bluuebunny/crossref_metadata_2025 huggingface dataset:
Extensive exploration of structure activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment merging and active learning
Authors: Correy Galen J. , Rachman Moira , Togo Takaya , Gahbauer Stefan , Doruk Yagmur U. , Stevens Maisie , Jaishankar Priyadarshini , Kelley Brian , Goldman Brian , Schmidt Molly , Kramer Trevor , Ashworth Alan , Riley Patrick , Shoichet Brian K. , Renslo Adam R. , Walters W. Patrick , Fraser James S.
Published: August 2024

The macrodomain contained in the SARS-CoV-2 non-structural protein 3 (NSP3) is required for viral pathogenesis and lethality. Inhibitors that block the macrodomain could be a new therapeutic strategy for viral suppression. We previously performed a large-scale X-ray crystallography-based fragment screen and discovered a sub-micromolar inhibitor by fragment linking. However, this carboxylic acid-containing lead had poor membrane permeability and other liabilities that made optimization difficult. Here, we developed a shape- based virtual screening pipeline - FrankenROCS - to identify new macrodomain inhibitors using fragment X-ray crystal structures. We used FrankenROCS to exhaustively screen the Enamine high-throughput screening (HTS) collection of 2.1 million compounds and selected 39 compounds for testing, with the most potent compound having an IC50value equal to 130 μM. We then paired FrankenROCS with an active learning algorithm (Thompson sampling) to efficiently search the Enamine REAL database of 22 billion molecules, testing 32 compounds with the most potent having an IC50equal to 220 μM. Further optimization led to analogs with IC50values better than 10 μM, with X-ray crystal structures revealing diverse binding modes despite conserved chemical features. These analogs represent a new lead series with improved membrane permeability that is poised for optimization. In addition, the collection of 137 X-ray crystal structures with associated binding data will serve as a resource for the development of structure-based drug discovery methods. FrankenROCS may be a scalable method for fragment linking to exploit ever-growing synthesis-on- demand libraries.
AcrIF11 is a potent CRISPR-specific ADP-ribosyltransferase encoded by phage and plasmid
Authors: Chen Daphne F. , Roe Leah T. , Li Yuping , Borges Adair L. , Zhang Jenny Y. , Babbar Palak , Maji Sourobh , Stevens Maisie G.V. , Correy Galen J. , Diolaiti Morgan E. , Smith Dominique H. , Ashworth Alan , Stroud Robert M. , Kelly Mark J.S. , Bondy-Denomy Joseph , Fraser James S.
Published: August 2024

Phage-encoded anti-CRISPR (Acr) proteins inhibit CRISPR-Cas systems to allow phage replication and lysogeny maintenance. Most of the Acrs characterized to date are stable stoichiometric inhibitors, and while enzymatic Acrs have been characterized biochemically, little is known about their potency, specificity, and reversibility. Here, we examine AcrIF11, a widespread phage and plasmid-encoded ADP-ribosyltransferase (ART) that inhibits the Type I-F CRISPR-Cas system. We present an NMR structure of an AcrIF11 homolog that reveals chemical shift perturbations consistent with NAD (cofactor) binding. In experiments that model both lytic phage replication and MGE/lysogen stability under high targeting pressure, AcrIF11 is a highly potent CRISPR-Cas inhibitor and more robust to Cas protein level fluctuations than stoichiometric inhibitors. Furthermore, we demonstrate that AcrIF11 is remarkably specific, predominantly ADP-ribosylating Csy1 when expressed inP. aeruginosa. Given the reversible nature of ADP-ribosylation, we hypothesized that ADPr eraser enzymes (macrodomains) could remove ADPr from Csy1, a potential limitation of PTM-based CRISPR inhibition. We demonstrate that diverse macrodomains can indeed remove the modification from Csy1 inP. aeruginosalysate. Together, these experiments connect thein vitroobservations of AcrIF11’s enzymatic activity to its potent and specific effectsin vivo, clarifying the advantages and drawbacks of enzymatic Acrs in the evolutionary arms race between phages and bacteria.
COA5 has an essential role in the early stage of mitochondrial complex IV assembly
Authors: Tang Jia Xin , Cabrera-Orefice Alfredo , Meisterknecht Jana , Taylor Lucie S. , Monteuuis Geoffray , Stensland Maria Ekman , Szczepanek Adam , Stals Karen , Davison James , He Langping , Hopton Sila , Nyman Tuula A. , Jackson Christopher B. , Pyle Angela , Winter Monika , Wittig Ilka , Taylor Robert W.
Published: August 2024

Pathogenic variants in cytochromecoxidase assembly factor 5 (COA5), a proposed complex IV (CIV) assembly factor, have been shown to cause clinical mitochondrial disease with two siblings affected by neonatal hypertrophic cardiomyopathy manifesting a rare, homozygousCOA5missense variant (NM_001008215.3: c.157G>C, p.Ala53Pro). The most striking observation in the affected individuals was an isolated impairment in the early stage of mitochondrial CIV assembly. In this study, we report an unrelated family in who we have identified the sameCOA5variant with patient-derived fibroblasts and skeletal muscle biopsies replicating an isolated CIV deficiency. A CRISPR/Cas9-edited homozygousCOA5knockout U2OS cell line with similar biochemical profile was generated to interrogate the functional role of the human COA5 protein. Mitochondrial complexome profiling pinpointed a role for COA5 in early CIV assembly, more specifically, its involvement in the stage between MTCO1 maturation and the incorporation of MTCO2. We therefore propose that the COA5 protein plays an essential role for the biogenesis of MTCO2 and its integration into the early CIV assembly intermediate for downstream assembly of the functional holocomplex.
Visuomotor paired associative stimulation for post-stroke hand motor impairments
Authors: Picardi Michela , Guidali Giacomo , Caronni Antonio , Rota Viviana , Corbo Massimo , Bolognini Nadia
Published: August 2024

