bluuebunny/crossref_metadata_2025 huggingface dataset:
An Anthropometric Study of the Morphologic Facial Index of Tibetan Youth in Tibet
Authors: Zhong Hua , Tong Qinghua
Published: February 2024

The purpose of this study was to understand sex differences and variations in facial indices among Tibetans and to create and evaluate anthropometric data on facial morphology. The study population consisted of 476 native Tibetans (241 males and 235 females) aged 18 to 24 years. The means and SD facial width was 133.53±7.31 mm for males and 133.95±8.10 mm for females; the difference between the sexes was not statistically significant. The means and SD facial height was 107.68±5.76 mm for males and 111.95±14.28 mm for females; the difference between the sexes was statistically significant (u=−8.394, P=0.000). The morphologic facial index was 80.86±5.82 (means±SD) for males and 83.91±11.90 (means±SD) for females; the difference between the sexes was statistically significant (u=−6.581, P=0.000). The proportion of the Tibetan male facial shape was hypereuryprosopic (45.6%) > euryprosopic (31.1%) > mesoprosopic (18.7%) > leptoprosopic (3.3%) > hyperleptoprosopic (1.2%). The proportion of the Tibetan female facial shape was hypereuryprosopic (25.5%) > mesoprosopic (22.6%) > euryprosopic (21.7%) > leptoprosopic (17.4%) > hyperleptoprosopic (12.8%). Facial width was positively correlated with height (male r=0.306, P=0.000; female r=0.144, P=0.027), weight (r=0.470, P=0.000 for males; r=0.337, P=0.000 for females), and BMI (r=0.378, P=0.000 for males; r=0.291, P=0.000 for females). Facial height was positively correlated with height (r=0.329, P=0.000 for males; r=0.137, P=0.035 for females) and weight (r=0.391, P=0.000 for males; r=0.170, P=0.009 for females). Facial height was positively correlated with BMI in Tibetan males (r=0.293, P=0.000), but no significant correlation was found in Tibetan females. The morphologic facial index of Tibetans was positively correlated with age (r=0.183, P=0.004 for males; r=0.171, P=0.009 for females). The results indicated that Tibetan youth in Tibet have a predominantly hypereuryprosopic facial shape and that facial features are related to age, height, and weight. Some common facial morphology features exist among the Tibet Tibetans, northeastern Indians, and Nepalese in the 3 different regions of the Sino-Tibetan language family. The data from this study provide basic information for the study of Tibetans in the fields of physical anthropology, forensic medicine, maxillofacial surgery, and plastic surgery.
Partial Reconstruction of the Auricle With the Tubed Postauricular Flap: A Case Report and Proposed Innovation for Flap Conditioning
Authors: Shteynberg Aleksandr , Silver Eric , Hazkour Nissim
Published: February 2024

The authors present a case of a partial auricular deformity acquired from a human bite that was reconstructed using a 3-stage posterior auricular tubed flap. Helical rim avulsions may be ideally reconstructed with a tubed flap created from lax postauricular soft tissue. During the third stage, division and inset of the inferior pedicle of the flap were complicated by venous congestion. The use of leech therapy and topical nitroglycerin successfully improved flap circulation. Given the occurrence of venous congestion due to a sudden change in flap blood circulation, the authors propose a pedicle compression device to be used in the future that assists with flap conditioning. This physiological delay helps minimize flap ischemia by allowing choke vessels to dilate within, thus increasing flap reliability. Therefore, when the pedicle is divided, improved circulation from the previously inset superior pedicle has been established with a decreased risk of venous congestion and arterial insufficiency.
Prognostic Factors for Anterior Cerebral Artery Aneurysms: A Single-Center Series
Authors: Zhou Han , Liu Heng-Jian , Wang Chao , Lin Yuan , Feng Yu-Gong
Published: February 2024

Objective:

The aim of the present study is to summarize the characteristics of anterior cerebral artery aneurysms and to explore the prognostic factors of microsurgical clipping treatment for anterior cerebral artery aneurysms.

Materials and Methods:

A total of 90 anterior cerebral artery aneurysms (ACAAs) are reviewed from January 2000 to July 2019. Patients are categorized into good outcome group and poor outcome group according to Glasgow outcome scale scores. Multiple factors, including clinical characteristics and aneurysms’ characteristics, are evaluated to identify the independent risk factors associated with prognosis of ACAAs.

Results:

This analysis reveals that in the ACAAs database the number of SAH (P=0.01), high H-H grade (P<0.001) and high Fisher grade (P<0.001) are correlated with prognosis of ACAAs. Finally, age (P=0.007, odds ratio=1.124, 95% CI: 1.033–1.223) and Hunt-Hess (grade III–V, P=0.022, odds ratio =59.77, 95% CI: 1.794–1991.298) are found to be independent risk factors for prognosis.

