bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between perimenopausal age and greater posttraumatic stress disorder and depression symptoms in trauma-exposed women
Authors: Michopoulos Vasiliki , Huibregtse Megan E. , Chahine E. Britton , Smith Alicia K. , Fonkoue Ida T. , Maples-Keller Jessica , Murphy Amy , Taylor Linzie , Powers Abigail , Stevens Jennifer S.
Published: August 2023

Objective

This study aimed to determine the relationship between stages of the menopause transition (premenopausal, perimenopausal, and postmenopausal) on symptoms of posttraumatic stress disorder (PTSD) and depression in trauma-exposed women.

Methods

A cross-sectional study conducted between 2005 and 2017 recruited and enrolled an urban community sample (n = 6,093) from nonpsychiatric medical clinic waiting rooms of Grady Memorial Hospital, a public safety net hospital in Atlanta, Georgia. Participants were female, 18 to 65 years old, and predominantly Black/African American.

Results

Of the 6,093 participants, 93.8% were Black/African American, 2.5% were White, and 3.8% were of all other races (Hispanic/Latino, Asian, multiracial). Participants younger than 40 years were categorized as premenopausal (n = 3,166), between 40 and 55 years of age were categorized as perimenopausal (n = 2,127), and older than 55 years were categorized as postmenopausal (n = 790). Menopause status was associated with total PTSD symptom severity (F2,5416= 9.61,P< 0.001), symptom severity within all three PTSD symptom clusters (avoidance/numbing symptoms:F2,5416= 7.10,P< 0.001; intrusive symptoms:F2,5416= 7.04,P< 0.001; hyperarousal symptoms:F2,5409= 8.31,P< 0.001), and depression symptom severity (F2,5148= 11.4,P< 0.001). Compared with both premenopausal and postmenopausal women, perimenopausal women reported significantly worse total PTSD symptoms, symptoms in the hyperarousal cluster, and depressive symptoms.

Conclusions

The current cross-sectional data show that symptoms of PTSD and depression in women are associated with reproductive age, such that perimenopausal women show higher symptom severity than premenopausal and postmenopausal women. Future longitudinal studies can reveal how changes in hormones over the course of the menopause transition impact the symptoms, neurobiology, and psychophysiology of PTSD.
The utility of P-I-R classification in predicting the on-treatment histological and clinical outcomes of patients with hepatitis B and advanced liver fibrosis
Authors: Chang Xiujuan , Lv Caihong , Wang Bingqiong , Wang Jing , Song Zheng , An Linjing , Chen Shuyan , Chen Yongping , Shang Qinghua , Yu Zujiang , Tan Lin , Li Qin , Liu Huabao , Jiang Li , Xiao Guangming , Chen Liang , Lu Wei , Hu Xiaoyu , Dong Zheng , Chen Yan , Sun Yameng , Wang Xiaodong , Li Zhiqin , Chen Da , You Hong , Jia Jidong , Yang Yongping
Published: August 2023

Background and Aims:

The predominantly progressive, indeterminate, and predominantly regressive (P-I-R) classification extends beyond staging and provides information on dynamic changes of liver fibrosis. However, the prognostic implication of P-I-R classification is not elucidated. Therefore, in the present research, we investigated the utility of P-I-R classification in predicting the on-treatment clinical outcomes.

Approach and Results:

In an extension study on a randomized controlled trial, we originally enrolled 1000 patients with chronic hepatitis B and biopsy-proven histological significant fibrosis, and treated them for more than 7 years with entecavir-based therapy. Among the 727 patients with a second biopsy at treatment week 72, we compared P-I-R classification and Ishak score changes in 646 patients with adequate liver sections for the histological evaluation. Progressive, indeterminate, and regressive cases were observed in 70%, 17%, and 13% of patients before treatments and 20%, 14%, and 64% after 72-week treatment, respectively, which could further differentiate the histological outcomes of patients with stable Ishak scores. The 7-year cumulative incidence of HCC was 1.5% for the regressive cases, 4.3% for the indeterminate cases, and 22.8% for the progressive cases (p<0.001). After adjusting for age, treatment regimen, platelet counts, cirrhosis, Ishak fibrosis score changes, and Laennec staging, the posttreatment progressive had a HR of 17.77 (vs. posttreatment regressive; 95% CI: 5.55–56.88) for the incidence of liver-related events (decompensation, HCC, and death/liver transplantation).

Conclusions:

The P-I-R classification can be a meaningful complement to the Ishak fibrosis score not only in evaluating the histological changes but also in predicting the clinical outcomes.
Validity and Internal Consistency of the Indonesian-Translated Communication and Symbolic Behavior Scales Developmental Profile to Screen Language Delay in Children Aged 6–24 Months
Authors: Supit Diane Meytha , Gunardi Hartono , Medise Bernie Endyarni , Tengkawan Jeslyn
Published: August 2023