ABSTRACT

Objectives

We assess the effectiveness of a visuomotorpaired associative stimulation(vm-PAS) protocol targeting the Action Observation Network (AON) in patients with chronic post-stroke upper-limb hemiparesis. Vm-PAS consisted of hand-grasping action observation stimuli repeatedly paired with transcranial magnetic stimulation (TMS) pulses over the ipsilesional primary motor cortex (M1).

Methods

Fifteen post-stroke patients underwent a session of the vm-PAS and, as a control, of the standard excitatory PAS (M1-PAS), during which slow-rate electrical stimulation of the paretic limb was paired with M1-TMS. Before and after each PAS, we assessed corticospinal excitability (CSE), short-interval intracortical inhibition (SICI), and paretic wrist’s voluntary movements.

Results

The two protocols induce distinct muscle-specific CSE enhancements: vm-PAS increases motor- evoked potentials (MEPs) recorded from the pareticfirst dorsal interosseousmuscle. Conversely, M1-PAS increases MEPs recorded from the electrically stimulatedextensor carpi radialismuscle. Vm-PAS efficacy correlates with hemiparesis chronicity: the higher the time elapsed since the stroke, the greater vm-PAS effects on CSE. Neither protocol affected SICI or wrist movements.

Conclusion

Vm-PAS leads to muscle-specific enhancements of CSE in post-stroke patients, highlighting its potential for driving post-stroke motor recovery.

Significance

Our findings show the efficacy of a cross-modal PAS protocol targeting the AON in an injured motor system.
Break-induced replication drives large-scale genomic amplifications in cancer cells
Authors: Benamar Mouadh , Eki Rebeka , Du Kang-Ping , Abbas Tarek
Published: August 2024

DNA double-strand breaks (DSBs) are highly toxic lesions that underly the efficacy of ionizing radiation (IR) and a large number of cytotoxic chemotherapies1–3. Yet, abnormal repair of DSBs is associated with genomic instability and may contribute to cancer heterogeneity and tumour evolution. Here, we show that DSBs induced by IR, by DSB-inducing chemotherapeutics, or by the expression of a rare-cutting restriction endonuclease induce large-scale genomic amplification in human cancer cells. Importantly, the extent of DSB-induced genomic amplification (DIGA) in a panel of melanoma cell lines correlated with the degree of cytotoxicity elicited by IR, suggesting that DIGA contributes significantly to DSB-induced cancer cell lethality. DIGA, which is mediated through conservative DNA synthesis, does not require origin re-licensing, and is enhanced by the depletion or deletion of the methyltransferases SET8 and SUV4-20H1, which function sequentially to mono- and di-methylate histone H4 lysine 20 (H4K20) at DSBs to facilitate the recruitment of 53BP1-RIF1 and its downstream effector shieldin complex to DSBs to prevent hyper-resection4–11. Consistently, DIGA was enhanced in cells lacking 53BP1 or RIF1, or in cells that lacked components of the shieldin complex or of other factors that help recruit 53BP1 to DSBs. Mechanistically, DIGA requires MRE11/CtIP and EXO1, factors that promote resection and hyper-resection at DSBs, and is dependent on the catalytic activity of the RAD51 recombinase. Furthermore, deletion or depletion of POLD3, POLD4, or RAD52, proteins involved in break-induced replication (BIR), significantly inhibited DIGA, suggesting that DIGA is mediated through a RAD51-dependent BIR-like process. DIGA induction was maximal if the cells encountered DSBs in early and mid S-phase, whereas cells competent for homologous recombination (in late S and G2) exhibited less DIGA induction. We propose that unshielded, hyper-resected ends of DSBs may nucleate a replication-like intermediate that enables cytotoxic long-range genomic DNA amplification mediated through BIR.
Applying Prospective Tree-Temporal Scan Statistics to Genomic Surveillance Data to Detect Emerging SARS-CoV-2 Variants and Salmonellosis Clusters in New York City
Authors: Greene Sharon K. , Latash Julia , Peterson Eric R. , Levin-Rector Alison , Luoma Elizabeth , Wang Jade C. , Bernard Kevin , Olsen Aaron , Li Lan , Waechter HaeNa , Mattias Aria , Rohrer Rebecca , Kulldorff Martin
Published: August 2024

