bluuebunny/crossref_metadata_2025 huggingface dataset:
Gender and Violence in International Relations: Evidence from the Statecraft Simulation
Authors: Nissen Katie , Cox Eric
Published: May 2023

To what extent does gender impact the level of conflict in an online international relations simulation environment? This article uses a survey of participants in the Statecraft simulation to determine the degree to which gender affects simulation outcomes. The authors worked with the Statecraft company to include a limited number of questions in Statecraft's end-of-simulation survey regarding participants’ gender, the level of conflict in the simulated world in which the student participated, and whether the student's world succeeded in building the Globe of Frost, the analog for solving global warming in the simulation. Based on student responses, we find that classes with a majority of male students were significantly more likely to report that their simulated world had a high level of conflict. Teams with majority males were also more likely to initiate conflict and focus on foreign policy rather than domestic policy, though those results were insignificant. Gender did not appear to affect whether or not a simulated world solved the global warming analog; though not significant, the coefficient suggests male-dominated worlds were slightly more likely to construct the Globe of Frost.
3D-GNOME 3.0: a three-dimensional genome modelling engine for analysing changes of promoter-enhancer contacts in the human genome
Authors: Wlasnowolski Michal , Kadlof Michal , Sengupta Kaustav , Plewczynski Dariusz
Published: May 2023

In the current update, we added a feature for analysing changes in spatial distances between promoters and enhancers in chromatin 3D model ensembles. We updated our datasets by the novel in situ CTCF and RNAPII ChIA-PET chromatin loops obtained from the GM12878 cell line mapped to the GRCh38 genome assembly and extended the 1000 Genomes SVs dataset. To handle the new datasets, we applied GPU acceleration for the modelling engine, which gives a speed-up of 30× versus the previous versions. To improve visualisation and data analysis, we embedded the IGV tool for viewing ChIA-PET arcs with additional genes and SVs annotations. For 3D model visualisation, we added a new viewer: NGL, where we provided colouring by gene and enhancer location. The models are downloadable in mmcif and xyz format. The web server is hosted and performs calculations on DGX A100 GPU servers that provide optimal performance with multitasking. 3D-GNOME 3.0 web server provides unique insights into the topological mechanism of human variations at the population scale with high speed-up and is freely available at https://3dgnome.mini.pw.edu.pl/.
GPS 6.0: an updated server for prediction of kinase-specific phosphorylation sites in proteins
Authors: Chen Miaomiao , Zhang Weizhi , Gou Yujie , Xu Danyang , Wei Yuxiang , Liu Dan , Han Cheng , Huang Xinhe , Li Chengzhi , Ning Wanshan , Peng Di , Xue Yu
Published: May 2023

Protein phosphorylation, catalyzed by protein kinases (PKs), is one of the most important post-translational modifications (PTMs), and involved in regulating almost all of biological processes. Here, we report an updated server, Group-based Prediction System (GPS) 6.0, for prediction of PK-specific phosphorylation sites (p-sites) in eukaryotes. First, we pre-trained a general model using penalized logistic regression (PLR), deep neural network (DNN), and Light Gradient Boosting Machine (LightGMB) on 490 762 non-redundant p-sites in 71 407 proteins. Then, transfer learning was conducted to obtain 577 PK-specific predictors at the group, family and single PK levels, using a well-curated data set of 30 043 known site-specific kinase-substrate relations in 7041 proteins. Together with the evolutionary information, GPS 6.0 could hierarchically predict PK-specific p-sites for 44046 PKs in 185 species. Besides the basic statistics, we also offered the knowledge from 22 public resources to annotate the prediction results, including the experimental evidence, physical interactions, sequence logos, and p-sites in sequences and 3D structures. The GPS 6.0 server is freely available at https://gps.biocuckoo.cn. We believe that GPS 6.0 could be a highly useful service for further analysis of phosphorylation.
The Effect of Developmental Delay and Autism Spectrum Disorder on External Auditory Canal Foreign Body Extraction
Authors: Nguyen Justin D. , Shih Michael C. , Nguyen Shaun A. , Liu Yi-Chun Carol , Mukerji Shraddha S.
Published: May 2023

Objectives

To determine the effect of developmental delay (DD) and autism spectrum disorder (ASD) on pediatric external auditory canal foreign body (EAC FB) retrieval outcomes.

Methods

A retrospective chart review of children presenting with EAC FB at a tertiary children's hospital was performed between January 2018 and December 2019. Charts were reviewed for demographics, presence of otalgia, complications, number of EAC FB episodes, indications for operating room removal, DD, and ASD status.

Results

A total of 1467 patients underwent EAC FB removal. One hundred thirty-seven children (9.3%) had DD, and, of those with DD, 63 (46%) had ASD. Children with DD were 1.76 years older compared with children with non-DD (NDD) (P < 0.0001) at the time of presentation, whereas children with ASD were 1.45 years older than children with NDD (P = 0.0023). Children with DD and ASD were more likely to require removal of FB in the operating room (OR) compared with the NDD group (36.5% vs 16.7%, P = 0.0001). This was not true for children with DD without ASD. Patients with DD reported significantly less otalgia when compared with NDD patients (26.3% vs 37.4%, P = 0.0097). A similar trend, although not statistically significant, was observed when comparing children with ASD with NDD patients. The NDD patients (1.1) had fewer EAC FB episodes than patients with DD (1.6, P < 0.0001) and ASD (1.8, P < 0.0016). Hazard ratios for multiple episodes of FB were 4.5 (95% confidence interval, 2.9–6.8) for DD, and 5.6 for ASD (95% confidence interval, 3.2–9.9). The complication rate for all groups was low.