Conclusions:

The age and high Hunt-Hess grade seem to be important factors affecting the prognosis of ACAAs.
Nasopharyngeal carriage rate, serotype distribution, and antimicrobial profiles of Streptococcus pneumoniae among patients with acute respiratory tract infection in Manado, North Sulawesi, Indonesia
Authors: Purwanto Diana Shintawati , Khoeri Miftahuddin Majid , Tafroji Wisnu , Margaretha Kaligis Stefana Helena , Wilar Rocky , Kepel Billy Johnson , Raranta Hessyani Patricia Theodora , Gaghiwu Lidia , Hammerschmidt Sven , Ervina Waode Fifin , Safari Dodi
Published: February 2024

We studied the carriage rate, distribution of serotype, and antimicrobial profile of Streptococcus pneumoniae (S. pneumoniae) among patients with acute respiratory tract infections (ARTI) in two primary health centers and a tertiary referral hospital from 2019 to 2020 in Manado, North Sulawesi, Indonesia before 13-valent PCV (PCV13) introduction. 106 nasopharyngeal swab samples were collected from children and adult patients. Serotyping of S. pneumoniae strain was performed with sequential multiplex PCR and Quellung reaction. Antimicrobial profile was performed by the disk diffusion method. We identified thirty-one patients carried S. pneumoniae strains (29%). The S. pneumoniae carriage rate was found to be higher among children aged 2-5 years (13/32; 40.6%) than in children under 1 year (8/27; 29.6%), children and adolescents under 18 years of age (5/20; 25.0%) and adult patients (5/27; 18.5%). The distribution of serotypes varied, including 14, 18C, 19A, 23F, 19F and 35B (two strains each) and 1, 3, 6B, 6C, 31, 9V, 15C, 16F, 17F, 23A, 35F (one strain each) and non-typeable (9/31; 29%). We found S. pneumoniae isolates were susceptible to vancomycin (30/31; 97%), chloramphenicol (29/31; 94%), clindamycin (29/31; 94%), erythromycin (22/31; 71%), azithromycin (22/31; 71%), tetracycline (14/31; 45%), penicillin (11/31; 35%), and sulfamethoxazole/trimethoprim (10/31; 32%). This study provides supporting baseline data on distribution of serotype and antimicrobial profile of S. pneumoniae among patients with ARTI before PCV13 introduction in Manado, North Sulawesi, Indonesia.
Effect of Chemotherapeutic Agents on Natural Transformation Frequency in Acinetobacter baylyi
Authors: Winter Macaulay Ralph , Vos Michiel , Buckling Angus , Johnsen Pål Jarle , Harms Klaus
Published: February 2024

Natural transformation is the ability of a bacterial cell to take up extracellular DNA which is subsequently available for recombination into the chromosome (or maintenance as an extrachromosomal element). Like other mechanisms of horizontal gene transfer, natural transformation is a significant driver for the dissemination of antimicrobial resistance. Recent studies have shown that many pharmaceutical compounds such as antidepressants and anti-inflammatory drugs can upregulate transformation frequency in the model species Acinetobacter baylyi. Chemotherapeutic compounds have been shown to increase abundance of antimicrobial resistance genes and increase colonisation rates of potentially pathogenic bacteria in patient gastrointestinal tracts, indicating an increased risk of infection and providing a pool of pathogenicity or resistance genes for transformable commensal bacteria. We here test for the effect of six cancer chemotherapeutic compounds on A. baylyi natural transformation frequency, finding two compounds, docetaxel and daunorubicin, to significantly decrease transformation frequency, and daunorubicin to also decrease growth rate significantly. Enhancing our understanding of the effect of chemotherapeutic compounds on the frequency of natural transformation could aid in preventing the horizontal spread of antimicrobial resistance genes.
Minutes of the open plenary meetings of the International Committee on Systematics of Prokaryotes, 11 October 2022 and 14 December 2023
Authors: Oren Aharon
Published: February 2024

Open virtual plenary meetings of the International Committee on Systematics of Prokaryotes (ICSP) were held on 11 October 2022 and on 14 December 2023. To comply with Articles 4(d) and 5(d)(1) of the statutes of the ICSP, the minutes of these meetings are published here.
The transcription factor RIP140 regulates interferon γ signaling in breast cancer
Authors: Jalaguier S. , Kuehn A. , Petitpas C. , Dulom A. , Jacquemont R. , Assi C. , Sixou S. , Jeschke U. , Colinge J. , Cavaillès V.
Published: February 2024

RIP140 (receptor interacting protein of 140 kDa) is an important player in breast cancer (BC) by regulating key cellular pathways such as nuclear hormone receptors signaling. In order to identify additional genes specifically regulated by RIP140 in BC, we performed an RNA sequencing after silencing its expression in MCF-7 cells. We identified the interferon γ (IFNγ) signaling as being substantially repressed by RIP140 knock-down. Using theGBP1(guanylate binding protein 1) gene as a reporter of IFNγ signaling, we demonstrated its robust induction by RIP140 through an ISRE motif, leading to a significant reduction of its induction upon IFNγ treatment. Furthermore, we showed that low levels of RIP140 amplified the IFNγ-dependent inhibition of BC cell proliferation. In line with these data, reanalysis of transcriptomic data obtained in human BC samples, revealed that IFNγ levels were associated with good prognosis only for BC patients exhibiting tumors expressing low levels of RIP140, thus confirming its effect on the anti-tumor activity of IFNγ provided by our experimental data. Altogether, this study identifies RIP140 as a new regulator of IFNγ signaling in breast tumorigenesis.
Integrated Short-TE and Hadamard-edited Multi-Sequence (ISTHMUS) for Advanced MRS
Authors: Hui Steve C.N. , Murali-Manohar Saipavitra , Zöllner Helge J. , Hupfeld Kathleen E. , Davies-Jenkins Christopher W. , Gudmundson Aaron T. , Song Yulu , Yedavalli Vivek , Wisnowski Jessica L , Gagoski Borjan , Oeltzschner Georg , Edden Richard A.E.
Published: February 2024

Background

To examine data quality and reproducibility using ISTHMUS, which has been implemented as the standardized MR spectroscopy sequence for the multi-site Healthy Brain and Child Development (HBCD) study.