Genomic surveillance data are used to detect communicable disease clusters, typically by applying rule-based signaling criteria, which can be arbitrary. We applied the prospective tree-temporal scan statistic (TreeScan) to genomic data with a hierarchical nomenclature to search for recent case increases at any granularity, from large phylogenetic branches to small groups of indistinguishable isolates. Using COVID-19 and salmonellosis cases diagnosed among New York City (NYC) residents and reported to the NYC Health Department, we conducted weekly analyses to detect emerging SARS-CoV-2 variants based on Pango lineages and clusters ofSalmonellaisolates based on allele codes. The SARS-CoV-2 Omicron subvariant EG.5.1 first signaled as locally emerging on June 22, 2023, seven weeks before the World Health Organization designated it as a variant of interest. During one year of salmonellosis analyses, TreeScan detected fifteen credible clusters worth investigating for common exposures and two data quality issues for correction. A challenge was maintaining timely and specific lineage assignments, and a limitation was that genetic distances between tree nodes were not considered. By automatically sifting through genomic data and generating ranked shortlists of nodes with statistically unusual recent case increases, TreeScan assisted in detecting emerging communicable disease clusters and in prioritizing them for investigation.
JYNNEOS vaccination induced short-lived neutralizing antibody responses to monkeypox virus in naïve individuals
Authors: Phipps Kara , Yates Jennifer , Machowski Jessica , Bialosuknia Sean , Hunt Danielle , DuPuis Alan , Payne Anne , Lee William , McDonough Kathleen A.
Published: August 2024

Current studies of the JYNNEOS-induced neutralizing antibody response to monkeypox virus (MPXV) are limited by either short-term durability data, quantification in an endemic population, or lack of an infectious MPXV neutralization assay. We used plaque reduction neutralization test (PRNT) with authentic MPXV and vaccinia viruse (VACV) to assess antibody responses over twelve months of eight donors vaccinated with two doses of JYNNEOS. One donor previously received the ACAM2000 vaccine; seven donors were smallpox-vaccine naïve. The IgG response of the donors to VACV (L1R, B5R, and A33R) and MPXV (E8L, H3L, A35R) antigens and PRNT titers to both viruses peaked at eight weeks post-vaccination and waned thereafter in naïve donors. MPXV PRNT titers were especially low; no naïve donors produced a detectable PRNT90 titer. Our results suggest the MPXV humoral response produced by JYNNEOS is limited in naïve donors and invites further investigation into current mpox vaccination strategies and correlates of protection.
CAR-based therapeutic targets in pediatric high-grade glioma
Authors: Griffioen Myrthe M.M.R. , Metselaar Dennis S.
Published: August 2024

High-grade glioma (HGG) patients have a dismal prognosis, due to a lack of effective treatments. In order to change the fate of HGG patients and decrease the current treatment-related side effects, therapy focus has shifted in the past years to immunotherapy, such as chimeric antigen receptor (CAR)-based treatments. Recent developments in CAR-based therapy show promising results in adult glioma patients, and the first clinical trials for pediatric patients with HGG are in progress. However, there are significant differences between pediatric HGG (pHGG) and their adult counterparts, including the composition of the tumor immune microenvironment (TIME), which strongly influences CAR treatment responsiveness. Therefore, we here provide a systematic overview of CAR-based therapeutic targets in pHGG entities, focusing on clinical trials and preclinical research, and comparing them to adult glioma. We conclude that target expression, TIME and CAR treatment-related toxicities vary across pHGG entities and differ from adult HGG, which suggests the need for more tailored immunotherapeutic CAR approaches in pHGG. Overall, we provide a target roadmap for future development of CAR-based therapeutic strategies for pediatric HGG patients, who are in desperate need for novel therapies.

Graphical abstract

The number of potential CAR-based therapeutic targets for glioblastoma and pHGG.CAR: Chimeric antigen receptor; pHGG: pediatric high-grade glioma; DHG: H3 G34-mutant diffuse hemispheric glioma; DMG: H3 K27-altered diffuse midline glioma; PFA: posterior fossa ependymoma type A. Image was created inBiorender.com.
SLC30A8 rare variant modify contribution of common genetic and lifestyle factors toward type 2 diabetes
Authors: Jang Hye-Mi , Hwang Mi Yeong , Park Yi Seul , Kim Bong-Jo , Kim Young Jin
Published: August 2024

This study aimed to investigate the modifying effects of rare genetic variants on the risk of type 2 diabetes in the context of common genetic and lifestyle factors. We conducted a comprehensive analysis of genetic and lifestyle factors associated with type 2 diabetes in a cohort of 146,284 Korean individuals. Among them, 4,603 individuals developed type 2 diabetes during the follow-up period of up to 18 years. We calculated a polygenic risk score (PRS) for type 2 diabetes and identified carriers of the rare allele I349F at SLC30A8. A Healthy Lifestyle Score (HLS) was also derived from physical activity, obesity, smoking, diet, and sodium intake levels. Using Cox proportional hazards models, we analyzed how PRS, HLS, and I349F influenced type 2 diabetes incidence. Results showed that high PRS and poor lifestyle were associated with increased risk. Remarkably, I349F carriers exhibited a lower type 2 diabetes prevalence (5.4% compared to 11.7% in non-carriers) and reduced the impact of high PRS from 23.18% to 12.70%. This trend was consistent across different HLS categories, with I349F carriers displaying a lower risk of type 2 diabetes. The integration of common and rare genetic variants with lifestyle factors enhanced type 2 diabetes predictability in the Korean population. Our findings highlight the critical role of rare genetic variants in risk assessments and suggest that standard PRS and HLS metrics alone may be inadequate for predicting type 2 diabetes risk among carriers of such variants.