Conclusions

Due to the different ways that children with DD and ASD present compared with NDD children, physicians should be vigilant when evaluating symptoms and conducting physical examinations for EAC FB in those patients. A lower threshold for referral to otolaryngologists may result in more favorable outcomes.
Microvillus Inclusion Disease Caused by MYO5B: Different Presentation and Phenotypes Despite Same Mutation
Authors: Andreassen Bente Utoft , Aunsholt Lise , Østergaard Elsebet , Ek Jakob , Maroun Lisa Leth , Jørgensen Marianne Hørby
Published: May 2023

Microvillus inclusion disease (MVID) is associated with specific variants in the MYO5B gene causing disrupt epithelial cell polarity. MVID may present at birth with intestinal symptoms or with extraintestinal symptoms later in childhood. We present 3 patients, of whom 2 are siblings, with MYO5B variants and different clinical manifestations, ranging from isolated intestinal disease to intestinal disease combined with cholestatic liver disease, predominant cholestatic liver disease clinically similar to low-gamma-glutamyl transferase PFIC, seizures, and fractures. We identified 1 previously unreported MYO5B variant and 2 known pathogenic variants and discuss genotype–phenotype correlations of these variants. We conclude that MVID may present phenotypically different and mimic other severe diseases. We suggest that genetic testing is included early during diagnostic investigations of children with gastrointestinal and cholestatic presentation.
The NIU (Nipple – Inframammary Fold – Upper Breast Border) Principle: A New Tool to Predict the Ideal Nipple/Areola Complex Position during Augmentation Mastopexy Preoperative Markings
Authors: Chahine Fadel , Habr Natasha
Published: May 2023

Background:

While the beauty of the breast depends on aesthetic proportions, the position of the nipple-areola complex on the breast mound and in relation to the implant during breast augmentation or mastopexy augmentation is critical [1][2][3]. In fact, lack of nipple position determination in relation to the breast footprint is a deficiency of most currently applied measurements and evaluation tools.

We hereby present a simple formula that allows accurate and proper prediction of the ideal nipple areola complex (NAC) positioning for every patient depending on the chosen implant in case of mastopexy augmentation, or revision mastopexy with exchange of implants.

Methods:

A prospective Level IV analysis of all consecutive patients undergoing primary mastopexy augmentation or revision mastopexy with exchange of implants was performed between January 2021 and January 2022.

48 consecutive patients were included in the study. The “NIU” (Nipple – Inframammary Fold – Upper Breast Border) principle was applied to all patients to determine the ideal position of the NAC.

Patients were photographed preoperatively and postoperatively in a standardized manner.

The main end point was to determine if the NAC is located at the most projected point of the breast upon follow up.

Results:

The NIU principle has been applied to 48 patients between January 2021 and January 2022. Of those patients, 27 underwent primary augmentation mastopexy, while 21 underwent revision augmentation mastopexy with exchange of implants.

The mean follow up duration was 9.2 months (6-18 months). All patients demonstrated proper NAC positioning upon follow up

Conclusion:

The NIU principle is a simple and reliable method to determine the ideal NAC position during mastopexy augmentation or mastopexy with implant exchange
“A New Injection Method of Nerve Block Combined with Local Infiltration Anesthesia for Relieving Pain of Horizontal Neck Lines Injection”
Authors: Su Xueshang , Li Zehui , Dai Yuduo , Wang Lianzhao , Li Haidong , Hu Jintian
Published: May 2023

Filler injection is one of the effective methods for the treatment of horizontal neck lines, but the pain caused by injection has become a huge burden for many patients both physically and mentally. Topical anesthesia and local refrigeration are common methods to relieve the pain of injection, but each has its disadvantages. The transverse cervical nerve is the main innervating nerve for pain sensation in the anterior skin of the neck. In this study, we performed nerve block anesthesia and local infiltration anesthesia on one side of the horizontal neck lines and applied topical anesthesia cream on the other side of the neck among 100 patients. The results showed that the pain patients suffered under nerve block anesthesia and local infiltration anesthesia was reduced by 81% compared with that of patients using the topical anesthesia on their neck lines. And such anesthetic technique had multiple benefits, for example, it won’t affect surgeon’s judgment on patient’s neck line shape and helps shorten the treatment time for patients. Therefore, it can be used as a new method to relieve the pain of patients undergoing horizontal neck line injection.
Neuromodulator Injection for Gummy Smile
Authors: Lisiecki Jeffrey L. , Chiodo Michael V. , Rohrich Rod J.
Published: May 2023

Neuromodulators have become a treatment of choice for the management of excess gingival show, or “gummy smile.” There have been many proposed algorithms for the optimal placement and dosage of neuromodulator to inject in these locations. In this article, we aim to clarify these points and provide surgeons with a reliable way to manage the gummy smile that results from hyperactive muscles of the midface.
“Electrochemical Lipolysis Induces Adipocyte Death and Fat Necrosis: In Vivo Pilot Study in Pigs”
Authors: Pham Tiffany T. , Heidari Andrew E. , Hong Ellen M. , Steward Earl , Qu Yueqiao , Chen Lily Y. , Dunn Brandyn S. , Seo Soo Hong , Syed Adeela , Dilley Katelyn , Lee Lauren , Hutchison Dana M. , Hansen Kyle D. , Patel Urja , Kim Sehwan , Hill Michael G. , Wong Brian J. F.
Published: May 2023

Background:

Current minimally invasive fat reduction modalities utilize equipment that can cost thousands of United States dollars. Electrochemical Lipolysis (ECLL), utilizing low-cost battery and electrodes (about $10), creates acid/base within fat (width ~3 mm), damaging adipocytes. Longitudinal effects of ECLL have not been studied. In this pilot study, we hypothesize in vivo ECLL induces fat necrosis, decreases adipocyte number/viability, and forms lipid droplets (LDs).