Methods

ISTHMUS is the consecutive acquisition of short-TE PRESS (32 transients) and long-TE HERCULES (224 transients) data with dual-TE water reference scans. Voxels were positioned in the centrum semiovale, dorsal anterior cingulate cortex, posterior cingulate cortex and bilateral thalamus regions. After acquisition, ISTHMUS data were separated into the PRESS and HERCULES portions for analysis and modeled separately using Osprey. In vivo experiments were performed in 10 healthy volunteers (6 female; 29.5±6.6 years). Each volunteer underwent two scans on the same day. Differences in metabolite measurements were examined. T2correction based on the dual-TE water integrals were compared with: 1) T2correction based the default white matter and gray matter T2reference values in Osprey; 2) shorter WM and GM T2values from recent literature; and 3) reduced CSF fractions.

Results

No significant difference in linewidth was observed between PRESS and HERCULES. Bilateral thalamus spectra had produced significantly higher (p<0.001) linewidth compared to the other three regions. Linewidth measurements were similar between scans, with scan-to-scan differences under 1 Hz for most subjects. Paired t-tests indicated a significant difference only in PRESS NAAG between the two thalamus scans (p=0.002). T2correction based on shorter T2values showed better agreement to the dual-TE water integral ratio.

Conclusions

ISTHMUS facilitated and standardized acquisition and post-processing and reduced operator workload to eliminate potential human error.

Highlights

ISTHMUS has been implemented into the HBCD study protocol.

It acquires both short-TE and Hadamard-edited transients.

ISTHMUS reduces operator workload.

ISTHMUS potentially allows improved T2 relaxation correction
Performance of GPT-4 on the American College of Radiology In-Service Examination
Authors: Payne David L. , Purohit Kush , Borrero Walter Morales , Chung Katherine , Hao Max , Mpoy Mutshipay , Jin Michael , Prasanna Prateek , Hill Virginia
Published: February 2024

Objectives

No study has evaluated the ability of ChatGPT-4 to answer image-rich diagnostic radiology board exam questions or assessed for model drift in GPT-4’s image interpretation abilities. In our study we evaluate GPT-4’s performance on the American College of Radiology (ACR) 2022 Diagnostic Radiology In-Training Examination (DXIT).

Methods

Questions were sequentially input into GPT-4 with a standardized prompt. Each answer was recorded and overall accuracy was calculated, as was logic-adjusted accuracy, and accuracy on image-based questions. This experiment was repeated several months later to assess for model drift.

Results

GPT-4 achieved 58.5% overall accuracy, lower than the PGY-3 average (61.9%) but higher than the PGY-2 average (52.8%). Adjusted accuracy was 52.8%. GPT-4 showed significantly higher (p = 0.012) confidence for correct answers (87.1%) compared to incorrect (84.0%). Performance on image-based questions was notably poorer (p < 0.001) at 45.4% compared to text-only questions (80.0%), with adjusted accuracy for image questions of 36.4%.

When the questions were repeated, GPT-4 chose a different answer 25.5% of the time and there was a small but insignificant decrease in accuracy.

Discussion

GPT-4 performed between PGY-2 and PGY-3 levels on the 2022 DXIT, but significantly poorer on image-based questions, and with large variability in answer choices across time points. This study underscores the potential and risks of using minimally-prompted general AI models in interpreting radiologic images as a diagnostic tool. Implementers of general AI radiology systems should exercise caution given the possibility of spurious yet confident responses.
A Neural Network Approach to Identify Left-Right Orientation of Anatomical Brain MRI
Authors: Nishimaki Kei , Iyatomi Hitoshi , Oishi Kenichi
Published: February 2024

Left-right orientation misidentification in brain MRIs presents significant challenges due to several factors, including metadata loss or ambiguity, which often occurs during the de-identification of medical images for research, conversion between image formats, software operations that strip or overwrite metadata, and the use of older imaging systems that stored orientation differently. This study presents a novel application of deep-learning to enhance the accuracy of left-right orientation identification in anatomical brain MRI scans. A three-dimensional Convolutional Neural Network model was trained using 350 MRIs and evaluated on eight distinct brain MRI databases, totaling 3,384 MRIs, to assess its performance across various conditions, including neurodegenerative diseases. The proposed deep-learning framework demonstrated a 99.6% accuracy in identifying the left-right orientation, thus addressing challenges associated with the loss of orientation metadata. GradCAM was used to visualize areas of the brain where the model focused, demonstrating the importance of the right planum temporale and surrounding areas in judging left-right orientation. The planum temporale is known to exhibit notable left-right asymmetry related to language functions, underscoring the biological validity of the model. More than half of the ten left-right misidentified MRIs involved notable brain feature variations, such as severe temporal lobe atrophy, arachnoidal cysts adjacent to the temporal lobe, or unusual cerebral torque, indicating areas for further investigation. This approach offers a potential solution to the persistent issue of left-right misorientation in brain MRIs and supports the reliability of neuroscientific research by ensuring accurate data interpretation.
Early-life exposures to specific commensal microbes prevent type 1 diabetes
Authors: Green Jamal , Deschaine John , Lubin Jean-Bernard , Flores Julia N. , Maddux Sarah , Duranova Tereza , Grimes Logan , Planet Paul J. , Eisenlohr Laurence C. , Silverman Michael A.
Published: February 2024

Early-life disruptions of the gut microbiome have long-lasting impacts on the risk of developing autoimmune diseases. How the composition of the early-life microbiota contributes to autoimmunity and whether manipulating it can prove therapeutically beneficial remains largely unexplored. Here we demonstrate that a simple consortium of nine early-life commensal bacteria (PedsCom) prevents type 1 diabetes (T1D) in diabetes-susceptible NOD mice. Remarkably, we find that this protection is completely dependent upon early-life colonization. During this critical time window of early-life colonization and immune development, specific microbes unexpectedly translocate from the gut to peripheral tissues and induce the tolerogenic responses required for T1D protection. These findings highlight how the timing and localization of microbial interactions during a pivotal stage of immune development contribute to protection from T1D. Altogether, these findings suggest an opportunity to develop microbial therapies for human infants to prevent autoimmune diseases.