The Communication and Symbolic Behavior Scales Developmental Profile (CSBS DP) is a valid and reliable screening tool for detecting language delay in children. However, it has not been translated into the Indonesian language. This study aimed to determine the validity and internal consistency of the Indonesian-translated CSBS DP as a screening tool for language delay in children aged 6–24 months. A cross-sectional study was carried out at the Growth and Development Clinic, Cipto Mangunkusumo Hospital, in 3 stages: (1) transcultural translation and adaptation of the measure into the Indonesian language; (2) determination of the internal consistency of the measure; and (3) determination of the concurrent validity of the measure by comparing CSBS DP with the Bayley Scales of Infant and Toddler Development, third edition (BSID-III) language scale on 149 caregivers–children dyads. We found good concurrent validity (r > .3) and good internal consistency with Cronbach's α values of 0.876–0.896. The concurrent validity of the Indonesian-translated questionnaire showed a sensitivity of 71.43% and a specificity of 81.48%. CSBS DP Indonesian-translated questionnaire is a valid and reliable screening test for language delay in children aged 6–24 months.
Using a Comprehensive On-Site Assessment Process to Reduce Central Line-Associated Bloodstream Infection Rates
Authors: Bartles Rebecca , Moore Andria , Martin Rosemary , Clarkson Rebecca , Ebinger Laura
Published: August 2023

Central line-associated bloodstream infection (CLABSI) rates increased substantially in the United States following the emergence of COVID-19 and subsequent surges. The pandemic resulted in hospital capacities being exceeded and crisis standards of care being implemented for sustained periods. As COVID-19 rates in the United States began to stabilize, some facilities did not return to previous CLABSI rates, indicating a change in practices that had a longer-term impact on CLABSI prevention. The authors' large health care system observed similar increases in CLABSI following the emergence of COVID-19, prompting investigation and intervention in the form of a quality improvement project. To identify changes related to ongoing increases in CLABSI, an assessment team conducted standardized on-site assessments at 11 facilities. Site assessments were considered an intervention, as they involved rigorous preassessment investigations and interviews, case reviews, practice observations, on-site staff interviews, and postassessment support for additional interventions. Nine facilities had enough postassessment data to analyze the impact of intervention. The overall CLABSI rate (infections per 1000 line days) at the 9 facilities in the 6 months prior to intervention was 1.42, and the postassessment rate in the 6 months following intervention was 0.44. This indicates the effectiveness of facility-specific investigation followed by targeted performance improvements to reduce the rate of CLABSI.
Esophageal Heterotopic Pancreas in an Asymptomatic 2-Year-Old With VACTERL Association
Authors: Kimsey Kathryn M. , Barnett Grafton S. , Keup Chris , Nguyen Johnny , Wilsey Michael J. , Smithers Charles J. , González Raquel
Published: August 2023

A 2-year-old male with VACTERL association and asthma presented to the emergency room due to asthma exacerbation. Chest radiography revealed lingular pneumonia and thickening of the left paraspinal line of the gastroesophageal junction. Chest computed tomography confirmed a heterogeneous fluid- and gas-filled structure at the left posterior lateral aspect of the esophagus, which was suspected to be an esophageal diverticulum on an upper gastrointestinal series. The esophageal diverticulum was excised via left thoracoscopy, and pathological examination revealed pancreatic tissue. Heterotopic pancreas lacks anatomical, vascular, or ductal continuity with the native pancreas. It is usually asymptomatic, but when discovered, it usually occurs later in life. It has been described in the foregut, but is not as common in the esophagus, especially in the pediatric population. This case report highlights the rare occurrence, and importance of considering, esophageal heterotopic pancreas within an esophageal diverticulum in an asymptomatic patient with VACTERL association.
Modified Technique to Rehabilitate American Society of Anesthesiology-III Patient, Through Flapless Procedure With Computed Tomography–Guided Surgery
Authors: Franco Rocco , Ferrari Giulia , Vazzana Giuseppe , Cicciù Marco , Minervini Giuseppe
Published: August 2023

Purpose:

The aim was to evaluate the safety and effectiveness of a computed tomography–guided surgery implant placement with a flapless technique and immediate functional loading in an American Society of Anesthesiology-III patient.

Methods:

This technical note involved a 64-year-old American Society of Anesthesiology-III patient. Her hopeless teeth were extracted and a restorative evaluation was provided as a prosthetic reference. The surgical procedure was based on the flapless technique that let us to use local anesthesia. The authors used an All-on-4 concept restoration for maxilla and conventional fixed prosthesis procedures for jaw rehabilitation. The authors placed 4 tilted implants in the upper maxilla and 6 right implants in the jaw. Implants were loaded with a provisional prosthesis on the same day of surgery. Five months later, provisional restoration was removed; the authors placed into the ceramic crowns 2 Procera Implant Bridge (Nobel Biocare) frameworks, developed through computer-aided design/computer-aided manufacturing technology.

Conclusions:

Computed tomography–guided surgery is a minimally invasive technique that allows, through a flapless approach, safer and more predictable procedures. In this technical note, the authors achieved accurate implant placement and precise fit of restoration with natural looking appearance; this patient-oriented-treatment led to a reduced healing time with better compliance.
Electric Scooter-related Craniofacial Injuries
Authors: Akalin Bora Edim , Alten Aytaç , Gündeş Elif
Published: August 2023

Objectives:

Injuries associated with the use of electric scooters are a serious problem in modern society and traffic in relation to their increasing frequency of use. Although injuries involving all body parts are seen in such injuries, craniofacial ones are also very common. The aim of this study was to evaluate the craniofacial and other accompanying injuries in electric scooter-related accidents in Istanbul.

Materials and Methods:

Between January 2020 and December 2022, patients with electric scooter-related trauma among the patients admitted to the emergency unit for trauma were evaluated retrospectively. All electronic medical records, CT scans, other examinations, and treatments were retrospectively reviewed, and craniofacial fractures and other injuries seen in the patients were classified.