Methods:

Two female Yorkshire pigs (50-60 kg) received ECLL (pig 1: 10 sites ECLL, 10 sites untreated; pig 2: 12 sites ECLL, 12 sites untreated). For ECLL, two electrodes were inserted into dorsal subcutaneous fat and direct current was applied for 5 minutes. Adverse effects of excessive pain, bleeding, infection, and agitation were monitored. Histology, live-dead (Calcein, Hoechst, Ethidium Homodimer), and morphology (Bodipy and Hoechst) assays were performed on day 0 post-procedure, 1, 2, 7, 14 (pig 1, pig 2), and 28 (pig 2). Average particle area (APA), fluorescence signal areas, and adipocytes and LD numbers were compared.

Results:

No adverse effects occurred. Live-dead showed adipocyte death on anode days 0-7 and cathode days 1-2 (not significant). Bodipy showed significant adipocyte loss at all sites (p<0.001) and LD formation cathode day 2 (p=0.0046). Histology revealed fat necrosis with significant increases in APA at anode and cathode by day 14 (+277.3% change compared to untreated, p <0.0001; +143.4%, p <0.0001) and day 28 (+498.6%, p <0.0001; +354.5%, p <0.0001).

Conclusions:

In vivo ECLL induces fat necrosis in pigs. Further studies are needed to evaluate volumetric fat reduction.

Clinical Relevance Statement In vivo electrochemical lipolysis (ECLL) induces adipocyte death and fat necrosis. ELL has the potential to be utilize in body fat contouring.
State Firearm Laws and Rate of Assault-Related Firearm Death
Authors: Kawano Bradley , Agarwal Suresh , Krishnamoorthy Vijay , Raghunathan Karthik , Fernandez-Moure Joseph S , Haines Krista L
Published: May 2023

BACKGROUND:

Studying firearm-related mortality is important to reduce preventable firearm death in the US. This study aims to determine the relationship between firearm laws and assault death with firearms.

STUDY DESIGN:

This ecologic study used public data from the CDC Wide-Ranging Online Data for Epidemiologic Research on decedents age 18 years or older who died from assault with firearms between 2009 and 2018 in all 50 states and Washington, DC. The outcomes were the rate of mortality per 100,000 persons from assault death by firearm used. Exposures of interest included the presence of 7 state firearm laws extracted from the RAND State Firearm Law Database. Welch’s t tests were performed to compare mean mortality rate in states with each firearm law to states without each law.

RESULTS:

There were 114,945 deaths from assault with firearms from 2009 to 2018. States with “stand your ground” laws had a higher assault mortality rate from all firearms and from other/unspecified firearms than states without stand your ground laws (p = 0.026; p = 0.023). States with background checks for private sales of handguns and long guns had a lower assault mortality rate from handguns and rifles, shotguns, and large firearms, respectively, than states without either law (p = 0.019; p = 0.030).

CONCLUSIONS:

Stand your ground laws are correlated with a higher rate of gun-related assault death, but background checks on private sales are correlated with a lower rate. Future studies should elucidate the specific pathways by which state laws reduce, or fail to reduce, firearm-related assault death.
Does celecoxib with sodium valproate have an augmentation effect on acute mania in bipolar disorder? A double-blind controlled clinical trial in Iran
Authors: Faridhosseini Farhad , Talaei Ali , Shahini Najmeh , Salimi Zanireh , Eslamzadeh Mahboubeh , Ahrari Samira , Pourgholami Meysam , Khadem-Rezaiyan Majid
Published: May 2023

Inflammatory processes in the brain play a role in acute mania etiopathogenesis. There is little evidence indicating the efficacy of celecoxib adjuvant therapy in treatmenting of manic episodes of bipolar disorder. Therefore, this clinical trial aimed to assess the celecoxib effect on treating acute mania. In a double-blind, placebo-controlled trial, 58 patients meeting the criteria for acute mania were enrolled. After considering eligibility, 45 patients were included in the study and randomly divided into two groups. The first group (23 patients) received sodium valproate 400 mg/day along with celecoxib 400 mg/day, and the second group (22 patients) received sodium valproate 400 mg/day and a placebo. The subjects were evaluated by the Young Mania Rating Scale (YMRS) at the beginning of the study and 9, 18, and 28 days following the initiation of the medication. Evaluation of baseline factors indicated a significant difference in age (P = 0.01) and psychiatric history (P = 0.02) between the two groups. However, other factors were similar between groups (P ≥ 0.05). Comparing the YMRS score between celecoxib and placebo groups revealed no significant difference on days 0, 9, 18, and 28. However, the YMRS score at the end of the study decreased by 16.05 ± 7.65 in the intervention group (P < 0.001) and 12.50 ± 5.98 in controls (P < 0.001) compared to the baseline, the trend of change was not significant between the two groups during the time of the study (F = 0.38; P = 0.84). Although celecoxib adjuvant therapy indicated no considerable side effects, a longer treatment duration may be needed to detect its beneficial effects for treating acute mania in bipolar patients.

