bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Silico Investigation of Biomechanical Response of a Human Brain Subjected to Primary Blast
Authors: Sutar Sunil , Ganpule S. G. 
Published: February 2024

Abstract
The brain response to the explosion-induced primary blast waves is actively sought. Over the past decade, reasonable progress has been made in the fundamental understanding of blast traumatic brain injury (bTBI) using head surrogates and animal models. Yet, the current understanding of how blast waves interact with human is in nascent stages, primarily due to the lack of data in human. The biomechanical response in human is critically required to faithfully establish the connection to the aforementioned bTBI models. In this work, the biomechanical cascade of the brain under a primary blast has been elucidated using a detailed, full-body human model. The full-body model allowed us to holistically probe short- (&lt;5 ms) and long-term (200 ms) brain responses. The full-body model has been extensively validated against impact loading in the past. We have further validated the head model against blast loading. We have also incorporated the structural anisotropy of the brain white matter. The blast wave transmission, and linear and rotational motion of the head were dominant pathways for the loading of the brain, and these loading paradigms generated distinct biomechanical fields within the brain. Blast transmission and linear motion of the head governed the volumetric response, whereas the rotational motion of the head governed the deviatoric response. Blast induced head rotation alone produced diffuse injury pattern in white matter fiber tracts. The biomechanical response under blast was comparable to the impact event. These insights will augment laboratory and clinical investigations of bTBI and help devise better blast mitigation strategies.
Analysis of Plastic Deformation of Pipes Due to Deflagration to Detonation Transition Using Static Equivalent Pressure
Authors: Müller Matthias , Bernhardi Otto-Ernst , Denecke Jens , Schildberg Hans-Peter , Schmidt Jürgen 
Published: February 2024

Abstract
Explosions of premixed gases with deflagration to detonation transition (DDT) are a risk in the process industry with potentially catastrophic consequences. Robust and simple design methods are required for industrial use. Such a simplified design method based on finite element analysis is proposed to model the dynamic behavior of pipes loaded by gas explosions of premixed gases including DDT. The focus is on so-called long pipes, where the DDT is not affected by reflections at blind flanges. First, it is reviewed how the pressure load of the gas explosion and the resulting material behavior has been modeled in previous publications. The analytical equations are then extended for describing the pressure load as a function of time and location by considering the leading compression wave as it affects the pressure load of the overdriven detonation. The extended analytical equations are parameterized using Chapman-Jouguet conditions and experimental results from publications for both static equivalent pressure and the location of the DDT. To describe the plastic material behavior at high strain rates, the well-known Johnson-Cook plasticity model is used. The material parameters of the model are derived from simple experiments, which are available in an industrial environment. The comparison of a finite element simulation with experimental data shows that the concept of equivalent static pressure can be extended to an finite element analysis, which in the future will allow the sizing of complete pipe systems including tees, bends, and flanges while considering plastic deformation.
Regulatory functions of homeobox domain transcription factors in fungi
Authors: Calvo A. M. , Dabholkar A. , Wyman E. M. , Lohmar J. M. , Cary J. W. 
Published: February 2024

ABSTRACT

Homeobox domain (HD) proteins present a crucial involvement in morphological differentiation and other functions in eukaryotes. Most HD genes encode transcription factors (TFs) that orchestrate a regulatory role in cellular and developmental decisions. In fungi, multiple studies have increased our understanding of these important HD regulators in recent years. These reports have revealed their role in fungal development, both sexual and asexual, as well as their importance in governing other biological processes in these organisms, including secondary metabolism, pathogenicity, and sensitivity to environmental stresses. Here, we provide a comprehensive review of the current knowledge on the regulatory roles of HD-TFs in fungi, with a special focus on
Aspergillus
species.
Pathogenesis of viral infections during pregnancy
Authors: Creisher Patrick S. , Klein Sabra L. 
Published: February 2024