Author summary

In our study, we investigated how rare genetic variants affect the risk of developing type 2 diabetes, particularly when combined with common genetic and lifestyle factors. We analyzed data from over 146,000 Korean individuals, following their health outcomes for up to 18 years. During this time, 4,603 participants developed type 2 diabetes. We calculated a polygenic risk score (PRS) based on common genetic variants and examined lifestyle factors such as physical activity, diet, and smoking. We also identified individuals carrying a rare genetic variant (I349F) in the SLC30A8 gene, which appeared to have a protective effect against type 2 diabetes. Our findings show that individuals with high PRS and unhealthy lifestyles are at increased risk for the disease. However, those carrying the I349F variant had a significantly lower risk, even among those with high PRS and poor lifestyle habits. This suggests that rare genetic variants can play a crucial role, and that combining genetic and lifestyle factors provides a more accurate prediction of diabetes risk. Our work highlights the importance of including rare genetic variants in personalized risk assessments for type 2 diabetes.
GERPACYST- The Trial Protocol Of The Prospective, Multicenter, Interdisciplinary German Pancreas Club Cyst Registry
Authors: Honselmann Kim Christin , Marschner Jonathan , Staufenbiel Anna , Bertram Julia , Deichmann Steffen , Engelke Carsten , Kirstein Martha , Marquardt Jens , Damm Marko , Borowitzka Fanny , Phillip Veit , Pergolini Ilaria , Harder Felix , Braren Rickmer , Gemoll Timo , Roth Susanne , Krug Sebastian , Michalski Christoph W. , Jaster Robert , Keck Tobias , Wellner Ulrich Friedrich ,   the GERPACYST Study Group
Published: August 2024

Background

Cystic lesions of the pancreas have continued to present a clinical challenge for the past decades now. The increasing rate of detection, the lack of high-quality data on the natural biology of pancreatic cysts and the resulting difficulty to predict malignant transformation in different types of pancreatic cysts make patients with these diseases hard to manage. The German Pancreas Club Cyst Registry (GERPACYST) (DRKS00025927) establishes a platform to discover the natural entity specific biology of pancreatic cysts, in a multicenter manner that should allow to assess risk models for malignancy.

Method

This manuscript is written according to the SPIRIT guidelines. Ethical approval was obtained from the University of Luebeck (2024-265_1). In GERPACYST patients aged ≥18 years with a pancreatic cyst under surveillance or scheduled for surgery should be enrolled. Participating centers will complete an electronic Case Report Form (eCRF) via REDCap which is designed as a longitudinal study minimizing the input of repeated measures. Changes in patient baseline data, cyst characteristics, both endoscopic and imaging data will be entered typically every 6-12 months during patient follow-up. Biobanking will be performed, when available. Duration of observation per patient is up to a maximum of 20 years or until end of follow-up or death.

Discussion

GERPACYST will provide a valuable platform for clinical outcomes research. Fundamental factors affecting the development of pancreatic cysts over time will be identified. New research questions might be answered during the study period.

Trial registration

The study was prospectively registered at the German Clinical Trial Register (DRKS) under DRKS00025927 on September, 14th, 2021 before inclusion of the first patient. The Universal Trial Number (UTN) is U1111-1302-9822.

Trial sponsor

The study is sponsored by the German Pancreas Club (DPC) e.V. The sponsor has no role in study design, collection, management, interpretation or writing of the report. It is a mere supportive sponsoring.
Cardiothoracic Ratio (CTR) Among Patients Presenting for Chest X-ray in Radiology Department at Mulago National Referral Hospital: A Patients’ Health Indicator for Clinical Application
Authors: Musisi Alen , Nakatudde Rebecca , Namuwonge Oliver , Babirye Deborah , Kintu Ismail , Olweny Francis , Malumba Richard , Nakalanzi Victoria , Mubuuke Aloysius Gonzaga
Published: August 2024

Introduction/background

The heart is vital, and even minor dysfunctions can significantly impact the body. Cardiologists need always to determine heart size, which varies with physiological changes. Advanced measurement techniques are costly and often inaccessible to a common man. Measuring the cardiothoracic ratio (CTR) via conventional X-ray is a common and more affordable option, but there’s a need for even cheaper alternatives

Objective

To determine relationship between CTR and presenting clinical indications and to relate CTR to the body parameters to find an appropriate relationship that can be utilized in low resource facilities in determining heart size.

Methodology

This cross-sectional study involved 386 patients undergoing chest radiographs at Mulago National Specialized Hospital’s radiology department. Data were summarized using frequencies and percentages. Associations between the cardiothoracic ratio (CTR) and independent variables were analyzed using Pearson’s chi-square, Fisher’s exact test, Spearman’s correlation coefficient, simple linear regression, and multivariate regression. Statistical significance was set at a p-value of < 0.05.

Results

The median cardiothoracic ratio (CTR) was 0.46, with an interquartile range of 0.42 to 0.50. Female patients had a higher CTR than males. Significant positive correlations were found between CTR; and BMI (p < 0.001, correlation 0.21), and BSA (p = 0.016, correlation 0.12), and BSI (p < 0.001, correlation 0.19). The diagnostic accuracy of a linear regression equation containing BSA as an estimator of CTR showed relatively fair performance compared to the linear regression equations with BSI and BMI. It showed sensitivity, specificity, and positive and negative predictive values of 29.2%, 86.0%, 63.6%, and 59.0% for males, and 8.3%, 98.1%, 75.0%, and 60.7% for females, respectively.