Trial registration: Iran clinical trial register: IRCT20200306046708N1.
Sparse spike trains and the limitation of rate codes underlying rapid behaviours
Authors: Fabian Joseph M. , O'Carrol David C. , Wiederman Steven D.
Published: May 2023

Animals live in dynamic worlds where they use sensorimotor circuits to rapidly process information and drive behaviours. For example, dragonflies are aerial predators that react to movements of prey within tens of milliseconds. These pursuits are likely controlled by identified neurons in the dragonfly, which have well-characterized physiological responses to moving targets. Predominantly, neural activity in these circuits is interpreted in context of a rate code, where information is conveyed by changes in the number of spikes over a time period. However, such a description of neuronal activity is difficult to achieve in real-world, real-time scenarios. Here, we contrast a neuroscientists'
post-hoc
view of spiking activity with the information available to the animal in real-time. We describe how performance of a rate code is readily overestimated and outline a rate code's significant limitations in driving rapid behaviours.
Quantitative single molecule analysis of podoplanin clustering in fibroblastic reticular cells uncovers CD44 function
Authors: Lim Shu En , Joseph Megan D. , de Winde Charlotte M. , Acton Sophie E. , Simoncelli Sabrina
Published: May 2023

Upon initial immune challenge, dendritic cells (DCs) migrate to lymph nodes and interact with fibroblastic reticular cells (FRCs) via C-type lectin-like receptor 2 (CLEC-2). CLEC-2 binds to the membrane glycoprotein podoplanin (PDPN) on FRCs, inhibiting actomyosin contractility through the FRC network and permitting lymph node expansion. The hyaluronic acid receptor CD44 is known to be required for FRCs to respond to DCs but the mechanism of action is not fully elucidated. Here, we use DNA-PAINT, a quantitative single molecule super-resolution technique, to visualize and quantify how PDPN clustering is regulated in the plasma membrane of FRCs. Our results indicate that CLEC-2 interaction leads to the formation of large PDPN clusters (i.e. more than 12 proteins per cluster) in a CD44-dependent manner. These results suggest that CD44 expression is required to stabilize large pools of PDPN at the membrane of FRCs upon CLEC-2 interaction, revealing the molecular mechanism through which CD44 facilitates cellular crosstalk between FRCs and DCs.
Elevated compositional change in plant assemblages linked to invasion
Authors: Kortz Alessandra R. , Moyes Faye , Pivello Vânia R. , Pyšek Petr , Dornelas Maria , Visconti Piero , Magurran Anne E.
Published: May 2023

Alien species are widely linked to biodiversity change, but the extent to which they are associated with the reshaping of ecological communities is not well understood. One possible mechanism is that assemblages where alien species are found exhibit elevated temporal turnover. To test this, we identified assemblages of vascular plants in the BioTIME database for those assemblages in which alien species are either present or absent and used the Jaccard measure to compute compositional dissimilarity between consecutive censuses. We found that, although alien species are typically rare in invaded assemblages, their presence is associated with an increase in the average rate of compositional change. These differences in compositional change between invaded and uninvaded assemblages are not linked to differences in species richness but rather to species replacement (turnover). Rapid compositional restructuring of assemblages is a major contributor to biodiversity change, and as such, our results suggest a role for alien species in bringing this about.
Deep learning models challenge the prevailing assumption that face-like effects for objects of expertise support domain-general mechanisms
Authors: Yovel Galit , Grosbard Idan , Abudarham Naphtali
Published: May 2023

The question of whether task performance is best achieved by domain-specific, or domain-general processing mechanisms is fundemental for both artificial and biological systems. This question has generated a fierce debate in the study of expert object recognition. Because humans are experts in face recognition, face-like neural and cognitive effects for objects of expertise were considered support for domain-general mechanisms. However, effects of domain, experience and level of categorization, are confounded in human studies, which may lead to erroneous inferences. To overcome these limitations, we trained deep learning algorithms on different domains (objects, faces, birds) and levels of categorization (basic, sub-ordinate, individual), matched for amount of experience. Like humans, the models generated a larger inversion effect for faces than for objects. Importantly, a face-like inversion effect was found for individual-based categorization of non-faces (birds) but only in a network specialized for that domain. Thus, contrary to prevalent assumptions, face-like effects for objects of expertise do not support domain-general mechanisms but may originate from domain-specific mechanisms. More generally, we show how deep learning algorithms can be used to dissociate factors that are inherently confounded in the natural environment of biological organisms to test hypotheses about their isolated contributions to cognition and behaviour.
An initial genomic blueprint of the healthy human oesophageal microbiome
Authors: Gilroy Rachel , Adam Mina E. , Kumar Bhaskar , Pallen Mark J.
Published: May 2023