Results:

A total of 20.358 patients were admitted to the trauma unit between January 2020 and December 2022. Two hundred ten patients (142 male, 68 female) had electric scooter-related trauma and 58.1 % of them had craniofacial injuries. Thirty patients (14.3 %) (23 male, 7 female) had craniofacial fractures, whereas 43.8 % of them had craniofacial soft tissue injuries. The nasal fracture was the most common craniofacial fracture (14 patients, 46.7%). Orbital wall and zygomaticomaxillary complex fractures were found to be the second most common fractures.

Conclusions:

The rate of electric scooter-related injuries among all trauma patients admitted to the emergency trauma unit during the mentioned period was 1.03%. The results of this study were found to be in accordance with the data in the literature. The craniofacial region is the most frequently injured body part in patients with electric scooter-related trauma, and patients should be comprehensively evaluated for possible soft tissue injuries, craniofacial fractures, and other accompanying system injuries.
Effectiveness of social distancing measures and lockdowns for reducing transmission of COVID-19 in non-healthcare, community-based settings
Authors: Murphy Caitriona , Lim Wey Wen , Mills Cathal , Wong Jessica Y. , Chen Dongxuan , Xie Yanmy , Li Mingwei , Gould Susan , Xin Hualei , Cheung Justin K. , Bhatt Samir , Cowling Benjamin J. , Donnelly Christl A.
Published: August 2023

Social distancing measures (SDMs) are community-level interventions that aim to reduce person-to-person contacts in the community. SDMs were a major part of the responses first to contain, then to mitigate, the spread of SARS-CoV-2 in the community. Common SDMs included limiting the size of gatherings, closing schools and/or workplaces, implementing work-from-home arrangements, or more stringent restrictions such as lockdowns. This systematic review summarized the evidence for the effectiveness of nine SDMs. Almost all of the studies included were observational in nature, which meant that there were intrinsic risks of bias that could have been avoided were conditions randomly assigned to study participants. There were no instances where only one form of SDM had been in place in a particular setting during the study period, making it challenging to estimate the separate effect of each intervention. The more stringent SDMs such as stay-at-home orders, restrictions on mass gatherings and closures were estimated to be most effective at reducing SARS-CoV-2 transmission. Most studies included in this review suggested that combinations of SDMs successfully slowed or even stopped SARS-CoV-2 transmission in the community. However, individual effects and optimal combinations of interventions, as well as the optimal timing for particular measures, require further investigation.

This article is part of the theme issue 'The effectiveness of non-pharmaceutical interventions on the COVID-19 pandemic: the evidence'.
Effectiveness of international border control measures during the COVID-19 pandemic: a narrative synthesis of published systematic reviews
Authors: Grépin Karen Ann , Aston John , Burns Jacob
Published: August 2023

The effectiveness of international border control measures during the COVID-19 pandemic is not well understood. Using a narrative synthesis approach to published systematic reviews, we synthesized the evidence from both modelling and observational studies on the effects of border control measures on domestic transmission of the virus. We find that symptomatic screening measures were not particularly effective, but that diagnostic-based screening methods were more effective at identifying infected travellers. Targeted travel restrictions levied against travellers from Wuhan were likely temporarily effective but insufficient to stop the exportation of the virus to the rest of the world. Quarantine of inbound travellers was also likely effective at reducing transmission, but only with relatively long quarantine periods, and came with important economic and social effects. There is little evidence that most travel restrictions, including border closure and those implemented to stop the introduction of new variants of concern, were particularly effective. Border control measures played an important role in former elimination locations but only when coupled with strong domestic public health measures. In future outbreaks, if border control measures are to be adopted, they should be seen as part of a broader strategy that includes other non-pharmaceutical interventions.

This article is part of the theme issue 'The effectiveness of non-pharmaceutical interventions on the COVID-19 pandemic: the evidence'.
Alkalicoccobacillus porphyridii sp. nov., isolated from a marine red alga, reclassification of Shouchella plakortidis and Shouchella gibsonii as Alkalicoccobacillus plakortidis comb. nov. and Alkalicoccobacillus gibsonii comb. nov., and emended description of the genus Alkalicoccobacillus Joshi et al. 2022
Authors: Kim Kyung Hyun , Han Dong Min , Lee Jae Kyeong , Jeon Che Ok
Published: August 2023

A Gram-stain-positive alkali-tolerant and strictly aerobic bacterium, designated strain P16T, was isolated from a marine red alga, Porphyridium cruentum, in the Yellow Sea, Republic of Korea. Cells were motile rods with peritrichous flagella and exhibited catalase and oxidase activities. The optimal growth of strain P16T was observed to occur at 30 °C and pH 8.0 and in the presence of 2.0 % (w/v) NaCl. Menaquinone-7 was identified as the sole respiratory quinone. Strain P16T contained anteiso-C15 : 0, iso-C15 : 0, iso-C14 : 0 and iso-C16 : 0, and diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine as major cellular fatty acids and polar lipids, respectively. The G+C content of strain P16T was 40.8 mol%. Strain P16T was most closely related to

Shouchella plakortidis

P203T,

Shouchella gibsonii

DSM 8722T and

Alkalicoccobacillus murimartini

LMG 21005T with 98.1, 98.1 and 98.0 % 16S rRNA gene sequence similarities, respectively. Phylogenetic analyses based on 16S rRNA gene and genome sequences revealed that strain P16T, S, plakortidis,