One sentence summary

A defined consortium of early-life microbes shapes immune development and prevents type 1 diabetes.
A Machine Learning Enhanced EMS Mutagenesis Probability Map for Efficient Identification of Causal Mutations inCaenorhabditis elegans
Authors: Guo Zhengyang , Wang Shimin , Wang Yang , Wang Zi , Ou Guangshuo
Published: February 2024

Chemical mutagenesis-driven forward genetic screens are pivotal in unveiling gene functions, yet identifying causal mutations behind phenotypes remains laborious, hindering their high-throughput application. Here, we reveal a non-uniform mutation rate caused by Ethyl Methane Sulfonate (EMS) mutagenesis in theC. elegansgenome, indicating that mutation frequency is influenced by proximate sequence context and chromatin status. Leveraging these factors, we developed a Machine Learning enhanced pipeline to create a comprehensive EMS mutagenesis probability map for theC. elegansgenome. This map operates on the principle that causative mutations are enriched in genetic screens targeting specific phenotypes among random mutations. Applying this map to Whole Genome Sequencing (WGS) data of genetic suppressors that rescue aC. elegansciliary kinesin mutant, we successfully pinpointed causal mutations without generating recombinant inbred lines. This methodology can be adapted in other species, offering a scalable approach for identifying causal genes and revitalizing the effectiveness of forward genetic screens.

Significance statement

Exploring gene functions through chemical mutagenesis-driven genetic screens is pivotal, yet the cumbersome task of identifying causative mutations remains a bottleneck, limiting their high-throughput potential. In this investigation, we uncovered a non-uniform mutation pattern induced by Ethyl Methane Sulfonate (EMS) mutagenesis in theC. elegansgenome, highlighting the influence of proximate sequence context and chromatin status on mutation frequency. Leveraging these insights, we engineered a machine learning enhanced pipeline to construct a comprehensive EMS mutagenesis probability map for theC. elegansgenome. This map operates on the principle that causative mutations are selectively enriched in genetic screens targeting specific phenotypes amid the backdrop of random mutations.

Applying this mapping tool to Whole Genome Sequencing (WGS) data derived from genetic suppressors rescuing aC. elegansciliary kinesin mutant, we achieved precise identification of causal mutations without resorting to the conventional generation of recombinant inbred lines. Our work not only advances understanding of mutation dynamics but also revitalizes the efficacy of forward genetic screens, contributing to the refinement of genetic exploration methodologies with implications for various organisms.
Dominant nonsense mutations in efemp1 alter vertebral and craniofacial characteristics in adult zebrafish
Authors: Gómez Arianna Ericka , Alvarado Kurtis , Yase Rohda Ahmed , Hsu Yi-Hsiang , Hulleman John D. , Kwon Ronald Young
Published: February 2024

Heritable Disorders of Connective Tissues (HDCT) are a heterogenous, pleiotropic group of conditions that broadly affect connective tissues.EFEMP1is a member of the fibulin family of extracellular matrix (ECM) glycoproteins which is expressed in various human tissues. Individuals withEFEMP1variants have recently been identified and appear to have Marfan-like characteristics. Clinical phenotypes of these individuals include hernias, advanced bone age, tall stature, myopia, joint laxity, and thin skin.EFEMP1-associated HDCTs have been identified in individuals with biallelic and monoallelic variants. There is an urgent need to better understand the role ofEFEMP1in regulating connective tissues including bone, and the pathophysiological mechanisms underlying the spectrum of genotype-phenotype relationships seen in EFEMP1-associated HDCTs. To investigate the role ofEFEMP1in developing and adult bone, we used CRISPR-based editing to generate two efemp1 zebrafish alleles encoding for premature termination codons (PTCs) predicted to delete or severely alter the fibulin-type domain. Both alleles exhibited similar phenotypes in juvenile and adult fish. In juvenile fish, we did not identify changes in body size or vertebral development. In adults, we found significant changes in body length, bone microarchitecture, and craniofacial measurements in both heterozygous and homozygous mutant fish. These results expand our understanding of the role ofefemp1in the skeleton and highlight the potential for dominant nonsense variants to play a role in manifestation of clinical phenotypes inEFEMP1-associated HDCTs.
Characterization of an amyloidogenic intermediate of transthyretin by NMR relaxation dispersion
Authors: Leach Benjamin I. , Ferguson James A. , Morgan Gareth , Sun Xun , Kroon Gerard , Oyen David , Dyson H. Jane , Wright Peter E.
Published: February 2024