SUMMARY
Viral infections during pregnancy are associated with significant adverse perinatal and fetal outcomes. Pregnancy is a unique immunologic and physiologic state, which can influence control of virus replication, severity of disease, and vertical transmission. The placenta is the organ of the maternal-fetal interface and provides defense against microbial infection while supporting the semi-allogeneic fetus via tolerogenic immune responses. Some viruses, such as cytomegalovirus, Zika virus, and rubella virus, can breach these defenses, directly infecting the fetus and having long-lasting consequences. Even without direct placental infection, other viruses, including respiratory viruses like influenza viruses and severe acute respiratory syndrome coronavirus 2, still cause placental damage and inflammation. Concentrations of progesterone and estrogens rise during pregnancy and contribute to immunological adaptations, placentation, and placental development and play a pivotal role in creating a tolerogenic environment at the maternal-fetal interface. Animal models, including mice, nonhuman primates, rabbits, and guinea pigs, are instrumental for mechanistic insights into the pathogenesis of viral infections during pregnancy and identification of targetable treatments to improve health outcomes of pregnant individuals and offspring.
Cryo-EM structure of rotavirus B NSP2 reveals its unique tertiary architecture
Authors: Chamera Sebastian , Wycisk Krzysztof , Czarnocki-Cieciura Mariusz , Nowotny Marcin 
Published: February 2024

ABSTRACT

Rotavirus (RV) NSP2 is a multifunctional RNA chaperone that exhibits numerous activities that are essential for replication and viral genome packaging. We performed an
in silico
analysis that highlighted a distant relationship of NSP2 from rotavirus B (RVB) to proteins from other human RVs. We solved a cryo-electron microscopy structure of RVB NSP2 that shows structural differences with corresponding proteins from other human RVs. Based on the structure, we identified amino acid residues that are involved in RNA interactions. Anisotropy titration experiments showed that these residues are important for nucleic acid binding. We also identified structural motifs that are conserved in all RV species. Collectively, our data complete the structural characterization of rotaviral NSP2 protein and demonstrate its structural diversity among RV species.

IMPORTANCE
Rotavirus B (RVB), also known as adult diarrhea rotavirus, has caused epidemics of severe diarrhea in China, India, and Bangladesh. Thousands of people are infected in a single RVB epidemic. However, information on this group of rotaviruses remains limited. As NSP2 is an essential protein in the viral life cycle, including its role in the formation of replication factories, it may be a target for future antiviral strategy against viruses with similar mechanisms.
Interaction between the SFTSV envelope glycoprotein Gn and STING inhibits the formation of the STING-TBK1 complex and suppresses the NF-κB signaling pathway
Authors: Jia Yupei , Li Feifei , Liu Zixiang , Liu Sihua , Huang Mengqian , Gao Xiaoning , Su Xin , Wang Zhiyun , Wang Tao 
Published: February 2024

ABSTRACT

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus with high pathogenicity. There has been a gradual increase in the number of reported cases in recent years, with high morbidity and mortality rates. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway plays an important role in the innate immune defense activated by viral infection; however, the role of the cGAS-STING signaling pathway during SFTSV infection is still unclear. In this study, we investigated the relationship between SFTSV infection and cGAS-STING signaling. We found that SFTSV infection caused the release of mitochondrial DNA into the cytoplasm and inhibits downstream innate immune signaling pathways by activating the cytoplasmic DNA receptor cGAS. We found that the SFTSV envelope glycoprotein Gn was a potent inhibitor of the cGAS-STING pathway and blocked the nuclear accumulation of interferon regulatory factor 3 and p65 to inhibit downstream innate immune signaling. Gn of SFTSV interacted with STING to inhibit STING dimerization and inhibited K27-ubiquitin modification of STING to disrupt the assembly of the STING-TANK-binding kinase 1 complex and downstream signaling. In addition, Gn was found to be involved in inducing STING degradation, further inhibiting the downstream immune response. In conclusion, this study identified the important role of the glycoprotein Gn in the antiviral innate immune response and revealed a novel mechanism of immune escape for SFTSV. Moreover, this study increases the understanding of the pathogenic mechanism of SFTSV and provides new insights for further treatment of SFTS.