Conclusion

BSA shows a moderately good relationship with CTR, while the influence of body habitus on CTR is minimal. Thus, using body parameters to predict CTR should be approached cautiously. We recommend conducting a similar study on a more diverse general population
Efficacy and safety of tirofiban after intravenous tenecteplase for acute ischemic stroke: the multicenter, randomized, placebo-controlled, double-blind, INSTANT trial protocol
Authors: Zhang Fan , Xiao Minghui , Zhang Cong , Yuan Guangxiong , Xie Zhiyong , Yin Yi , Zhou Ruize , Yuan Shanggui , Xiao Genxiang , Mei Donghuan , Zeng Xiaobing , Liu Huashi , Li Huadong , Liu Hongwen , Tan Jinchang , Chen Bin , Fu Qingqing , Li Bin , Lai Jinxing , Sun Wei , Xie Shuhua , Lai Zhaohui , Qiu Zhongming , Jiang Zidian , Liu Xianghong , Zeng Guoyong
Published: August 2024

Background

It is very common that symptoms do not improve or even worsen after intravenous thrombolysis (IVT) in acute ischemic stroke. However, it remains unknown whether early administration of tirofiban after IVT may improve clinical outcomes.

Objective

This trial aims to assess the efficacy and safety of early administration of tirofiban after intravenous thrombolysis with Tenecteplase in acute ischemic stroke within 24 hours of symptom onset.

Methods and design

The INSTANT trial is an investigator-initiated, randomized, placebo-controlled, double-blind, multicenter trial. Up to 310 patients with acute non-large/medium-sized vascular occlusion and non-atrial fibrillation stroke who are treated with intravenous tenecteplase will be consecutively randomized to intravenous tirofiban or placebo in a 1:1 ratio over two years across 50 intravenous thrombolysis-capable stroke centers in China. Subjects will be treated with intravenous tirofiban or placebo at a dose of 0.3 μg per kilogram of body weight per minute for 30 minutes, followed by a continuous infusion of 0.075 μg per kilogram per minute for up to 47.5 hours.

Outcomes

The primary efficacy outcome is the proportion of patients with excellent functional outcomes (defined as a score of 0-1 on the modified Rankin scale (mRS)) at 90 days. The secondary outcome is the proportion of patients achieving functional independence, defined as a mRS score of 0-2 at 90 days. Safety outcomes include symptomatic intracranial hemorrhage within 48 hours and mortality at 90 days.

Discussion

This randomized, double-blind, placebo-controlled trial will provide data regarding the role of early antiplatelet therapy with intravenous tirofiban after IVT.

Trial registry number

ChiCTR2300074368 (www.chictr.org.cn).
Strigolactone receptor DAD2 promotes lateral root formation inPetunia hybrida
Authors: Khuvung Khopeno , Courty Pierre-Emmanuel , Reinhardt Didier
Published: August 2024

Strigolactone regulates various aspects of plant development and interactions with beneficial microbes. While the role of SL in shoot development is highly conserved between monocots and dicots, its role in root system architecture is controversial and context-dependent, although most of the SL appears to be produced there. A central parameter in plant fitness is root-to-shoot ratio, which is determined by growth and branching activity of both, the root as well as the shoot. We used previously characterized mutants defective in SL biosynthesis and sensing to test the role of SL in root growth and branching. Here, we show that a mutant defective in the petunia strigolactone receptor (dad2) exhibits defects in root meristem activity and root branching. Notably, this phenotype is not observed in the SL biosynthetic mutantdad1, suggesting that DAD2 may perceive a strigolactone analogue that is produced in a DAD1-independently fashion. DAD2 is induced in cortex cells adjacent to lateral root primordia, where it allows them to penetrate the cortex and to grow out of the main root. We propose a model by which inducible SL perception in cells adjacent to LRPs promotes auxin-induced cell wall remodeling in the cortex to allow passage of lateral roots.

1-sentence summary

Lateral roots are initiated inside the main root, hence, they have to penetrate several cell layers to grow out. We propose that strigolactone cooperates with auxin to mediate lateral root emergence.
High-Throughput Assay for Predicting Diarrhea Risk Using a 2D Human Intestinal Stem Cell-Derived Model
Authors: Pike Colleen M , Levi James A , Boone Lauren A , Peddibhotla Swetha , Johnson Jacob , Zwarycz Bailey , Bunger Maureen K , Thelin William , Boazak Elizabeth M
Published: August 2024

Gastrointestinal toxicities (GITs) are the most prevalent adverse events (AE) reported in clinical trials, often resulting in dose-limitations that reduce drug efficacy and delay development and treatment optimization. Preclinical animal models do not accurately replicate human GI physiology, leaving few options for early detection of GI side effects prior to human studies. Development of an accurate model that predicts GIT earlier in drug discovery programs would better support successful clinical trial outcomes. Chemotherapeutics, which exhibit high rates of clinical GIT, frequently target mitotic cells. Therefore, we hypothesized that a model utilizing proliferative cell populations derived from human intestinal crypts would predict the occurrence of clinical GITs with high accuracy. Here, we describe the development of a multiparametric assay utilizing the RepliGut® Planar system, an intestinal stem cell-derived platform cultured in an accessible high throughput Transwell™ format. This assay addresses key physiological elements of GIT by assessing cell proliferation (EdU incorporation), cell abundance (DAPI quantification), and barrier function (TEER). Using this approach, we demonstrate that primary proliferative cell populations reproducibly respond to marketed chemotherapeutics at physiologic concentrations. To determine the ability of this model to predict clinical diarrhea risk, we evaluated a set of 30 drugs with known clinical diarrhea incidence in three human donors, comparing results to known plasma drug concentrations. This resulted in highly accurate predictions of diarrhea potential for each endpoint (balanced accuracy of 91% for DAPI, 90% for EdU, 88% for TEER) with minimal variation across human donors. In vitro toxicity screening using primary proliferative cells may enable improved safety evaluations, reducing the risk of AEs in clinical trials and ultimately lead to safer and more effective treatments for patients.
The Y951N patient mutation inactivates the intramolecular switch in human mitochondrial DNA POLγ
Authors: Forslund Josefin M. E. , Nguyen Tran V.H. , Parkash Vimal , Berner Andreas , Goffart Steffi , Pohjoismäki Jaakko L.O. , Wanrooij Paulina , Johansson Erik , Wanrooij Sjoerd
Published: August 2024

