cell survival and growth in cystine-deficient conditions, and this rescue is dependent on the catabolic activity of γ-glutamyltransferases (GGTs). Finally, pharmacologic targeting of GGTs’ activity prevents the breakdown of circulating GSH, lowers tumor cysteine levels, and slows tumor growth. Our findings indicate a non-canonical role for GSH in supporting tumors by acting as a reservoir of amino acids. Depriving tumors of extracellular GSH or inhibiting its breakdown is potentially a therapeutically tractable approach for patients with cancer. Further, these findings change our view of GSH and how amino acids, including cysteine, are supplied to cells.
Targetable treatment resistance in thyroid cancer with clonal hematopoiesis
Authors: Tiedje Vera , Vela Pablo Sánchez , Yang Julie L. , Untch Brian R. , Boucai Laura , Stonestrom Aaron J. , Costa Alberto Bueno , Expósito Sebastià Franch , Srivastava Avi , Kerpelev Marina , Greenberg Jillian , Wereski Mathew , Kulick Amanda , Chen Kevin , Qin Tianyue , Im Soo-Yeon , Krishnan Aishwarya , Martinez Benitez Anthony R. , Pluvinet Raquel , Sahin Merve , Menghrajani Kamal , Krishnamoorthy Gnana P. , de Stanchina Elisa , Zehir Ahmet , Satija Rahul , Knauf Jeffrey , Bowman Robert L , Esteller Manel , Devlin Sean , Berger Michael F. , Koche Richard P. , Fagin James A. , Levine Ross L
Published: October 2024

Anaplastic thyroid cancer (ATC) is a clinically aggressive malignancy with a dismal prognosis. Combined BRAF/MEK inhibition offers significant therapeutic benefit in patients withBRAFV600E-mutant ATCs. However, relapses are common and overall survival remains poor. Compared with differentiated thyroid cancer, a hallmark of ATCs is significant infiltration with myeloid cells, particularly macrophages. ATCs are most common in the aging population, which also has an increased incidence ofTET2-mutant clonal hematopoiesis (CH). CH-mutant macrophages have been shown to accelerate CH-associated pathophysiology including atherosclerosis. However, the clinical and mechanistic contribution of CH-mutant clones to solid tumour biology, prognosis and therapeutic response has not been elucidated. Here we show thatTET2-mutant CH is enriched in the tumour microenvironment of patients with solid tumours and associated with adverse prognosis in ATC patients. We find thatTet2-mutant macrophages selectively infiltrate mouseBrafV600E-mutant ATC and that their overexpression of Tgfβ-family ligands mediates resistance to BRAF/MEK inhibition. Importantly, inhibition of Tgfβ signaling restores sensitivity to MAPK pathway inhibition, opening a path for synergistic strategies to improve outcomes of patients with ATCs and concurrent CH.
Generalized design of sequence-ensemble-function relationships for intrinsically disordered proteins
Authors: Krueger Ryan , Brenner Michael P. , Shrinivas Krishna
Published: October 2024

The design of folded proteins has advanced significantly in recent years. However, many proteins and protein regions are intrinsically disordered (IDPs) and lack a stable fold i.e., the sequence of an IDP encodes a vast ensemble of spatial conformations that specify its biological function. This conformational plasticity and heterogeneity makes IDP design challenging. Here, we introduce a computational framework for de novo design of IDPs through rational and efficient inversion of molecular simulations that approximate the underlying sequence to ensemble relationship. We highlight the versatility of this approach by designing IDPs with diverse properties and arbitrary sequence constraints. These include IDPs with target ensemble dimensions, loops and linkers, highly sensitive sensors of physicochemical stimuli, and binders to target disordered substrates with distinct conformational biases. Overall, our method provides a general framework for designing sequence-ensemble-function relationships of biological macromolecules.
An abstract relational map emerges in the human medial prefrontal cortex with consolidation
Authors: Baram Alon , Nili Hamed , Barreiros Ines , Samborska Veronika , Behrens Timothy E. J. , Garvert Mona M.
Published: October 2024

Understanding the structure of a problem, such as the relationships between stimuli, supports fast learning and flexible reasoning. Recent theoretical suggestions have highlighted the usefulness of explicit structural representations that are fully divorced from sensory details for generalisation. Rodent work has suggested that abstraction of structure occurs gradually, over time, in cortex. However, direct evidence of such explicit relational representations in humans is scarce, and its relationship to consolidation mechanisms is underexplored. Here, we use a graph-learning paradigm to find such a relational map in the human medial prefrontal cortex. Importantly, this representation was absent early after learning but emerged on the time scale of days. These results shed new light on neural representations underlying the remarkable human ability to draw accurate inferences from little data.
Phenomenology of TMD parton distributions in Drell-Yan and
Z0
boson production in a hadron structure oriented approach
Authors: Aslan F. , Boglione M. , Gonzalez-Hernandez J. O. , Rainaldi T. , Rogers T. C. , Simonelli A.
Published: October 2024