The aggregation pathway of transthyretin (TTR) proceeds through rate-limiting dissociation of the tetramer and partial misfolding of the monomers, which assemble into amyloid structures through a downhill polymerization mechanism. The structural features of the aggregation-prone monomeric intermediate are poorly understood. Characterization of amyloidogenic intermediates is challenging due to their propensity to aggregate at concentrations necessary for structural studies. NMR relaxation dispersion offers a unique opportunity to characterize these intermediates when they exchange on favorable timescales with NMR-visible ground states. To characterize the structural transitions associated with tetramer dissociation, we have analyzed ground-state chemical shift differences between the native tetramer and an engineered monomer in which the critical F87 side chain is replaced by glutamate. The secondary structure and overall fold of the F87E monomer is similar to that of the tetramer except for β-strand H. This strand populates two conformations, where it is either docked on the protein core or is displaced from the edge of the β-sheet formed by β-strands D, A, G, and H (DAGH β-sheet) and is dynamically disordered. Chemical shift differences derived from analysis of1H/15N single, double and zero quantum relaxation dispersion data provide insights into the structure of a low-lying excited state that exchanges with the ground state of the F87E monomer at a rate of 3800 s-1. Disruption of the subunit interfaces of the TTR tetramer leads to destabilization of edge strands in both β-sheets of the F87E monomer. Conformational fluctuations are propagated through the entire hydrogen bonding network of the DAGH β-sheet, from the inner β-strand H, which forms the strong dimer interface in the TTR tetramer, to outer strand D which is unfolded in TTR fibrils. Fluctuations are also propagated from the AB loop in the weak dimer interface to the EF helix, which undergoes structural remodeling in fibrils. The conformational fluctuations in both regions are enhanced at acidic pH where amyloid formation is most favorable. The relaxation dispersion data provide insights into the conformational dynamics of the amyloidogenic state of monomeric TTR that predispose it for structural remodeling and progression to amyloid fibrils.
Elevated prevalence of the global panzootic chytrid strain in Ecuadorian anurans of the Amazonian lowlands
Authors: Smart Utpal , McCracken Shawn F. , Brunner Rebecca M. , Rivera Clarissa , Rodriguez David
Published: February 2024

Considerable attention has been directed to studying the infection dynamics of the fungal pathogen,Batrachochytrium dendrobatidis(Bd), affecting amphibians in the high elevations of the Neotropics. Lowland forests of the same realm, on the other hand, remain relatively understudied in this context. Herein, an attempt to bridge this gap was made by investigating the occurrence ofBdin several anuran taxa inhabiting the Amazonian lowlands in the northeast of Ecuador. To this end, 207 anurans belonging to 10 different families, 25 different genera, and 55 distinct host species were sampled forBdDNA in 2008. Data on the taxonomy, morphology (i.e., weight and snout-vent length), and life-long aquatic dependency of hosts (i.e., aquatic index) were also collated to serve as potential predictors of infection prevalence. Genotyping via quantitative PCR revealed the presence of the global panzootic lineage ofBd(Bd-GPL) in the Ecuadorian Amazon. The overall infection prevalence ofBdwas determined to be 58%, which is a relatively high prevalence rate ofBdreported for any amphibian population from the lowlands of the Neotropics to date. A total of 88% of sampled anuran families tested positive for the infection at varying proportions. A logistic regression analysis showed a significant negative relationship between host weight and the proportion ofBdinfections (p < 0.05). However, no significant associations were observed between host taxonomy, aquatic dependency, or snout-vent length andBdprevalence. Our findings contribute to the understanding ofBddynamics in the Neotropical lowlands and emphasize the need for future research on the ecological factors influencingBdin the Amazon and their implications for amphibian conservation.
Lysosomal integrity suppresses TIR-1/SARM1 aggregation to restrain toxic propagation of p38 innate immunity
Authors: Tse-Kang Samantha Y. , Pukkila-Worley Read
Published: February 2024

Innate immunity in bacteria, plants and animals requires the specialized subset of TIR-domain proteins that are NAD+hydrolases. Aggregation of these TIR proteins engages their enzymatic activity, but it is not known how this protein multimerization is regulated. Here, we discovered that TIR oligomerization is exquisitely controlled to prevent immune toxicity. We found that p38 propagates its own activation by promoting the feedforward expression and aggregation of the lone enzymatic TIR protein in the nematodeC. elegans, TIR-1/SARM1. We performed a forward genetic screen to determine how the p38 positive feedforward loop is regulated. We discovered that the integrity of the specific lysosomal sub-compartment that expresses TIR-1/SARM1 is actively maintained to limit inappropriate aggregation of this protein and restrain toxic p38 immune activation. Thus, innate immune defenses in intestinal epithelial cells are regulated by specific control of TIR-1/SARM1 multimerization.
Foam rolling intervention improves lactate clearance after high-intensity exercise
Authors: Kasahara Kazuki , Oneyama Keita , Ito Takeru , Nakamura Masatoshi , Ochi Genta
Published: February 2024

Purpose

The effects foam rolling (FR) intervention on lactate clearance and the impaired executive function associated with fatigue after high-intensity exercise remain unclear. This study examined whether FR is an effective tool for fatigue recovery.

Methods

Eighteen healthy adults (10 males, 8 females; 21.8±1.7 years) without consistent exercise habits participated. The participants performed high-intensity exercises using an ergometer with a progressive load. Post-exercise FR intervention was compared with the control condition. Measurements included lactate, vigor/fatigue by the Profile of Mood States 2nd edition, cognitive function (cognitive task performance), and leg and body rating of perceived exertion (RPE) pre-and post-exercise, and post-intervention (5 min post-exercise).

Results

The blood lactate concentration post-FR intervention (−7.3±3.0 mmol/L) was significantly reduced. Increased lactate clearance by FR correlated with faster recovery of executive function for those with greater lactate clearance, although cognitive fatigue was not observed after high-intensity exercise (P= .086,r= 0.41). Lactate clearance was not significantly correlated with RPE in the FR condition, whereas RPE decreased with increased lactate clearance for those with greater lactate clearance in the control condition (leg;r= 0.778, body;r= 0.669).