Background. The oesophageal microbiome is thought to contribute to the pathogenesis of oesophageal cancer. However, investigations using culture and molecular barcodes have provided only a low-resolution view of this important microbial community. We therefore explored the potential of culturomics and metagenomic binning to generate a catalogue of reference genomes from the healthy human oesophageal microbiome, alongside a comparison set from saliva. 
Results. Twenty-two distinct colonial morphotypes from healthy oesophageal samples were genome-sequenced. These fell into twelve species clusters, eleven of which represented previously defined species. Two isolates belonged to a novel species, which we have named Rothia gullae. We performed metagenomic binning of reads generated from UK samples from this study alongside reads generated from Australian samples in a recent study. Metagenomic binning generated 136 medium or high-quality metagenome-assembled genomes (MAGs). MAGs were assigned to 56 species clusters, eight representing novel Candidatus species, which we have named Ca.Granulicatella gullae, Ca. Streptococcus gullae, Ca. Nanosynbacter quadramensis, Ca. Nanosynbacter gullae, Ca.Nanosynbacter colneyensis, Ca. Nanosynbacter norwichensis, Ca. Nanosynococcus oralis and Ca. Haemophilus gullae. Five of these novel species belong to the recently described phylum Patescibacteria. Although members of the Patescibacteria are known to inhabit the oral cavity, this is the first report of their presence in the oesophagus. Eighteen of the metagenomic species were, until recently, identified only by hard-to-remember alphanumeric placeholder designations. Here we illustrate the utility of a set of recently published arbitrary Latinate species names in providing user-friendly taxonomic labels for microbiome analyses.
Our non-redundant species catalogue contained 63 species derived from cultured isolates or MAGs. Mapping revealed that these species account for around half of the sequences in the oesophageal and saliva metagenomes. Although no species was present in all oesophageal samples, 60 species occurred in at least one oesophageal metagenome from either study, with 50 identified in both cohorts.
Conclusions. Recovery of genomes and discovery of new species represents an important step forward in our understanding of the oesophageal microbiome. The genes and genomes that we have released into the public domain will provide a base line for future comparative, mechanistic and intervention studies
Polygenic risk affects the penetrance of monogenic kidney disease
Authors: Khan Atlas , Shang Ning , Nestor Jordan G. , Weng Chunhua , Hripcsak George , Harris Peter C. , Gharavi Ali G. , Kiryluk Krzysztof
Published: May 2023

Background

Chronic kidney disease (CKD) is a genetically complex disease determined by an interplay of monogenic, polygenic, and environmental risks. Most forms of monogenic kidney diseases have incomplete penetrance and variable expressivity. It is presently unknown if some of the variability in penetrance can be attributed to polygenic factors.

Methods

Using the UK Biobank (N=469,835 participants) and the All of Us (N=98,622 participants) datasets, we examined two most common forms of monogenic kidney disorders, autosomal dominant polycystic kidney disease (ADPKD) caused by deleterious variants in thePKD1orPKD2genes, and COL4A-associated nephropathy (COL4A-AN caused by deleterious variants inCOL4A3,COL4A4, orCOL4A5genes). We used the eMERGE-III electronic CKD phenotype to define cases (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 or kidney failure) and controls (eGFR >90 mL/min/1.73m2 in the absence of kidney disease diagnoses). The effects of the genome-wide polygenic score (GPS) for CKD were tested in monogenic variant carriers and non-carriers using logistic regression controlling for age, sex, diabetes, and genetic ancestry.

Results

As expected, the carriers of known pathogenic and rare predicted loss-of-function variants inPKD1orPKD2had a high risk of CKD (ORmeta=17.1, 95% CI: 11.1-26.4, P=1.8E-37). The GPS was comparably predictive of CKD in both ADPKD variant carriers (ORmeta=2.28 per SD, 95%CI: 1.55-3.37, P=2.6E-05) and non-carriers (ORmeta=1.72 per SD, 95% CI=1.69-1.76, P< E-300) independent of age, sex, diabetes, and genetic ancestry. Compared to the middle tertile of the GPS distribution for non-carriers, ADPKD variant carriers in the top tertile had a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile had only a 3-fold increased risk of CKD. Similarly, the GPS was predictive of CKD in both COL4-AN variant carriers (ORmeta=1.78, 95% CI=1.22-2.58, P=2.38E-03) and non-carriers (OR =1.70, 95%CI: 1.68-1.73 P<E-300). The carriers in the top tertile of the GPS had a 2.5-fold higher risk of CKD while the risk for carriers in the bottom tertile was similar to the middle tertile of non-carriers.

Conclusions

Variable penetrance of kidney disease in ADPKD and COL4-AN is partially explained by differences in polygenic risk profiles. Accounting for polygenic factors has the potential to improve risk stratification in monogenic kidney disease and may have implications for genetic counseling.
Modeling Protein Structure Using Geometric Vector Field Networks
Authors: Mao Weian , Zhu Muzhi , Chen Hao , Shen Chunhua
Published: May 2023

Proteins serve as the foundation of life. Most diseases and challenges in life sciences are intimately linked to protein structures. In this paper, we propose a novel vector field network (VFN) for modeling protein structure. Unlike previous methods that extract geometric information relying heavily on hand-crafted features, VFN establishes a new geometric representation paradigm through a novel vector field operator. This vector field operator can not only eliminate the reliance on hand-crafted features, but also capture the implicit geometric relationships between residues. Thus, it enables VFN to have better generalizability and flexibility. We evaluate VFN on the protein inverse folding task. Experiment results show that VFN can significantly improve the performance of the state-of-the-art method, PiFold, by 3.0% (51.7%vs. 54.7%) in terms of the sequence recovery score, and outperform the recent solid baseline, Protein MPNN, by 8.7% (46.0%vs. 54.7%). Furthermore, we scale up VFN with all known protein structure data. Finally, the model achieves a recovery score of57.1%, pushing the accuracy to the next level.
Anaplerotic nutrient stress drives synergy of angiogenesis inhibitors with therapeutics targeting tumor metabolism
Authors: Khadka Sunada , Lin Yu-Hsi , Ackroyd Jeffrey , Chen Yi-An , Sheng Yanghui , Qian Wubin , Guo Sheng , Chen Yining , Behr Eliot , Barekatain Yasaman , Uddin Md. Nasir , Arthur Kenisha , Yan Victoria , Hsu Wen-Hao , Chang Qing , Poral Anton , Tran Theresa , Chaurasia Surendra , Georgiou Dimitra K. , Asara John M. , Barthel Floris P. , Millward Steve W. , DePinho Ronald A. , Muller Florian L.
Published: May 2023