IMPORTANCE
Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly discovered virus associated with severe hemorrhagic fever in humans. However, the role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway during SFTSV infection is still unclear. We found that SFTSV infection inhibits downstream innate immune signaling pathways by activating the cytoplasmic DNA receptor cGAS. In addition, SFTSV Gn blocked the nuclear accumulation of interferon regulatory factor 3 and p65 to inhibit downstream innate immune signaling. Moreover, we determined that Gn of SFTSV inhibited K27-ubiquitin modification of STING to disrupt the assembly of the STING-TANK-binding kinase 1 complex and downstream signaling. We found that the SFTSV envelope glycoprotein Gn is a potent inhibitor of the cGAS-STING pathway. In conclusion, this study highlights the crucial function of the glycoprotein Gn in the antiviral innate immune response and reveals a new method of immune escape of SFTSV.
Biosynthesis and function of 7-deazaguanine derivatives in bacteria and phages
Authors: de Crécy-Lagard Valérie , Hutinet Geoffrey , Cediel-Becerra José D. D. , Yuan Yifeng , Zallot Rémi , Chevrette Marc G. , Ratnayake R. M. Madhushi N. , Jaroch Marshall , Quaiyum Samia , Bruner Steven 
Published: February 2024

SUMMARY
Deazaguanine modifications play multifaceted roles in the molecular biology of DNA and tRNA, shaping diverse yet essential biological processes, including the nuanced fine-tuning of translation efficiency and the intricate modulation of codon-anticodon interactions. Beyond their roles in translation, deazaguanine modifications contribute to cellular stress resistance, self-nonself discrimination mechanisms, and host evasion defenses, directly modulating the adaptability of living organisms. Deazaguanine moieties extend beyond nucleic acid modifications, manifesting in the structural diversity of biologically active natural products. Their roles in fundamental cellular processes and their presence in biologically active natural products underscore their versatility and pivotal contributions to the intricate web of molecular interactions within living organisms. Here, we discuss the current understanding of the biosynthesis and multifaceted functions of deazaguanines, shedding light on their diverse and dynamic roles in the molecular landscape of life.
New aspects characterizing non-obese NAFLD by the analysis of the intestinal flora and metabolites using a mouse model
Authors: Zhang Wenji , Cheng Wenli , Li JingHui , Huang Zhenrui , Lin Hui , Zhang Wenjuan 
Published: February 2024

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) is a major public health problem due to the high incidence affecting approximately one-third of the world’s population. NAFLD is usually linked to obesity and excessive weight. A subset of patients with NAFLD expresses normal or low body mass index; thus, the condition is called non-obese NAFLD or lean NAFLD. However, patients and healthcare professionals have little awareness and understanding of NAFLD in non-obese individuals. Furthermore, preclinical results from non-obese animal models with NAFLD are unclear. Gut microbiota and their metabolites in non-obese/lean-NAFLD patients differ from those in obese NAFLD patients. Therefore, we analyzed the biochemical indices, intestinal flora, and intestinal metabolites in a non-obese NAFLD mouse model established using a methionine-choline-deficient (MCD) diet. The significantly lean MCD mice had a remarkable fatty liver with lower serum triglyceride and free fatty acid levels, as well as higher alanine transaminase and aspartate transaminase levels than normal mice. 16S RNA sequencing of fecal DNA showed that the overall richness and diversity of the intestinal flora decreased in MCD mice, whereas the Firmicutes:Bacteroidota ratio was increased. g_
Tuzzerella
, s_
Bifidobacterium pseudolongum
, and s_
Faecalibaculum rodentium
were the predominant species in non-obese NAFLD mice. Fecal metabolomics using liquid chromatography-tandem mass spectrometry revealed the potential biomarkers for the prognosis and diagnosis of non-obese NAFLD, including high levels of tyramine glucuronide, 9,12,13-TriHOME, and pantetheine 4′-phosphate, and low levels of 3-carbamoyl-2-phenylpropionaldehyde, N-succinyl-L,L-2,6-diaminopimelate, 4-methyl-5-thiazoleethanol, homogentisic acid, and estriol. Our findings could be useful to identify and develop drugs to treat non-obese NAFLD and lean NAFLD.