Conclusions

These results indicated FR intervention may be an effective recovery tool for exhausting exercises.
AIBP controls TLR4 inflammarafts and mitochondrial dysfunction in a mouse model of Alzheimer’s disease
Authors: Kim Yi Sak , Choi Soo-Ho , Kim Keun-Young , Navia-Pelaez Juliana M. , Perkins Guy A. , Choi Seunghwan , Kim Jungsu , Nazarenkov Nicolaus , Rissman Robert A. , Ju Won-Kyu , Ellisman Mark H. , Miller Yury I.
Published: February 2024

Microglia-driven neuroinflammation plays an important role in the development of Alzheimer’s disease (AD). Microglia activation is accompanied by the formation and chronic maintenance of TLR4 inflammarafts, defined as enlarged and cholesterol-rich lipid rafts serving as an assembly platform for TLR4 dimers and complexes of other inflammatory receptors. The secreted apoA-I binding protein (APOA1BP or AIBP) binds TLR4 and selectively targets cholesterol depletion machinery to TLR4 inflammaraft expressing inflammatory, but not homeostatic microglia. Here we demonstrated that amyloid-beta (Aβ) induced formation of TLR4 inflammarafts in microglia in vitro and in the brain of APP/PS1 mice. Mitochondria in Apoa1bp-/-APP/PS1 microglia were hyperbranched and cupped, which was accompanied by increased ROS and the dilated ER. The size and number of Aβ plaques and neuronal cell death were significantly increased, and the animal survival was decreased in Apoa1bp-/-APP/PS1 compared to APP/PS1 female mice. These results suggest that AIBP exerts control of TLR4 inflammarafts and mitochondrial dynamics in microglia and plays a protective role in AD associated oxidative stress and neurodegeneration.
Gene expression plasticity of the mammalian brain circadian clock in response to photoperiod
Authors: Cox Olivia H. , Gianonni-Guzmán Manuel A. , Cartailler Jean-Philippe , Cottam Matthew A. , McMahon Douglas G.
Published: February 2024

Seasonal daylength, or circadian photoperiod, is a pervasive environmental signal that profoundly influences physiology and behavior. In mammals, the central circadian clock resides in the suprachiasmatic nuclei (SCN) of the hypothalamus where it receives retinal input and synchronizes, or entrains, organismal physiology and behavior to the prevailing light cycle. The process of entrainment induces sustained plasticity in the SCN, but the molecular mechanisms underlying SCN plasticity are incompletely understood. Entrainment to different photoperiods persistently alters the timing, waveform, period, and light resetting properties of the SCN clock and its driven rhythms. To elucidate novel molecular mechanisms of photoperiod plasticity, we performed RNAseq on whole SCN dissected from mice raised in Long (LD 16:8) and Short (LD 8:16) photoperiods. Fewer rhythmic genes were detected in Long photoperiod and in general the timing of gene expression rhythms was advanced 4-6 hours. However, a few genes showed significant delays, includingGem. There were significant changes in the expression clock-associated geneTimelessand in SCN genes related to light responses, neuropeptides, GABA, ion channels, and serotonin. Particularly striking were differences in the expression of the neuropeptide signaling genesProkr2andCck, as well as convergent regulation of the expression of three SCN light response genes,Dusp4,Rasd1, andGem. Transcriptional modulation ofDusp4andRasd1,and phase regulation ofGem,are compelling candidate molecular mechanisms for plasticity in the SCN light response through their modulation of the critical NMDAR-MAPK/ERK-CREB/CRE light signaling pathway in SCN neurons. Modulation ofProkr2andCckmay critically support SCN neural network reconfiguration during photoperiodic entrainment. Our findings identify the SCN light response and neuropeptide signaling gene sets as rich substrates for elucidating novel mechanisms of photoperiod plasticity.
Integrated multi-omics analyses reveal the pro-inflammatory and pro-fibrotic pulmonary macrophage subcluster in silicosis
Authors: Kang Hanyujie , Gu Xueqing , Cao Siyu , Tong Zhaohui , Song Nan
Published: February 2024

Background

Silicosis is a lethal occupational disease caused by long-term exposure to respirable silica dust. Pulmonary macrophages play a crucial role in mediating the initiation of silicosis. However, the phenotypic and functional heterogeneities of pulmonary macrophages in silicosis have not been well-studied.

Methods

The silicosis mouse model was established by intratracheal administration of silica suspension. Bronchoalveolar lavage fluids (BALFs) of mice were collected for the multiplex cytokine analysis. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were performed to reveal the heterogeneity and spatial localization of macrophages in the lung tissues. The formation of the fibrotic nodules was characterized by histology, hydroxyproline assay, and immunohistochemical staining, respectively. The expression of the pro-inflammatory or pro-fibrotic genes was investigated by quantitative polymerase chain reaction (qPCR).

Results

We found that the level of pro-inflammatory cytokines and chemokines is significantly increased in the BALFs of silicosis mice. Apparent collagen deposition can also be observed in the silicotic lung tissues. By scRNA-seq, we have identified a subpopulation of Mmp12himacrophages significantly expanding in the lung tissues of mice with silicosis. Spatial transcriptomics analysis further confirmed that the Mmp12himacrophages are mainly enriched in silicosis nodules. Pseudotime trajectory showed that these Mmp12himacrophages, highly expressing both pro-inflammatory and pro-fibrotic genes are derived from Ly6c+monocytes. Additionally, 4-octyl itaconate (4-OI) treatment, which can alleviate pulmonary fibrosis in silicosis mice, also reduces the enrichment of the Mmp12himacrophages. Moreover, we found a subset of macrophages in BALFs derived from patients with silicosis exhibited similar characteristics of Mmp12himacrophages in silicosis mice models.