Tumor angiogenesis is a cancer hallmark, and its therapeutic inhibition has provided meaningful, albeit limited, clinical benefit. While anti-angiogenesis inhibitors deprive the tumor of oxygen and essential nutrients, cancer cells activate metabolic adaptations to diminish therapeutic response. Despite these adaptations, angiogenesis inhibition incurs extensive metabolic stress, prompting us to consider such metabolic stress as aninduced vulnerabilityto therapies targeting cancer metabolism. Metabolomic profiling of angiogenesis-inhibited intracranial xenografts showed universal decrease in tricarboxylic acid cycle intermediates, corroborating a state of anaplerotic nutrient deficit or stress. Accordingly, we show strong synergy between angiogenesis inhibitors (Avastin, Tivozanib) and inhibitors of glycolysis or oxidative phosphorylation through exacerbation of anaplerotic nutrient stress in intracranial orthotopic xenografted gliomas. Our findings were recapitulated in GBM xenografts that do not have genetically predisposed metabolic vulnerabilities at baseline. Thus, our findings cement the central importance of the tricarboxylic acid cycle as the nexus of metabolic vulnerabilities and suggest clinical path hypothesis combining angiogenesis inhibitors with pharmacological cancer interventions targeting tumor metabolism for GBM tumors.
HISTONE DEACETYLASE 19 REGULATESSHOOT MERISTEMLESSEXPRESSION IN THE CARPEL MARGIN MERISTEM CONTRIBUTING TO OVULE NUMBER DETERMINATION AND TRANSMITTING TRACT DIFFERENTIATION
Authors: Manrique S , Cavalleri A , Guazzotti A , Villarino GH , Simonini S , Bombarely A , Higashiyama T , Grossniklaus U , Mizzotti C , Pereira AM , Coimbra S , Sankaranarayanan S , Onelli E , Masiero S , Franks RG , Colombo L
Published: May 2023

The gynoecium is critical for the reproduction of flowering species as it contains the ovules and the tissues required for pollen germination and guidance. These tissues are collectively known as the reproductive tract (ReT) and comprise stigma, style and transmitting tract (TT). The ovules and the ReT originate from a meristem within the pistil named carpel margin meristem (CMM).

SHOOT MERISTEMLESS (STM) is a key transcription factor required for meristem formation and maintenance. In all above-ground meristems, including the CMM,STMhas to be locally downregulated to allow proper organ differentiation. However, how this downregulation is achieved in the CMM is unknown.

In this work, we have studied HISTONE DEACETYLASE 19 (HDA19) role in ovule and ReT differentiation, based on the observation thathda19-3mutant displays reduced ovule number and fails to properly differentiate the TT. Fluorescence activated cell sorting (FACS) coupled with RNA-seq revealed that in the CMM ofhda19-3mutant, genes promoting organ development are downregulated while meristematic markers, includingSTM, are upregulated. We found that HDA19 is fundamental to downregulateSTMin the CMM, allowing ovule formation and TT differentiation.STMis ectopically expressed inhda19-3at intermediate stages of pistil development, and its downregulation by RNA interference alleviatedhda19-3 phenotypic defects. Furthermore, chromatin immunoprecipitation assays indicated thatSTMis a direct target of HDA19 during pistil development and thatSEEDSTICK(STK)is required for the histone acetylation-mediated regulation ofSTM.

Our results have led to the identification of the factors required forSTMsilencing in the gynoecium allowing organogenesis and tissue differentiation from the CMM.
EZH2 inhibition stimulates viral mimicry in resting splenic B cells
Authors: Kim Seung J. , Kiser Patti K. , DeKoter Rodney P. , Dick Frederick A.
Published: May 2023

In mammalian cells expression of repetitive genomic sequences is repressed by heterochromatin, underscoring the potential threat of repeat expression to cellular homeostasis. However, the specific consequences of ectopic repeat expression remains unclear. Here we demonstrate that EZH2 inhibitors stimulate repeat misexpression and cell death in resting splenic B cells. We show that B cells are uniquely sensitive to these agents because of high levels of H3K27me3 at repeats and correspondingly low DNA methylation. We generated a pattern recognition receptor loss-of-function mouse model called RIC with mutations inRigi,Ifih1(MDA5), andCgasto specifically block the consequences of repeat misexpression. In both WT and RIC mutant B cells, EZH2 inhibition caused focused loss of H3K27me3 at repetitive elements and upregulated their expression. However, expression of inflammatory chemokines and cell death were interrupted by the RIC mutations. Furthermore, the chemokine expression patterns induced by EZH2 inhibitors resemble the B cell response to Epstein-Barr virus infection. This study demonstrates a viral mimicry effect induced by pharmacological activation of repeat expression that induces inflammation and B cell death.
Resident and recruited macrophages differentially contribute to cardiac healing after myocardial ischemia
Authors: Weinberger Tobias , Messerer Denise , Joppich Markus , Fischer Max , Garcia Clarisabel , Kumaraswami Konda , Wimmler Vanessa , Ablinger Sonja , Räuber Saskia , Fang Jiahui , Liu Lulu , Liu Wing Han , Winterhalter Julia , Lichti Johannes , Tomas Lukas , Esfandyari Dena , Percin Guelce , Salamanca Sandra Martin , Hidalgo Andres , Waskow Claudia , Engelhardt Stefan , Todica Andrei , Zimmer Ralf , Pridans Clare , Gomez-Perdiguero Elisa , Schulz Christian
Published: May 2023