We present a first practical implementation of a recently proposed hadron structure oriented (HSO) approach to transverse momentum dependent (TMD) phenomenology applied to Drell-Yan-like processes, including lepton pair production at moderate Q2 and Z0 boson production. We compare and contrast general features of our methodology with other common practices and emphasize aspects that we view as improvements. Separately, we discuss the importance of treatments that preserve various theoretical properties of the nonperturbative parts of TMD parametrizations for future applications that have the extraction of hadron structure as a primary goal. These include the HSO’s preservation of a basic TMD parton-model-like framework even while accounting for full TMD factorization and evolution, explicit preservation of the integral relationship between TMD and collinear parton density functions, and the ability to meaningfully compare different theoretical models of nonperturbative TMD parton distributions. In our examples, we show that there is significant sensitivity at moderate Q2 to both the form of the nonperturbative transverse momentum dependence and the parametrization of collinear parton densities. However, we also find that evolving to Q2=MZ2, without fitting, results in a satisfactory postdiction of existing data for Z0 production, nearly independently of the modeling of nonperturbative transverse momentum behavior. We argue that this demonstrates that moderate Q measurements should be given greater weight than high Q measurements in extractions of nonperturbative transverse momentum dependence. We also obtain new extractions of the nonperturbative Collins-Soper kernel within the HSO approach. We discuss its features and compare with some earlier extractions.

Published by the American Physical Society
2024
Electric dipole moments as probes of the
RD(*)
anomaly
Authors: Iguro Syuhei , Kitahara Teppei
Published: October 2024

The measurements of the lepton flavor universality (LFU) in B(B¯→D(*)lν¯) indicate a significant deviation from the standard model prediction at a 3–4σ level, revealing a violation of the LFU (RD(*) anomaly). It is known that the RD(*) anomaly can be easily accommodated by an SU(2)L-singlet vector leptoquark (LQ) coupled primarily to third-generation fermions, whose existence is further motivated by a partial gauge unification. In general, such a LQ naturally leads to additional CP-violating phases in the LQ interactions. In this paper, we point out that the current RD(*) anomaly prefers the CP-violating interaction although B(B¯→D(*)lν¯) are CP-conserving observables. The CP-violating LQ predicts a substantial size of the bottom-quark electric dipole moment (EDM), the chromo-EDM, and also the tau-lepton EDM. Eventually at low energy, the nucleon and electron EDMs are radiatively induced. Therefore, we conclude that the RD(*) anomaly with the SU(2)L-singlet vector LQ provides unique predictions: neutron and proton EDMs with opposite signs and a magnitude of O(10−27)  e cm, and suppressed electron EDM. Furthermore, we show that a similar EDM pattern is predicted in an SU(2)L-doublet scalar LQ scenario that can accommodate the RD(*) anomaly as well. These EDM signals could serve as crucial indicators in future experiments.

Published by the American Physical Society
2024
Quantum radiation reaction: Analytical approximations and obtaining the spectrum from moments
Authors: Torgrimsson Greger
Published: October 2024

We derive analytical χ≪1 approximations for spin-dependent quantum radiation reaction for locally constant and locally monochromatic fields. We show how to factor out fast spin oscillations and obtain the degree of polarization in the plane orthogonal to the magnetic field from the Frobenius norm of the Mueller matrix. We show that spin effects lead to a transseries in χ, with powers χk, logarithms (lnχ)k, and oscillating terms, cos(…/χ) and sin(…/χ). In our approach we can obtain each moment, ⟨(kP)m⟩, of the light-front longitudinal momentum independently of the other moments and without considering the spectrum. We show how to obtain a low-energy expansion of the spectrum from the moments by treating m as a continuous, complex parameter and performing an inverse Mellin transform. We also show how to obtain the spectrum, without making a low-energy approximation, from a handful of moments using the principle of maximum entropy.

Published by the American Physical Society
2024
Determinants of ChatGPT adoption among students in higher education: the moderating effect of trust
Authors: Foroughi Behzad , Iranmanesh Mohammad , Ghobakhloo Morteza , Senali Madugoda Gunaratnege , Annamalai Nagaletchimee , Naghmeh-Abbaspour Bita , Rejeb Abderahman
Published: October 2024

Purpose

ChatGPT is a cutting-edge chatbot powered by artificial intelligence that could revolutionise and advance the teaching and learning process. Drawing on the technology acceptance model (TAM) and information system (IS) success model, this study aims to investigate determinants of students’ intention to use ChatGPT for education purposes.

Design/methodology/approach

The partial least squares technique was used to analyse 406 usable data collected from university students in Malaysia.

Findings

The results confirmed the relationships between perceived usefulness (PU), perceived ease of use (PEU), attitude and intention to use proposed by TAM. PU and PEU are influenced by system quality. Surprisingly, trust in information moderates negatively the influences of PEU and PU on attitude.

Practical implications

The findings provide insight for higher education institutions, unit instructors and ChatGPT developers on what may promote the use of ChatGPT in higher education.

Originality/value

The study contributes to the literature by exploring the determinants of ChatGPT adoption, extending the TAM model by incorporating IS success factors and assessing the moderating effect of trust in information.