Conclusions

Our study suggested that a group of Mmp12himacrophages highly express both pro-inflammatory and pro-fibrotic factors in silicosis mice, and thus may contribute to the progression of fibrosis. The findings have proposed new insights for understanding the heterogeneity of lung macrophages in silicosis, suggesting that the subset of Mmp12himacrophages may be a potential therapy target to further halt the progression of silicosis.
Nerve injury inhibitsOprd1andCnr1transcription through REST in primary sensory neurons
Authors: Subedi Ashok , Tiwari Aadhya , Etemad Asieh , Huang Yuying , Chatterjee Biji , McLeod Samantha M. , Lu Yungang , Gonzalez DiAngelo , Ghosh Krishna , Singh Sanjay K. , Ruiz Elisa , Grimm Sandra L. , Coarfa Cristian , Pan Hui-Lin , Majumder Sadhan
Published: February 2024

The transcription repressor REST in the dorsal root ganglion (DRG) is upregulated by peripheral nerve injury and promotes the development of chronic pain. However, the genes targeted by REST in neuropathic pain development remain unclear. The expression levels of 4 opioid receptor (Oprm1,Oprd1,Oprl1,Oprk1)and the cannabinoid CB1 receptor (Cnr1) genes in the DRG regulate nociception. In this study, we determined the role of REST in the control of their expression in the DRG induced by spared nerve injury (SNI) in both male and female mice. Transcriptomic analyses of male mouse DRGs followed by quantitative reverse transcription polymerase chain reaction analyses of both male and female mouse DRGs showed that SNI upregulated expression ofRestand downregulated mRNA levels of all 4 opioid receptor andCnr1genes, butOprm1was upregulated in female mice. Analysis of publicly available bioinformatic data suggested that REST binds to the promoter regions ofOprm1andCnr1. Chromatin immunoprecipitation analyses indicated differing levels of REST at these promoters in male and female mice. Full-lengthRestconditional knockout in primary sensory neurons reduced SNI-induced pain hypersensitivity and rescued the SNI-induced reduction in the expression ofOprd1andCnr1in the DRG in both male and female mice. Our results suggest that nerve injury represses the transcription ofOprd1andCnr1via REST in primary sensory neurons and that REST is a potential therapeutic target for neuropathic pain.
Glutamate as a co-agonist for acid-sensing ion channels to aggravate ischemic brain damage
Authors: Lai Ke , Pritišanac Iva , Liu Zhen-Qi , Liu Han-Wei , Gong Li-Na , Li Ming-Xian , Lu Jian-Fei , Qi Xin , Xu Tian-Le , Forman-Kay Julie , Shi Hai-Bo , Wang Lu-Yang , Yin Shan-Kai
Published: February 2024

Glutamate is traditionally viewed as the first messenger to activate N-methyl-D-aspartate receptors (NMDARs) and downstream cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other NMDAR-independent mechanisms3–7. Here we show that glutamate and its structural analogs, including NMDAR antagonist L-AP5 (or APV), robustly potentiated currents mediated by acid-sensing ion channels (ASICs) which are known for driving acidosis-induced neurotoxicity in stroke4. Glutamate increased the proton affinity and open probability of ASICs, aggravating ischemic neurotoxicity in bothin vitroandin vivomodels. Site-directed mutagenesis and structure-basedin silicomolecular docking and simulations uncovered a novel glutamate binding cavity in the extracellular domain of ASIC1a. Computational drug screening of NMDAR competitive antagonist analogs identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs, providing strong neuroprotection efficacy comparable to that in ASIC1a or other cation ion channel knockout mouse models4–7. We conclude that glutamate serves as the first messenger for ASICs to exacerbate neurotoxicity, and that selective blockage of glutamate binding sites on ASICs without affecting NMDARs may be of strategic importance for developing effective stroke therapeutics devoid of the psychotic side effects of NMDAR antagonists.
FECDO-Flexible and Efficient Coding for DNA Odyssey
Authors: Sun Fajia , Qian Long
Published: February 2024

DNA has been pursued as a compelling medium for digital data storage during the past decade. While large-scale data storage and random access have been achieved in artificial DNA, the synthesis cost keeps hindering DNA data storage from popularizing into daily life. In this study, we proposed a more efficient paradigm for digital data compressing to DNA, while excluding arbitrary sequence constraints. Both standalone neural networks and pre-trained language models were used to extract the intrinsic patterns of data, and generated probabilistic portrayal, which was then transformed into constraint-free nucleotide sequences with a hierarchical finite state machine. Utilizing these methods, a 12%-26% improvement of compression ratio was realized for various data, which directly translated to up to 26% reduction in DNA synthesis cost. Combined with the progress in DNA synthesis, our methods are expected to facilitate the realization of practical DNA data storage.
Differential weighting of information during aloud and silent reading: Evidence from representational similarity analysis of fMRI data
Authors: Bailey Lyam M. , Matheson Heath E. , Fawcett Jonathon M. , Bodner Glen E. , Newman Aaron J.
Published: February 2024