S. gibsonii

and

A. murimartini

formed a single phylogenetic lineage cluster, and genomic relatedness analyses showed that they are different species. Based on phylogenetic, phenotypic, chemotaxonomic and molecular features, strain P16T represents a novel species of the genus

Alkalicoccobacillus

, for which the name Alkalicoccobacillus porphyridii sp. nov. is proposed. The type strain is P16T (=KACC 19520T=JCM 32931T). In addition,

S. plakortidis

and

S. gibsonii

are reclassified as Alkalicoccobacillus plakortidis comb. nov. (type strain P203T=DSM 19153T=NCIMB 14288T) and Alkalicoccobacillus gibsonii comb. nov. (type strain PN-109T=ATCC 700164T=DSM 8722T=KCCM 41407T), respectively.
Flagellin O-linked glycans are required for the interactions between Campylobacter jejuni and Acanthamoebae castellanii
Authors: Nasher Fauzy , Wren Brendan W.
Published: August 2023

The predation and engulfment of bacteria by Acanthamoebae facilitates intimate interactions between host and prey. This process plays an important and underestimated role in the physiology, ecology and evolution of pathogenic bacteria. Acanthamoebae species can be reservoirs for many important human pathogens including Campylobacter jejuni. C. jejuni is the leading cause of bacterial foodborne enteritis worldwide, despite being a microaerophile that is incapable of withstanding atmospheric levels of oxygen long-term. The persistence and transmission of this major pathogen in the natural environment outside its avian and mammalian hosts is not fully understood. Recent evidence has provided insight into the relationship of

C. jejuni

and Acanthamoebae spp. where Acanthamoebae are a transient host for this pathogen. Mutations to the flagella components were shown to affect C. jejuni–A. castellanii interactions. Here, we show that the motility function of flagella is not a prerequisite for C. jejuni–A. castellanii interactions and that specific O-linked glycan modifications of the

C. jejuni

major flagellin, FlaA, are important for the recognition, interaction and phagocytosis by A. castellanii. Substitution of the O-linked glycosylated serine 415 and threonine 477 with alanine within FlaA abolished

C. jejuni

interactions with A. castellanii and these mutants were indistinguishable from a ΔflaA mutant. By contrast, mutation to serine 405 did not affect

C. jejuni

11168H and A. castellanii interactions. Given the abundance of flagella glycosylation among clinically important pathogens, our observations may have a wider implication for understanding host–pathogen interactions.
Cancer-associated fibroblasts promote drug resistance inALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis
Authors: Daum Ann-Kathrin , Schlicker Lisa , Schneider Marc A. , Muley Thomas , Klingmüller Ursula , Schulze Almut , Thomas Michael , Christopoulos Petros , Sültmann Holger
Published: August 2023

Targeted therapy interventions using tyrosine kinase inhibitors (TKIs) provide encouraging treatment responses inALK-rearranged lung adenocarcinomas, yet resistances occur almost inevitably. Apart from tumor cell-intrinsic resistance mechanisms, accumulating evidence supports a role of cancer-associated fibroblasts (CAFs) in affecting the therapeutic vulnerability of lung cancer cells. Here, we aimed to investigate underlying molecular networks shaping the therapeutic susceptibility ofALK-driven lung adenocarcinoma cells via tumor microenvironmental cues using three-dimensional (3D) spheroid co-culture settings. We show that CAFs promote therapy resistance of lung tumor cells against ALK inhibition by reducing apoptotic cell death and increasing cell proliferation. Using single-cell RNA-sequencing analysis, we show that genes involved in lipogenesis constitute the major transcriptional difference between TKI-treated homo- and heterotypic lung tumor spheroids. CAF-conditioned medium and CAF-secreted factors HGF and NRG1 were both able to promote resistance of 3D-culturedALK-rearranged lung tumor cells via AKT signaling, which was accompanied by enhancedde novolipogenesis and supression of lipid peroxidation. Notably, simultaneous targeting of ALK and SREBP-1 was able to overcome the established CAF-driven lipid metabolic-supportive niche of TKI-resistant lung tumor spheroids. Our findings highlight a crucial role of CAFs in mediating ALK-TKI resistance via lipid metabolic reprogramming and suggest new ways to overcome resistance towards molecular directed drugs by targeting vulnerabilities downstream of oncogenic signaling.
Revisiting prostate segmentation in magnetic resonance imaging (MRI): On model transferability, degradation and PI-RADS adherence
Authors: Fernandez-Quilez Alvaro , Nordström Tobias , Eftestøl Trygve , Alvestad Andreas Bremset , Jäderling Fredrik , Kjosavik Svein Reidar , Eklund Martin
Published: August 2023

Purpose

To investigate the effect of scanner and prostate MRI acquisition characteristics when compared to PI-RADSv2.1 technical standards in the performance of a deep learning prostate segmentation model trained with data from one center (INST1), longitudinally evaluated at the same institution and when transferred to other institutions.