Cardiac macrophages are heterogenous in phenotype and functions, which has been associated with differences in their ontogeny. Despite extensive research, our understanding of the precise role of different subsets of macrophages in ischemia/reperfusion injury remains incomplete. We here investigated macrophage lineages and ablated tissue macrophages in homeostasis and after I/R injury in a CSF1R-dependent manner. Genomic deletion of a fms-intronic regulatory element (FIRE) in the Csf1r locus resulted in specific absence of resident homeostatic and antigen-presenting macrophages, without affecting the recruitment of monocyte-derived macrophages to the infarcted heart. Specific absence of homeostatic, monocyte-independent macrophages altered the immune cell crosstalk in response to injury and induced proinflammatory neutrophil polarization, resulting in impaired cardiac remodelling without influencing infarct size. In contrast, continuous CSF1R inhibition led to depletion of both resident and recruited macrophage populations. This augmented adverse remodelling after I/R and led to an increased infarct size and deterioration of cardiac function. In summary, resident macrophages orchestrate inflammatory responses improving cardiac remodelling, while recruited macrophages determine infarct size after I/R injury. These findings attribute distinct beneficial effects to different macrophage populations in the context of myocardial infarction.

GRAPHICAL ABSTRACT
De novoamyloid peptides with subtle sequence variations differ in their self-assembly and nanomechanical properties
Authors: Abernathy Hannah G. , Saha Jhinuk , Kemp Lisa K. , Wadhwani Parvesh , Clemons Tristan D. , Morgan Sarah E. , Rangachari Vijayaraghavan
Published: May 2023

Proteinaceous amyloids are well known for their widespread pathological roles but lately have emerged also as key components in several biological functions. The remarkable ability of amyloid fibers to form tightly packed conformations in a cross β-sheet arrangement manifests in their robust enzymatic and structural stabilities. These characteristics of amyloids make them attractive for designing proteinaceous biomaterials for various biomedical and pharmaceutical applications. In order to design customizable and tunable amyloid nanomaterials, it is imperative to understand the sensitivity of the peptide sequence for subtle changes based on amino acid position and chemistry. Here we report our results from four rationally-designed amyloidogenic decapeptides that subtly differ in hydrophobicity and polarity at positions 5 and 6. We show that making the two positions hydrophobic renders the peptide with enhanced aggregation and material properties while the introduction of polar residues in position 5 dramatically changes the structure and nanomechanical properties of the fibrils formed. A charged residue at position 6, however, completely abrogates amyloid formation. In sum, we show that subtle changes in the sequence do not make the peptide innocuous but rather sensitive to aggregation, reflected in the biophysical and nanomechanical properties of the fibrils. We conclude that tolerance of peptide amyloid for subtle changes in the sequence should not be neglected for the effective design of customizable amyloid nanomaterials.
Ambulatory electrocardiographic longitudinal monitoring in dystrophin-deficient dogs identifies decreased Very Low Frequency power as a hallmark of impaired Heart Rate Variability in Duchenne Muscular Dystrophy
Authors: Barthélémy Inès , Su Jin Bo , Cauchois Xavier , Relaix Frédéric , Ghaleh Bijan , Blot Stéphane
Published: May 2023

Background

Duchenne muscular dystrophy (DMD) patients exhibit a late left ventricular systolic dysfunction preceded by an occult phase, during which myocardial fibrosis progresses and some early functional impairments can be detected. These latter include electrocardiographic (ECG) and heart rate variability (HRV) abnormalities.

Methods

A longitudinal study aiming at describing the sequence of ECG and HRV abnormalities, relative to cardiac function degradation, using Holter ECG, was performed in the GRMD (Golden retriever muscular dystrophy) dog model, known to develop a DMD-like disease, including cardiomyopathy.

Results

Most of the known ECG and HRV abnormalities described in DMD patients were also found in GRMD dogs, and several of them could be detected months before the decrease of fractional shortening. One of the earliest evidenced abnormalities was a decrease in the very low frequency (VLF) component of the power spectrum, and this decrease was correlated with the further reduction of fractional shortening. Such decreased VLF probably reflects impaired autonomic function and abnormal vasomotor tone.

Conclusion

This study provides new insights into the knowledge of the GRMD dog model and DMD cardiomyopathy and emphasizes the interest to monitor the VLF power in DMD patients, still unexplored in this disease, whilst it is highly predictive of deleterious clinical events in many other pathological conditions.

Abbreviations

cTpnI

Cardiac Troponin I

DMD

Duchenne Muscular Dystrophy

ECG

Electrocardiogram

GRMD

Golden Retriever Muscular Dystrophy

HF

High Frequency

HR

Heart Rate

HRV

Heart Rate Variability

LF

Low Frequency

LGE

Late Gadolinium Enhancement

LTV

Long-Term Variability

LVEF

Left Ventricular Ejection Fraction

NT-proBNP

N-Terminal part of the pro-Brain Natriuretic Peptide

pNN50

percentage of interval differences of successive RR intervals of more than 50 ms

pNN10 %(meanRR)

percentage of interval differences of successive RR intervals of more than 10% of the mean RR