Mitochondrial DNA (mtDNA) stability, essential for cellular energy production, relies on DNA polymerase gamma (POLγ). Here, we show that the POLγ Y951N disease causing mutation induces replication stalling and severe mtDNA depletion. However, unlike other POLγ disease causing mutations, Y951N does not directly impair exonuclease activity and only mildly affects polymerase activity. Instead, we found that Y951N compromises the enzyme’s ability to efficiently toggle between DNA synthesis and degradation, and is thus the first patient-derived mutation with impaired polymerase-exonuclease switching. These findings provide new insights into the intramolecular switch when POLγ proofreads the newly-synthesized DNA strand, and reveal a new mechanism for causing mitochondrial DNA instability.

Significance Statement

DNA polymerase gamma (POLγ) is essential for copying mitochondrial DNA (mtDNA), which is crucial for our energy production. POLγ must accurately switch between making new DNA (polymerase activity) and correcting errors (exonuclease activity). While it is known that mutations in POLγ can cause mitochondrial diseases by directly impairing these enzymatic functions, this study reveals a new mechanism. The Y951N mutation disrupts POLγ’s ability to switch between these activities, leading to severe blockages in DNA replication and a loss of mtDNA in human cells, even without significant direct impairment of polymerase or exonuclease activities. These findings provide new insights into the origins of mitochondrial diseases.
Sex specific knee joint soft tissue mineralization with Fibrillin-1 mutation in male Tight Skin mice
Authors: Keenan Craig , Wang Xi , Dikmen Tayfun , Wen Yan , Ramos-Mucci Lorenzo , Shorter Emily , Abraham David , Bou-Gharios George , Poulet Blandine
Published: August 2024

Articular soft tissue mineralization and ossification are clear pathological signs of osteoarthritis joints. However their molecular and cellular aetiologies remain largely unknown. TGF-ß family members are known contributors to both pathological ossification and osteoarthritis development. In this study, we used a Fibrillin-1 mutant mouse, the Tight Skin mouse (TSK), to define the detrimental effects of abnormal Fbn1 in TSK mice and known high TGF-ß activity in joint pathology such as articular soft tissue mineralization and ossification.

Knee joints of male and Female TSK and Wild-type (WT) littermates were analysed my micro-CT imaging and histology for articular soft tissue pathologies, as well as OA severity. Both aged (10, 26, 35 and 52wks) and following in vivo non-invasive repetitive joint overloading were used.

We find that male TSK mice develop spontaneous soft tissue ossification from 26wks of age, followed by increased osteoarthritis at 1 year-old. In addition, knee joint overloading induced ligament and meniscal mineralisation and ossification in both WT and TSK male mice, but were significantly more severe in TSK knees, including ossification of the patella ligament and synovial lining. In contrast, female TSK knees did not develop more severe soft tissue mineralisation compared to littermate WT mice in neither aged nor overloaded knees.

We conclude that Fbn1 mutation, and possibly overactive TGF-ß activity in TSK mice, induce articular soft tissue ossification and osteoarthritis in a sex-specific manner. Further studies are needed to confirm the specific signalling involved and the relative protection from female mice from such pathologies.
Polyunsaturated fatty acid-derived lipid mediator networks characterize COVID-19 severity and risk for critical illness
Authors: Papadaki Maria , Pavlos Eleftherios , Dubourdeau Marc , Bailif Vincent , Badirou Kamal , Galani Ioanna-Evdokia , Papelis Dimitris , Kamperi Natalia , Triantafyllia Vasiliki , Siouti Lena , Salagianni Maria , Manioudaki Maria , Paschalidis Nikolaos , Vatsellas Giannis , Koukaki Evangelia , Rapti Vasiliki , Thanos Dimitris , Rovina Nikoletta , Poulakou Garyfallia , Cobat Aurelie , Casanova Jean-Laurent , Tamvakopoulos Constantin , Andreakos Evangelos
Published: August 2024

Severe COVID-19 is characterized by excessive inflammation leading to the development of pneumonia and acute respiratory distress syndrome. Bioactive lipid mediators (LMs) derived from ω6 and ω3 polyunsaturated fatty acids are central to the regulation of inflammation, controlling both its initiation and resolution. Still, their role in COVID-19 remains underexplored. By employing a holistic approach involving the analysis of white blood cell transcriptomes, targeted lipidomics, cytokine and immune cell profiling, across the spectrum of disease severity groups, we now show that LM networks are profoundly altered in COVID-19, correlate with inflammatory patterns, and stratify patients according to disease severity. Central to this are CYP450-derived LMs such as 20-HETE, lipid peroxidation metabolites such as iPF2a-VI, and lipoxygenase-derived LMs such as 12-HETE, all of which are major vasoactive mediators of inflammation. Among them, 20-HETE appears to be a promising prognostic biomarker for ICU admission and a potential therapeutic target for severe COVID-19 disease. Our study thus underscores the significance of LM networks in COVID-19 pathophysiology and sheds light into the broader mechanisms driving viral pneumonia in humans.
Genome-wide patterns of selection–drift variation strongly associate with organismal traits across the green plant lineage
Authors: Uthanumallian Kavitha , Del Cortona Andrea , Coelho Susana M. , De Clerck Olivier , Duchene Sebastian , Verbruggen Heroen
Published: August 2024