Materials and Methods

In this retrospective study, a nn-UNet for prostate MRI segmentation was trained with data from 204 patients from one institution (INST1) (0.50mm2in-plane, 3.6mm thickness and 16cm field of view [FOV]). Post-deployment performance at INST1 was tested with 30 patients acquired with a different protocol and in a different period of time (0.60mm2in-plane, 4.0mm thickness and 19cm FOV). Transferability was tested on 248 patient sequences from five institutions (INST2, INST3, INST4, INST5 and INST6) acquired with different scanners and with heterogeneous degrees of PI-RADS v2.1 technical adherence. Performance was assessed using Dice Score Coefficient, Hausdorff Distance, Absolute Boundary Distance and Relative Volume Difference.

Results

The model presented a significant degradation for the whole gland (WG) in the presence of a change of acquisition protocol at INST1 (DSC:99.46±0.12% and 91.24±3.32%,P<.001; RVD:-0.006±0.127% and 8.10±8.16%,P<.001). The model had a significantly higher performance in centers adhering to PI-RADS v2.1 when compared to those that did not (DSC: 86.24±9.67% and 74.83±15.45%,P<.001; RVD: -6.50±18.46% and 1.64±29.12%,P=.003).

Conclusions

Adherence to PI-RADSv2.1 technical standards benefits inter-institutional transferability of a deep learning prostate segmentation model. Post-deployment evaluations are critical to ensure model performance is maintained over time in the presence of protocol acquisition modifications.
Olfactomedin-4+neutrophils exacerbate intestinal epithelial damage and worsen host survival afterClostridioides difficileinfection
Authors: Huber A. , Jose S. , Kassam A. , Weghorn K. N. , Powers-Fletcher Maggie , Sharma D. , Mukherjee A. , Mathew A. , Kulkarni N. , Chandramouli S. , Alder M. N. , Madan R.
Published: August 2023

Neutrophils are key first responders toClostridioides difficileinfection (CDI). Excessive tissue and blood neutrophils are associated with worse histopathology and adverse outcomes, however their functional role during CDI remains poorly defined. Utilizing intestinal epithelial cell (IEC)-neutrophil co-cultures and a pre-clinical animal model of CDI, we show that neutrophils exacerbateC. difficile-induced IEC injury. We utilized cutting-edge single-cell transcriptomics to illuminate neutrophil subtypes and biological pathways that could exacerbate CDI-associated IEC damage. As such, we have established the first transcriptomics atlas of bone marrow (BM), blood, and colonic neutrophils after CDI. We found that CDI altered the developmental trajectory of BM and blood neutrophils towards populations that exhibit gene signatures associated with pro-inflammatory responses and neutrophil-mediated tissue damage. Similarly, the transcriptomic signature of colonic neutrophils was consistent with hyper-inflammatory and highly differentiated cells that had amplified expression of cytokine-mediated signaling and degranulation priming genes. One of the top 10 variable features in colonic neutrophils was the gene for neutrophil glycoprotein, Olfactomedin 4 (OLFM4). CDI enhanced OLFM4 mRNA and protein expression in neutrophils, and OLFM4+cells aggregated to areas of severe IEC damage. Compared to uninfected controls, both humans and mice with CDI had higher concentrations of circulating OLFM4; and in mice, OLFM4 deficiency resulted in faster recovery and better survival after infection. Collectively, these studies provide novel insights into neutrophil-mediated pathology after CDI and highlight the pathogenic role of OLFM4+neutrophils in regulating CDI-induced IEC damage.

One Sentence Summary

Utilizing single-cell transcriptomics, IEC-epithelial co-cultures, and pre-clinical models of CDI, we have identified a subset of neutrophils that are marked by OLFM4 expression as pathogenic determinants of IEC barrier damage after CDI.
Structural insights into DNA Topoisomerase II of African Swine Fever Virus
Authors: Cong Jingyuan , Xin Yuhui , Kang Huiling , Yang Yunge , Wang Chenlong , Li Xuemei , Rao Zihe , Chen Yutao
Published: August 2023

Type II topoisomerases are ubiquitous enzymes that play a pivotal role in modulating the topological configuration of dsDNA. These Topo Ⅱ enzymes are indispensable for DNA metabolism and have been extensively investigated in both prokaryotic and eukaryotic organisms. However, understanding of virus-encoded Topo II remains limited. One intriguing example is the African swine fever virus (ASFV), which stands as the sole mammalian-infecting virus encoding a Topo II. In this work, we utilized multiple approaches involving cryo-EM, X-ray crystallography, atomic force microscopy and biochemical assays to investigate the structure and function of ASFV Topo Ⅱ, pP1192R. We determined the structures of pP1192R in different conformational states and confirming its enzymatic activity in vitro. Collectively, our results unveil the basic mechanisms of viral Topo II, thereby not only augmenting our understanding of this kind of intriguing enzymes but also presenting a potential avenue for the intervention strategies to mitigate the impact of African swine fever virus.
A non-genetic model of vascular shunts informs on the cellular mechanisms of formation and resolution of arteriovenous malformations
Authors: Ouarné Marie , Pena Andreia , Ramalho Daniela , Conchinha Nadine V. , Costa Tiago , Figueiredo Ana , Saraiva Marta Pimentel , Carvalho Yulia , Misikova Lenka Henao , Oh S. Paul , Franco Cláudio A.
Published: August 2023

Arteriovenous malformations (AVMs), a disorder characterized by direct shunts between arteries and veins, are associated with genetic mutations. However, the mechanisms leading to the transformation of a capillary into a shunt remain unclear and how shunts can be reverted into capillaries is poorly understood. Here, we report that oxygen-induced retinopathy (OIR) protocol leads to the consistent and stereotypical formation of AV shunts in non-genetically altered mice. OIR-induced AV shunts show all the canonical markers of AVMs. Genetic and pharmacological interventions demonstrated that changes in endothelial cell (EC) volume of venous origin (hypertrophic venous cells) are the initiating step promoting AV shunt formation, whilst EC proliferation or migration played minor roles. Inhibition of mTOR pathway prevents pathological increases in EC volume and significantly reduces the formation of AV shunts. Importantly, we demonstrate that ALK1 signaling cell-autonomously regulates EC volume, demonstrating that our discoveries link with hereditary hemorrhagic telangiectasia (HHT)-related AVMs. Finally, we demonstrate that a combination of EC volume control and EC migration is associated with the regression of AV shunts.