QTc

corrected QT interval

RMSSD

square root of the mean squared differences of successive RR intervals

SDNN

Standard Deviation of the RR intervals

LVFS

Left Ventricular Fractional Shortening

STV

Short-Term Variability

VLF

Very Low Frequency

PVB

Premature Ventricular Beat

VT

Ventricular Tachycardia.
Sprouty4 is required for Mdm2 regulation of invasion, focal adhesion formation and metastasis in cells lacking p53
Authors: Queiroz Rafaela Muniz de , Efe Gizem , Guzman Asja , Hashimoto Naoko , Kawashima Yusuke , Tanaka Tomoaki , Rustgi Anil K , Prives Carol
Published: May 2023

Although the E3 ligase Mdm2 and its homologue and binding partner MdmX are the major regulators of the p53 tumor suppressor protein, it is now evident that Mdm2 and MdmX have multiple functions that are independent of p53. For example, Mdm2 can regulate cell migration, although mechanistic insight into this function is still lacking. Here we show in cells lacking p53 expression that knockdown of Mdm2 or MdmX, as well as pharmacological inhibition of the Mdm2/MdmX complex, not only reduces cell migration and invasion, but also impairs cell spreading and focal adhesion formation. In addition, Mdm2 knockdown decreases metastasisin vivo. Remarkably, Mdm2 modulates the expression of Sprouty4, which is required for the Mdm2 mediated effects on cell migration, focal adhesion formation and metastasis. Our findings describe a molecular mechanism by which the Mdm2-X complex, through Sprouty4, regulates cellular processes leading to decreased metastatic capability independent of p53.
Toll-like receptor 7 (TLR7)-mediated antiviral response protects mice from lethal SARS-CoV-2 infection
Authors: Ghimire Roshan , Shrestha Rakshya , Amaradhi Radhika , Patton Titus , Whitley Cody , Chanda Debarati , Liu Lin , Ganesh Thota , More Sunil , Channappanavar Rudragouda
Published: May 2023

SARS-CoV-2-induced impaired antiviral and excessive inflammatory responses cause fatal pneumonia. However, the key pattern recognition receptors that elicit effective antiviral and lethal inflammatory responsesin-vivoare not well defined. CoVs possess single-stranded RNA (ssRNA) genome that is abundantly produced during infection and stimulates both antiviral interferon (IFN) and inflammatory cytokine/ chemokine responses. Therefore, in this study, using wild-type control and TLR7 deficient BALB/c mice infected with a mouse-adapted SARS-COV-2 (MA-CoV-2), we evaluated the role of TLR7 signaling in MA-CoV-2-induced antiviral and inflammatory responses and disease outcome. We show that TLR7-deficient mice are more susceptible to MA-CoV-2 infection as compared to infected control mice. Further evaluation of MA-CoV-2 infected lungs showed significantly reduced mRNA levels of antiviral type I (IFNα/β) and type III (IFNλ) IFNs, IFN stimulated genes (ISGs, ISG15 and CXCL10), and several pro-inflammatory cytokines/chemokines in TLR7 deficient compared to control mice. Reduced lung IFN/ISG levels and increased morbidity/mortality in TLR7 deficient mice correlated with high lung viral titer. Detailed examination of total cells from MA-CoV-2 infected lungs showed high neutrophil count in TLR7 deficient mice compared to control mice. Additionally, blocking TLR7 activity post-MA-CoV-2 infection using a specific inhibitor also enhanced disease severity. In summary, our results conclusively establish that TLR7 signaling is protective during SARS-CoV-2 infection, and despite robust inflammatory response, TLR7-mediated IFN/ISG responses likely protect the host from lethal disease. Given similar outcomes in control and TLR7 deficient humans and mice, these results show that MA-CoV-2 infected mice serve as excellent model to study COVID-19.
Context dependent function of the transcriptional regulator Rap1 in gene silencing and activation inSaccharomyces cerevisiae
Authors: Bondra Eliana R , Rine Jasper
Published: May 2023

InSaccharomyces cerevisiae,heterochromatin is formed through interactions between site-specific DNA-binding factors, including the transcriptional activator Rap1, and Sir proteins. Despite a vast understanding of the establishment and maintenance of Sir-silenced chromatin, the mechanism of gene silencing by Sir proteins has remained a mystery. Utilizing high resolution chromatin immunoprecipitation, we found that Rap1, the native activator of the bi-directionalHMLα promoter, bound its recognition sequence in silenced chromatin and its binding was enhanced by the presence of Sir proteins. In contrast to prior results, various components of transcription machinery were not able to accessHMLα in the silenced state. These findings disproved the long-standing model of indiscriminate steric occlusion by Sir proteins and led to investigation of the transcriptional activator Rap1 in Sir-silenced chromatin. Using a highly sensitive assay that monitors loss-of-silencing events, we identified a novel role for promoter-bound Rap1 in the maintenance of silent chromatin through interactions with the Sir complex. We also found that promoter-bound Rap1 activatedHMLα when in an expressed state, and aided in the transition from transcription initiation to elongation. Highlighting the importance of epigenetic context in transcription factor function, these results point toward a model in which the duality of Rap1 function was mediated by local chromatin environment rather than binding-site availability.

Significance Statement

The coarse partitioning of the genome into regions of active euchromatin and repressed heterochromatin is an important, and conserved, level gene expression regulation in eukaryotes. Repressor Activator Protein (Rap1) is a transcription factor that promotes the activation of genes when recruited to promoters, and aids in the establishment of heterochromatin through interactions with silencer elements. Here, we investigate the role of Rap1 when bound to a promoter in silent chromatin and dissect the context-specific epigenetic cues that regulate the dual properties of this transcription factor. Together, our data highlight the importance of protein-protein interactions and local chromatin state on transcription factor function.