IMPORTANCE

Patients and healthcare professionals have little awareness and understanding of NAFLD in non-obese individuals. In fact, about 40% of people with NAFLD worldwide are non-obese, and nearly one-fifth are lean. Lean NAFLD unfortunately may be unnoticed for years and remains undetected until hepatic damage is advanced and the prognosis is compromised. This study focused on the lean NAFLD, screened therapeutic agents, and biomarkers for the prognosis and diagnosis using MCD-induced male C57BL/6J mice. The metabolites tyramine glucuronide, 9,12,13-TriHOME, and pantetheine 4′-phosphate, together with the predominant flora including g_
Tuzzerella
, s_
Bifidobacterium pseudolongum
, and s_
Faecalibaculum rodentium
, were specific in non-obese NAFLD mice and might be used as targets for non-obese NAFLD drug exploration. This study is particularly significant for non-obese NAFLDs that need to be more actively noticed and vigilant.
Sleep deprivation-induced anxiety-like behaviors are associated with alterations in the gut microbiota and metabolites
Authors: Zhang Nana , Gao Xuefeng , Li Donghao , Xu Lijuan , Zhou Guanzhou , Xu Mengqi , Peng Lihua , Sun Gang , Pan Fei , Li Yan , Ren Rongrong , Huang Ruolan , Yang Yunsheng , Wang Zikai 
Published: February 2024

ABSTRACT

The present study aimed to characterize the gut microbiota and serum metabolome changes associated with sleep deprivation (SD) as well as to explore the potential benefits of multi-probiotic supplementation in alleviating SD-related mental health disorders. Rats were subjected to 7 days of SD, followed by 14 days of multi-probiotics or saline administration. Open-field tests were conducted at baseline, end of SD (day 7), and after 14 days of saline or multi-probiotic gavage (day 21). Metagenomic sequencing was conducted on fecal samples, and serum metabolites were measured by untargeted liquid chromatography tandem-mass spectrometry. At day 7, anxiety-like behaviors, including significant decreases in total movement distance (
P
= 0.0002) and staying time in the central zone (
P
= 0.021), were observed. In addition, increased levels of lipopolysaccharide (LPS;
P
= 0.028) and decreased levels of uridine (
P
= 0.018) and tryptophan (
P
= 0.01) were detected in rats after 7 days of SD. After SD, the richness of the gut bacterial community increased, and the levels of
Akkermansia muciniphila
,
Muribaculum intestinale
, and
Bacteroides caecimuris
decreased. The changes in the host metabolism and gut microbiota composition were strongly associated with the anxiety-like behaviors caused by SD. In addition, multi-probiotic supplementation for 14 days modestly improved the anxiety-like behaviors in SD rats but significantly reduced the serum level of LPS (
P
= 0.045). In conclusion, SD induces changes in the gut microbiota and serum metabolites, which may contribute to the development of chronic inflammatory responses and affect the gut-brain axis, causing anxiety-like behaviors. Probiotic supplementation significantly reduces serum LPS, which may alleviate the influence of chronic inflammation.

IMPORTANCE
The disturbance in the gut microbiome and serum metabolome induced by SD may be involved in anxiety-like behaviors. Probiotic supplementation decreases serum levels of LPS, but this reduction may be insufficient for alleviating SD-induced anxiety-like behaviors.
Epidrugs: alternative chemotherapy targeting
Theileria annulata
schizont stage parasites
Authors: Kamble Sonam , Singh Sakshi , Suresh Akash , Singothu Siva , Dandesena Debabrata , Bhandari Vasundhra , Sharma Paresh 
Published: February 2024