We demonstrate that an increase in the EC volume is the key mechanism driving the initial stages of AV shunt formation, leading to asymmetric capillary diameters. Based on our results, we propose a coherent and unifying timeline leading to the fast conversion of a capillary vessel into an AV shunt. Our data advocates for further investigation into the mechanisms regulating EC volume in health and disease as a way to identify therapeutic approaches to prevent and revert AVMs.
3D modeling of CpG DNA binding with matrix lumican shows leucine-rich repeat motif involvement as in TLR9- CpG DNA interactions
Authors: Choi Tansol , Maiti George , Chakravarti Shukti
Published: August 2023

Lumican is an extracellular matrix proteoglycan, known to regulate toll-like receptor (TLR) signaling in innate immune cells. In experimental settings, lumican suppresses TLR9 signaling by binding to, and sequestering its synthetic ligand, CpG-DNA, in non-signal permissive endosomes. However, the molecular details of lumican interactions with CpG-DNA are obscure. Here, the 3-D structure of the 22 base-long CpG-DNA (CpG ODN_2395) bound to lumican or TLR9 were modeled using homology modeling and docking methods. Some of the TLR9-CpG ODN_2395 features predicted by our model are consistent with the previously reported TLR9-CpG DNA crystal structure, substantiating our current analysis. Our modeling indicated a smaller buried surface area for lumican-CpG ODN_2395 (1803 A2) compared to that of TLR9-CpG ODN_2395 (2094 A2), implying a potentially lower binding strength for lumican and CpG-DNA than TLR9 and CpG-DNA. The docking analysis identified 32 amino acids in lumican LRR1-11 interacting with CpG ODN_2395, primarily through hydrogen bonding, salt-bridges and hydrophobic interactions. Our study provides molecular insights into lumican and CpG-DNA interactions that may lead to molecular targets for modulating TLR9 mediated inflammation and autoimmunity.
Segment Anything for Microscopy
Authors: Archit Anwai , Nair Sushmita , Khalid Nabeel , Hilt Paul , Rajashekar Vikas , Freitag Marei , Gupta Sagnik , Dengel Andreas , Ahmed Sheraz , Pape Constantin
Published: August 2023

We present Segment Anything for Microscopy, a tool for interactive and automatic segmentation and tracking of objects in multi-dimensional microscopy data. Our method is based on Segment Anything, a vision foundation model for image segmentation. We extend it by training specialized models for microscopy data that significantly improve segmentation quality for a wide range of imaging conditions. We also implement annotation tools for interactive (volumetric) segmentation and tracking, that speed up data annotation significantly compared to established tools. Our work constitutes the first application of vision foundation models to microscopy, laying the groundwork for solving image analysis problems in these domains with a small set of powerful deep learning architectures.
Prospective Fecal Microbiomics Biomarkers for Chronic Wasting Disease
Authors: Didier Adam , Bourner Maureen , Kleks Guy , Zolty Avihai , Kumar Brajendra , Nichols Tracy , Durynski Karie , Bender Susan , Gibison Michelle , Murphy Lisa , Ellis Julie C. , Dong Dawei W. , Kashina Anna
Published: August 2023

Chronic wasting disease (CWD) is a naturally occurring prion disease in cervids that has been rapidly proliferating in the US. Here we investigated a potential link between CWD infection and gut microbiome by analyzing 50 fecal samples obtained from CWD-positive animals of different sexes from various regions in the US, compared to 50 CWD-negative controls using high throughput sequencing of the 16S ribosomal RNA and targeted metabolomics. Our analysis reveals promising trends in the gut microbiota that could potentially be CWD-dependent, including several bacterial taxa at each rank level, as well as taxa pairs, that can differentiate between CWD-negative and CWD-positive deer. At each rank level, these taxa and taxa pairs could facilitate identification of around 70% of both the CWD-negative and the CWD-positive samples. Our results provide a potential tool for diagnostics and surveillance of CWD in the wild, as well as conceptual advances in our understanding of the disease.