Single word reading depends on multiple types of information processing: readers must process low-level visual properties of the stimulus, form orthographic and phonological representations of the word, and retrieve semantic content from memory. Reading aloud introduces an additional type of processing wherein readers must execute an appropriate sequence of articulatory movements necessary to produce the word. To date, cognitive and neural differences between aloud and silent reading have mainly been ascribed to articulatory processes. However, it remains unclear whether articulatory information is used to discriminate unique words, at the neural level, during aloud reading. Moreover, very little work has investigated how other types of information processing might differ between the two tasks. The current work used representational similarity analysis (RSA) to interrogate fMRI data collected while participants read single words aloud or silently. RSA was implemented using a whole-brain searchlight procedure to characterize correspondence between neural data and each of five models representing a discrete type of information. Both conditions elicited decodability of visual, orthographic, phonological, and articulatory information, though to different degrees. Compared with reading silently, reading aloud elicited greater decodability of visual, phonological, and articulatory information. By contrast, silent reading elicited greater decodability of orthographic information in right anterior temporal lobe. These results support an adaptive view of reading whereby information is weighted according to its task relevance, in a manner that best suits the reader’s goals.
MicroRNA-26b protects against MASH development in mice and can be efficiently targeted with lipid nanoparticles
Authors: Peters Linsey J.F. , Rakateli Leonida , Huchzermeier Rosanna , Bonnin-Marquez Andrea , Maas Sanne L. , Lin Cheng , Jans Alexander , Geng Yana , Gorter Alan , Gijbels Marion J. , Rensen Sander S. , Olinga Peter , Hendrikx Tim , Krawczyk Marcin , Brisbois Malvina , Jankowski Joachim , Bidzhekov Kiril , Weber Christian , Biessen Erik A.L. , Shiri-Sverdlov Ronit , Houben Tom , Döring Yvonne , Bartneck Matthias , van der Vorst Emiel P.C.
Published: February 2024

Background & Aims

The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing, urging more research into the underlying mechanisms. MicroRNA-26b (miR-26b) might play a role in several MASH-related pathways. Therefore, we aimed to determine the role of miR-26b in MASH and its therapeutic potential using miR-26b mimic-loaded lipid nanoparticles (LNPs).

Methods

Apoe-/-Mir26b-/-,Apoe-/-LysMcreMir26bfl/flmice, and respective controls were fed a western-type diet to induce MASH. Plasma and liver samples were characterized regarding lipid metabolism, hepatic inflammation, and fibrosis. Additionally, miR-26b mimic-loaded LNPs were injected inApoe-/-Mir26b-/-mice to rescue the phenotype and key results were validated in human precision-cut liver slices. Finally, kinase profiling was used to elucidate underlying mechanisms.

Results

Apoe-/-Mir26b-/-mice showed increased hepatic lipid levels, coinciding with increased expression of scavenger receptor a and platelet glycoprotein 4. Similar effects were found in mice lacking myeloid-specificmiR-26b. Additionally, hepatic TNF and IL-6 levels and amount of infiltrated macrophages were increased inApoe-/-Mir26b-/-mice. Moreover,Tgfbexpression was increased by themiR-26bdeficiency, leading to more hepatic fibrosis. A murine treatment model with miR-26b mimic-loaded LNPs reduced hepatic lipids, rescuing the observed phenotype. Kinase profiling identified increased inflammatory signaling uponmiR-26bdeficiency, which was rescued by LNP treatment. Finally, miR-26b mimic-loaded LNPs also reduced inflammation in human precision-cut liver slices.

Conclusions

Overall, our study demonstrates that the detrimental effects ofmiR-26bdeficiency in MASH can be rescued by LNP treatment. This novel discovery leads to more insight into MASH development, opening doors to potential new treatment options using LNP technology.

Graphical abstract
Epigallocatechin-3-gallate inhibit the protein arginine methyltransferase 5 and Enhancer of Zeste homolog 2 in breast cancer bothin vitroandin vivo
Authors: Nalla Kirankumar , Chatterjee Biji , Poyya Jagadeesh , Swain Aishwarya , Ghosh Krishna , Pan Archana , Joshi Chandrashekhar G , Manavathi Bramanandam , Kanade Santosh R
Published: February 2024

Histone methyltransferases are selectively catalyzing the methylation of lysine or arginine residues of target histone and non-histone proteins, classified as lysine methyltransferases and arginine methyltransferases. The EZH2 and PRMT5 catalyze trimethylation of H3 at K27 and symmetric dimethylation of H4 at R3 respectively. These histone repressive marks have been considered as hallmarks in cancer. Both PRMT5 and EZH2 over expressed in several cancers and have been considered as important target of drug development. As a result, many synthetic molecules as inhibitors of both PRMT5 and EZH2 are at different level of preclinical and clinical phases. Cancer atlas data analysis revealed that both PRMT5 and EZH2 had shown more than 90% amplification in breast cancer alone. We screened an array of phytocompounds towards the inhibition of PRMT5 and EZH2 usingin silico, in vitroassays. Among them Epigallocatechin-3-gallate (EGCG) has interacted with human PRMT5: MEP50 and EZH2 efficiently. The EGCG interacted within the SAM binding site, with a π-cation interaction at Lys 333 and H-bonds with Tyr324, Tyr334, Gly365, Leu437, and Glu444. Surface plasmon resonance analysis revealed that EGCG has strong binding affinity in nanomolar concentrations with both PRMT5-MEP50 than EZH2. Further in vitro methylation and cell-based assays proved the inhibitory potential of EGCG by reducing the catalytic products of PRMT5 and EZH2 i.e., H4R3me2s & H3K27me3 respectively and showed that it induced autophagy and apoptosis. Furthermorein vivo, mouse xenografts studies demonstrated that oral dosage, reduced tumor size significantly with reduction in proliferation marker Ki67 and these histone repressive marks. Finally conclude that inhibition of PRMT5 and EZH2 by EGCG potentially can be used to develop combined therapeutic approaches.