There are many gaps in our knowledge of how life cycle variation and organismal body architecture associate with molecular evolution. Using the diverse range of green algal body architectures and life cycle types as a test case, we hypothesize that increases in cytomorphological complexity are likely to be associated with a decrease in the effective population size, because larger-bodied organisms typically have smaller populations, resulting in increased drift. For life cycles, we expect haploid-dominant lineages to evolve under stronger selection intensity relative to diploid-dominant life cycles owing to masking of deleterious alleles in heterozygotes. We use a genome-scale data set spanning the phylogenetic diversity of green algae and phylogenetic comparative approaches to measure the relative selection intensity across different trait categories. We show stronger signatures of drift in lineages with more complex body architectures compared with unicellular lineages, which we consider to be a consequence of smaller effective population sizes of the more complex algae. Significantly higher rates of synonymous as well as nonsynonymous substitutions relative to other algal body architectures highlight that siphonous and siphonocladous body architectures, characteristic of many green seaweeds, form an interesting test case to study the potential impacts of genome redundancy on molecular evolution. Contrary to expectations, we show that levels of selection efficacy do not show a strong association with life cycle types in green algae. Taken together, our results underline the prominent impact of body architecture on the molecular evolution of green algal genomes.
Study of quantum decoherence at the Protvino to ORCA experiment
Authors: Bera Chinmay , Deepthi K. N.
Published: August 2024

Protvino to ORCA (oscillation research with cosmics in the abyss) (P2O) is an upcoming neutrino oscillation experiment with a very long baseline of 2595 km. Because of the substantial baseline, this experiment provides a unique opportunity to study the Earth matter effects over very large distances. This makes it a suitable experiment to investigate the environmental decoherence in neutrino oscillations, where the neutrino system could interact with a stochastic environment and lead to a loss in the coherence of neutrino states. In this work, we consider an open quantum system framework to simulate the neutrino oscillations in the P2O experiment and obtain bounds on the decoherence parameters in different phenomenological models. Here, we also consider that the decoherence parameter Γ depends on neutrino energy Eν as Γjk(Eν)=Γ0(EνE0)n. Furthermore, assuming the presence of decoherence in nature, we study the effect of it on the determination of neutrino mass hierarchy and CP violation at the P2O experiment.

Published by the American Physical Society
2024
Predicting Bubble Fragmentation in Superfluids
Authors: McMillan Jake , Flynn Thomas A. , Doran Ryan
Published: August 2024

In classical fluids, the Weber number is a dimensionless parameter that characterizes the flow of a multiphase fluid. The superfluid analogy of a classical multiphase fluid can be realized in a system of two or more immiscible Bose-Einstein condensates. These superfluid mixtures have been shown to display a wider variety of exotic dynamics than their single component counterparts. Here we systematically study the dynamics of a binary immiscible Bose-Einstein condensate in two dimensions, where a small bubble of the second component is used to “stir” the first component. We begin by rigorously mapping out the critical velocity for vortex shedding as a function of the size of the bubble, in analogy to the critical velocity of a laser spoon. Observing that the dynamics of the system depend on the initial size and velocity of the bubble, we then show that a dimensionless parameter with the same form as the Weber number accurately predicts the resulting bubble fragmentation.

Published by the American Physical Society
2024
Exponentially faster preparation of quantum dimers via driven-dissipative stabilization
Authors: Lim Kian Hwee , Mok Wai-Keong , You Jia-Bin , Kong Jian Feng , Aghamalyan Davit
Published: August 2024

We propose a rapid, high-fidelity, and noise-resistant scheme to generate many-body entanglement between multiple qubits stabilized by dissipation into a 1D bath. Using a carefully designed time-dependent drive, our scheme achieves a provably exponential speedup over state-of-the-art dissipative stabilization schemes in 1D baths, which require a timescale that diverges as the target fidelity approaches unity and scales exponentially with the number of qubits. To prepare quantum dimer pairs, our scheme only requires local 2-qubit control Hamiltonians, with a protocol time that is independent of system size. This provides a scalable and robust protocol for generating a large number of entangled dimer pairs on-demand, serving as a fundamental resource for many quantum metrology and quantum information processing tasks.

Published by the American Physical Society
2024
Intrinsic Motivation in Dynamical Control Systems
Authors: Tiomkin Stas , Nemenman Ilya , Polani Daniel , Tishby Naftali
Published: August 2024

Biological systems often choose actions without an explicit reward signal, a phenomenon known as intrinsic motivation. The computational principles underlying this behavior remain poorly understood. In this study, we investigate an information-theoretic approach to intrinsic motivation, based on maximizing an agent's empowerment (the mutual information between its past actions and future states). We show that this approach generalizes previous attempts to formalize intrinsic motivation, and we provide a computationally efficient algorithm for computing the necessary quantities. We test our approach on several benchmark control problems, and we explain its success in guiding intrinsically motivated behaviors by relating our information-theoretic control function to fundamental properties of the dynamical system representing the combined agent-environment system. This opens the door for designing practical artificial, intrinsically motivated controllers and for linking animal behaviors to their dynamical properties.