Importance

This is a comprehensive study that tests the connection between the composition of the gut microbiome in deer in response to Chronic Wasting Disease (CWD). We analyzed 50 fecal samples obtained from CWD-positive animals compared to 50 CWD-negative controls to identify CWD-dependent changes in the gut microbiome, matched with the analysis of fecal metabolites. Our results show promising trends suggesting that fecal microbial composition can directly correspond to CWD disease status. These results point to microbial composition of the feces as a potential tool for diagnostics and surveillance of CWD in the wild, including non-invasive CWD detection in asymptomatic deer and deer habitats, and enable conceptual advances in our understanding of the disease.
Cryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms
Authors: Lai Louis Tung Faat , Balaraman Jayashree , Zhou Fei , Matthies Doreen
Published: August 2023

Magnesium ions (Mg2+) play an essential role in cellular physiology. In mitochondria, protein and ATP synthesis and various metabolic pathways are directly regulated by Mg2+. MRS2, a magnesium channel located in the inner mitochondrial membrane, mediates the influx of Mg2+into the mitochondrial matrix and regulates Mg2+homeostasis. Knockdown of MRS2 in human cells leads to reduced uptake of Mg2+into mitochondria and disruption of the mitochondrial metabolism. Despite the importance of MRS2, the Mg2+translocation and regulation mechanisms of MRS2 are still unclear. Here, using cryo-EM we determined the structure of human MRS2 in the presence and absence of Mg2+at 2.8 Å and 3.3 Å, respectively. From the homo-pentameric structures, we identified R332 and M336 as major gating residues, which were then tested using mutagenesis and two cellular divalent ion uptake assays. A network of hydrogen bonds was found connecting the gating residue R332 to the soluble domain, potentially regulating the gate. Two Mg2+-binding sites were identified in the MRS2 soluble domain, distinct from the two sites previously reported in CorA, a homolog of MRS2 in prokaryotes. Altogether, this study provides the molecular basis for understanding the Mg2+translocation and regulatory mechanisms of MRS2.
Human Immunodeficiency Virus 1 Capsid Uncoating in the Nucleus Progresses Through Defect Formation in the Capsid Lattice
Authors: Gifford Levi B. , Melikyan Gregory B.
Published: August 2023

The HIV-1 core consists of a cone-shaped capsid shell made of ∼250 capsid protein (CA) hexamers and 12 pentamers encapsulating the viral genome. HIV-1 capsid disassembly, referred to as uncoating, is a highly regulated process that is important for productive infection, however, the location, timing, and regulation of uncoating remain controversial. Here, we employ amber codon suppression to directly label CA and visualize capsid trafficking and uncoating in live cells. In addition to direct CA labeling, a fluid phase fluorescent probe is incorporated into the viral core to detect the formation of small defects in the capsid lattice. This double-labeling strategy does not significantly impact HIV-1 infectivity, maturation, nuclear import, or capsid stability. Single virus tracking reveals nuclear import of intact cores defined as complexes containing both the fluid phase marker and robust CA signal. Subsequent uncoating of HIV-1 cores in the nucleus is manifested by a sequential loss of both fluorescent markers. This two-step uncoating – release of the core content marker followed by loss of CA – is observed in different cells, including a macrophage line. Importantly, the lag between the two steps of uncoating (∼30 min) appears independent of the cell type and is much longer than upon uncoating of cell-free viruses. These data suggest that HIV- 1 uncoating in the nucleus is initiated through a localized defect in the capsid lattice that precedes a global loss of CA. Our results imply that intact HIV-1 cores enter the cell nucleus and uncoat in a stepwise fashion, before integrating into the host genome.
Hypothetical geneRv0495cregulates redox homeostasis inMycobacterium tuberculosis
Authors: Pal Rahul , Talwar Sakshi , Pandey Manitosh , Nain Vaibhav , Sharma Taruna , Tyagi Shaifali , Barik Vishawjeet , Chaudhary Shweta , Gupta Sonu Kumar , Kumar Yashwant , Nanda Ranjan , Singhal Amit , Pandey Amit Kumar
Published: August 2023

Mycobacterium tuberculosis(Mtb) has evolved sophisticated surveillance mechanisms to regulate and neutralize redox imbalances and associated lethal consequences. Failing this, the accumulated ROS induces toxicity by oxidizing a variety of biological molecules including proteins, nucleic acids and lipids. In the present study we identified Mtb’sRv0495cgene as an important regulator of oxidized cytosolic environment. Compared to wild type Mtb strain lackingthe Rv0495cgene, ΔRv0495c, had increased ROS and NAD+/NADH ratio creating a highly oxidized intracellular environment. ΔRv0495cstrain demonstrated slow growth phenotype underin vitroandex-vivogrowth conditions and demonstrated enhanced susceptibility to drugs, oxidative, nitrosative and hypoxic growth conditions. In addition, the increase in the superoxide radicals triggered a Fenton-like reaction rendering the ΔRv0495csusceptible to free iron. The increase in the intracellular ROS levels of the ΔRv0495cwas further corroborated by an increase in the expression of proteins involved in antioxidant defense and enhanced ROS-mediated oxidation and degradation of mycobacterial lipids. This superoxide-induced lipid degradation resulted in altered colony morphology and loss of membrane integrity in the ΔRv0495c. Surprisingly, despite showing a growth defect phenotype in anex-vivomacrophage infection model, the absence of theRv0495cgene in Mtb enhanced the pathogenicity and augmented the ability of the Mtb to grow inside the host. Gene expression analysis revealed a Rv0495c mediated immunomodulation of the host controls inflammation and helps creates a favorable niche for long-term survival of Mtb inside the host. In summary, the current study underscores the fact that the truce in the war between the host and the pathogen favors long-term disease persistence in tuberculosis. We believe targeting Rv0495c could potentially be explored as a strategy to potentiate the current anti-TB regimen.
Gate keeping the sebaceous gland
Authors: Sachdeva Suveer , Ahmed Araz , Proctor Gordon , Miletich Isabelle
Published: August 2023