ABSTRACT

The growing emergence of resistance to current anti-theilerial agents necessitates the exploration of alternative approaches to drug discovery. This study evaluated the antiparasitic efficacy of 148 compounds derived from an epigenetic inhibitor library against the schizont stage of a
Theileria annulata
-infected cell line. Initial screening at a concentration of 10 µM identified 27 compounds exhibiting promising anti-theilerial activity. Further investigation, including determination of the 50% inhibitory concentration (IC
50
) and host cell cytotoxicity assay, highlighted seven highly effective compounds (SAHA, BVT-948, Trichostatin A, Methylstat, Plumbagin, Ryuvidine, and TCE-5003) against
T. annulata
-infected cells. Analysis of the active compounds revealed their inhibitory action against various human targets, such as HDAC (SAHA and Trichostatin A), SET domain (Ryuvidine), PRMT (BVT-948 and TCE-5003), histone demethylase (Methylstat), and ROS/apoptosis inducer (Plumbagin). We identified gene orthologs of these targets in
Theileria
and conducted molecular docking studies, demonstrating effective binding of the compounds with their respective targets in the parasite, supported by
in vitro
data. Additionally, we performed
in silico
ADME/T predictions, which indicated potential mutagenic and hepatotoxic effects of Plumbagin, Methylstat, and TCE-5003, rendering them unsuitable for drug development. Conversely, SAHA, Trichostatin A, and BVT-948 showed promising characteristics and may represent potential candidates for future development as chemotherapeutic agents against tropical theileriosis. These findings provide valuable insights into the search for novel anti-theilerial drugs and offer a basis for further research in this area.

IMPORTANCE

Theileria annulata
is a protozoan parasite responsible for tropical theileriosis, a devastating disease affecting cattle. Traditional chemotherapy has limitations, and the study explores the potential of epidrugs as an alternative treatment approach. Epidrugs are compounds that modify gene expression without altering the underlying DNA sequence, offering a novel way to combat parasitic infections. This research is pivotal as it addresses the urgent need for innovative therapies against
T. annulata
, contributing to the development of more effective and targeted treatments for infected livestock. Successful implementation of epidrugs could not only enhance the well-being of cattle but also have broader implications for the control of parasitic diseases, showcasing the paper’s significance in advancing veterinary science and improving livestock health globally.
Identification of fungal natural products with potent inhibition in
Toxoplasma gondii
Authors: Jiang Tiantian , Godinez-Macias Karla P. , Collins Jennifer E. , Lee Jin Woo , Wendt Karen L. , Carolino Krypton , Chakrabarti Debopam , Cichewicz Robert H. , Winzeler Elizabeth A. 
Published: February 2024

ABSTRACT

In an effort to identify novel compounds with potent inhibition against
Toxoplasma gondii,
a phenotypic screen was performed utilizing a library of 683 pure compounds derived primarily from terrestrial and marine fungi. An initial screen with a fixed concentration of 5 µM yielded 91 hits with inhibition comparable to an equal concentration of artemisinin. These compounds were then triaged based on known biological and chemical concerns and liabilities. From these, 49 prioritized compounds were tested in a dose response format with
T. gondii
and human foreskin fibroblasts (HFFs) for cytotoxicity. Ten compounds were identified with an IC
50
less than 150 nM and a selectivity index (SI) greater than 100. An additional eight compounds demonstrated submicromolar IC
50
and SI values equal to or greater than 35. While the majority of these scaffolds have been previously implicated against apicomplexan parasites, their activities in
T. gondii
were largely unknown. Herein, we report the
T. gondii
activity of these compounds with chemotypes including xanthoquinodins, peptaibols, heptelidic acid analogs, and fumagillin analogs, with multiple compounds demonstrating exceptional potency in
T. gondii
and limited toxicity to HFFs at the highest concentrations tested.

IMPORTANCE

Current therapeutics for treating toxoplasmosis remain insufficient, demonstrating high cytotoxicity, poor bioavailability, limited efficacy, and drug resistance. Additional research is needed to develop novel compounds with high efficacy and low cytotoxicity. The success of artemisinin and other natural products in treating malaria highlights the potential of natural products as anti-protozoan therapeutics. However, the exploration of natural products in
T. gondii
drug discovery has been less comprehensive, leaving untapped potential. By leveraging the resources available for the malaria drug discovery campaign, we conducted a phenotypic screen utilizing a set of natural products previously screened against
Plasmodium falciparum
. Our study revealed 18 compounds with high potency and low cytotoxicity in
T. gondii
, including four novel scaffolds with no previously reported activity in
T. gondii
. These new scaffolds may serve as starting points for the development of toxoplasmosis therapeutics but could also serve as tool compounds for target identification studies using chemogenomic approach.