Published by the American Physical Society
2024
More than just a family affair? The preventive effect of privatized CEO communication on the perception of an organization in crisis
Authors: Denner Nora , Viererbl Benno , Weismantel Maike
Published: August 2024

Purpose

This study examines the role of CEO communication in effective crisis management. Specifically, it examines whether the communication of private information about a CEO can create a positive pre-crisis image that serves as a buffer during actual crises.

Design/methodology/approach

This study uses a 2x2 experimental design to analyze the effect of CEO communication (private information vs no private information) on pre-crisis image and its effectiveness in different types of crises (victim crisis vs preventable crisis).

Findings

The results of this research show that the communication of private information about a CEO contributes to the improvement of public image perceptions when a crisis occurs. This effect is influenced by the recipient’s identification with the organization as well as perceptions of empathy and competence toward the CEO. Notably, stronger effects are observed in the context of a victim crisis.

Originality/value

This study contributes to the field by highlighting the importance of CEO communication in crisis management and its potential to proactively build a positive pre-crisis image. In addition, it examines how this mechanism varies by crisis type, providing valuable insights for crisis communication strategies.
Service failure and negative Word-of-Mouth in Chinese retail banking: a moderated-mediation approach
Authors: Zhao Cong , Noman Abu Hanifa Md. , Abedin Mohammad Zoynul
Published: August 2024

Purpose

As opposed to conventional promotional methods, Word-of-Mouth (WOM) communication, especially when negative, significantly shapes customers’ repurchase decisions and preferences. Therefore, this study aims to examine the interplay between negative WOM and bank service failures, with a focus on the mediating role of customer switching intentions and the moderating role of switching costs in this relationship.

Design/methodology/approach

Using an online semi-structured questionnaire survey, a dataset comprising 411 responses was gathered from retail bank customers in China. This dataset was subsequently analyzed using SPSS PROCESS.

Findings

Consistent with the social exchange theory, our study revealed a significant relationship between service failure and both bank customers’ intention to switch and negative WOM communication. Additionally, we observed that switching intentions significantly influence negative WOM communications, acting as a mediator between service failures and negative WOM. Furthermore, our findings indicated that switching costs moderate the direct effect of service failures on negative WOM and moderate the indirect effect of service failures on negative WOM through switching intentions.

Research limitations/implications

This study provides significant policy implications aimed at minimizing bank service failures and subsequent negative WOM communications among bank customers.

Originality/value

This study empirically investigates the role of service failures in promoting negative WOM communication, demonstrating a partial mediation effect of switching intentions in this relationship. Moreover, the study highlights that switching costs moderate service failures’ impact on customers’ switching intentions.
Teachers’ understandings of the anger they feel toward their principals: a phenomenographic study
Authors: Özaslan Gökhan , Karakuzu Ölemez Sümeyranur Meryem , Polat Sultan , Balıkcı İlker Berat , Uyanık Mustafa
Published: August 2024

Purpose

The purpose of this study is to reveal the different ways in which a group of teachers understand the anger they feel toward the school principals with whom they interact.

Design/methodology/approach

The present study was designed and conducted as a phenomenography. In phenomenographic research, the number of different ways in which participants understand a particular phenomenon is revealed. The data from semi-structured interviews with 15 teachers who differed in terms of school level, gender and age were analyzed according to the phenomenographic tradition.

Findings

The analysis revealed that although the participants had eight different understandings of the anger in question, all participants had an understanding that was described as “An emotion arising from not being treated with the respect we deserve.”

Practical implications

The source of anger for the participating teachers was the behavior of their principals, which made them feel that they were not considered respectable and valuable. Incorporating this insight into the training of school leaders may lead to useful outcomes in improving the quality of interactions between principals and teachers.

Originality/value

As one of the few examples of phenomenographic research in educational management, the present study contributes to providing a solid foundation for exploring the anger that teachers feel toward their principals by showing how and in what ways participating teachers may understand this feeling.
Effect of smart tourism technology experience (STTE) on tourist satisfaction and tourist happiness in Bordeaux: the mediation role of self-gratification
Authors: Yuksel Faruk , Kement Uzeyir , Dogan Seden , Erkol Bayram Gul , Bayar Sinan Baran , Cobanoglu Cihan
Published: August 2024

Purpose

This study aims to investigate the effects of smart tourism technology experience (STTE) on tourist satisfaction and happiness in Bordeaux, with a focus on understanding the mediating role of self-gratification. By examining these relationships, the study seeks to provide insights into how smart tourism technologies can enhance tourist experiences.

Design/methodology/approach

The study uses partial least squares-structural equation modeling (PLS-SEM) to analyze data collected from 380 tourists who visited Bordeaux. The measurement model assesses reliability and validity, while the structural model evaluates the proposed hypotheses and the mediation effects of self-gratification.

Findings

The results confirm that STTE positively impacts tourist satisfaction, with accessibility, informativeness and personalization significantly enhancing tourist satisfaction, while interactivity does not. Tourist satisfaction, in turn, positively affects tourist happiness. Furthermore, self-gratification partially mediates the relationship between tourist satisfaction and happiness, highlighting its importance in the smart tourism context.

Originality/value

This research extends the understanding of STTE by demonstrating its effects on tourist satisfaction and happiness. It introduces the mediating role of self-gratification, providing a novel perspective on how personalized smart tourism experiences contribute to overall tourist happiness.