Sebaceous gland (SG) secretions are pivotal to skin and eye health. At the SG-epidermis confluence is an overlooked epidermal collar we named the follicular epidermis (FE). Here, we show that the FE is similar among different SG types and contains unique Axin2+ stem cells in a niche at its basal FE-perpendicular flexure (FE-PF). Lineage tracing and ablation assays demonstrate Axin2+ cells as integral for FE homeostasis. Wnt-secretion arrest experiments resulted in FE-obstruction via hyperproliferation and inhibited differentiation inferring FE-PF Axin2+ cells are Wnt-producers maintaining FE-patency. Upon constitutive Axin2+ cell Wnt signalling, FE-PF-specific cell proliferation with early-stage signs of malignancy formed alongside a keratin-plugging FE-obstruction type. While keratin-based obstructions are recognized, inhibited differentiation obstructions are not, which suggests a one-size-fits-all therapeutic approach is not optimal. We offer a molecular identification toolkit to aid anti-obstruction advances in dermatology/ophthalmology and highlight the FE-PF as a skin tumorigenic site.

This work characterises a novel site in the skin, it’s stem cells and niche, a site prone to cancer. Obstructions can occur at this site by two mechanisms, one of which is novel, bringing into question current therapy and prompting a rethink of disease in dermatology and ophthalmology to account for this novel site.

Graphical Abstract
Real-time identification of epistatic interactions in SARS-CoV-2 from large genome collections
Authors: Innocenti Gabriel , Galardini Marco
Published: August 2023

The emergence and rapid spread of the SARS-CoV-2 virus has highlighted the importance of genomic epidemiology in understanding the evolution of pathogens and for guiding public health interventions. In particular, the Omicron variant underscored the role of epistasis in the evolution of lineages with both higher infectivity and immune escape, and therefore the necessity to update surveillance pipelines to detect them as soon as they emerge. In this study we applied a method based on mutual information (MI) between positions in a multiple sequence alignment (MSA), which is capable of scaling up to millions of samples. We showed how it could reliably predict known experimentally validated epistatic interactions, even when using as little as 10,000 sequences, which opens the possibility of making it a near real-time prediction system. We tested this possibility by modifying the method to account for sample collection date and applied it retrospectively to MSAs for each month between March 2020 and March 2023. We could detect a cornerstone epistatic interaction in the Spike protein between codons 498 and 501 as soon as 6 samples with a double mutation were present in the dataset, thus demonstrating the method’s sensitivity. Lastly we provide examples of predicted interactions between genes, which are harder to test experimentally and therefore more likely to be overlooked. This method could become part of continuous surveillance systems tracking present and future pathogen outbreaks.
DEBBIES to compare life history strategies across ectotherms
Authors: Smallegange Isabel M. , Lucas Sol
Published: August 2023

Demographic models are used to explore how life history traits structure life history strategies across species. This study presents the DEBBIES dataset that contains estimates of eight life history traits (length at birth, puberty and maximum length, maximum reproduction rate, fraction energy allocated to respiration versus reproduction, von Bertalanffy growth rate, mortality rates) for 185 ectotherm species. The dataset can be used to parameterise dynamic energy budget integral projection models (DEB-IPMs) to calculate key demographic quantities like population growth rate and demographic resilience, but also link to conservation status or biogeographical characteristics. Our technical validation shows a satisfactory agreement between observed and predicted longevity, generation time, age at maturity across all species. Compared to existing datasets, DEBBIES accommodates (i) easy cross-taxonomical comparisons, (ii) many data-deficient species, and (iii) population forecasts to novel conditions because DEB-IPMs include a mechanistic description of the trade-off between growth and reproduction. This dataset has the potential for biologists to unlock general predictions on ectotherm population responses from only a few key life history traits.
SC2Spa: a deep learning based approach to map transcriptome to spatial origins at cellular resolution
Authors: Liao Linbu , Madan Esha , Palma António M. , Kim Hyobin , Kumar Amit , Bhoopathi Praveen , Winn Robert , Trevino Jose , Fisher Paul , Brakebusch Cord Herbert , Gogna Rajan , Won Kyoung Jae
Published: August 2023

Integrating single cell RNAseq (scRNAseq) and spatial transcriptomics (ST) data is still challenging especially when the spatial resolution is poor. For cellular resolution spatial mapping, we have developed deep learning-based SC2Spa to learn the intricate spatial mapping rules from the transcriptome to its location from ST data. Benchmarking tests show that SC2Spa uniquely recapitulates tissue architecture from scRNAseq. SC2Spa successfully mapped scRNAseq even to various low resolution Visium data. SC2Spa identified spatially variable genes and suggested negative regulatory relationships between genes. SC2Spa armored with deep learning provides a new way to map the transcriptome to its spatial location and perform subsequent analyses.
Source tracing ofLeishmania donovaniin emerging foci of visceral leishmaniasis in West Nepal
Authors: Monsieurs Pieter , Cloots Kristien , Uranw Surendra , Banjara Megha Raj , Ghimire Prakash , Burza Sakib , Hasker Epco , Dujardin Jean-Claude , Domagalska Malgorzata Anna
Published: August 2023

We sequencedLeishmania donovanigenomes in blood samples collected in emerging foci of Visceral Leishmaniasis, in West Nepal. We detected lineages which are very different from pre-elimination main parasite population: a new lineage and a rare one previously reported once in East Nepal. We highlight the need for genomic surveillance.