bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of HSP105 in the Differential Diagnosis of Basaloid Skin Tumors: A Study of 73 Cases
Authors: Deng Li-Jia , Zhou Kai-Yi , Wang Qin-Xiao , Luo Si-Yu , Fang Sheng
Published: October 2024

Background:

Basaloid skin tumors include subtypes of basal cell carcinoma (BCC) and the basaloid variant of squamous cell carcinoma (SCC). Due to their similarity in pathology and clinical presentation, their diagnosis is not straightforward. The aim of this study was to analyze the immunohistochemical expression of HSP105 in basaloid skin tumors, which include BCC, basosquamous carcinoma (BSC), metatypical basal cell carcinoma (MBCC), basaloid squamous cell carcinoma (BSCC), BCC with squamous differentiation as well as conventional SCC.

Methods:

This retrospective study included 17 cases of BCC, 11 cases of BSC, 8 instances of MBCC, 10 cases of BCC with squamous differentiation, 8 cases of BSCC, and 19 cases of SCC. Their clinical characteristics were summarized, and the paraffin blocks of tumor biopsy specimens were collected for HSP105 immunostaining.

Results:

In contrast to the BCC group, which stained predominantly negative, SCC stained diffusely positive for HSP105. BSCs showed some areas of HSP105 positivity with a transitional expression signature. HSP105 was only weakly positive in a few cases of MBCC. Although BSCC was stained positive for HSP105, the HSCORE was significantly lower than that of the classic SCC. In BCC with squamous differentiation, focal staining for HSP105 was only seen in the area of squamous differentiation.

Conclusion:

There was a difference in immunohistochemical staining of HSP105 in basaloid skin tumors which helps in differential diagnosis. Differentiation between BCC, SCC, BSCC, MBCC, and BCC with squamous differentiation can be aided by immunohistochemistry using HSP105.
Decoding Brain Development and Aging
Authors: Hagiwara Akifumi , Kamio Satoru , Kikuta Junko , Nakaya Moto , Uchida Wataru , Fujita Shohei , Nikola Stikov , Akasahi Toshiaki , Wada Akihiko , Kamagata Koji , Aoki Shigeki
Published: October 2024

The aging process induces a variety of changes in the brain detectable by magnetic resonance imaging (MRI). These changes include alterations in brain volume, fluid-attenuated inversion recovery (FLAIR) white matter hyperintense lesions, and variations in tissue properties such as relaxivity, myelin, iron content, neurite density, and other microstructures. Each MRI technique offers unique insights into the structural and compositional changes occurring in the brain due to normal aging or neurodegenerative diseases. Age-related brain volume changes encompass a decrease in gray matter and an increase in ventricular volume, associated with cognitive decline. White matter hyperintensities, detected by FLAIR, are common and linked to cognitive impairments and increased risk of stroke and dementia. Tissue relaxometry reveals age-related changes in relaxivity, aiding the distinction between normal aging and pathological conditions. Myelin content, measurable by MRI, changes with age and is associated with cognitive and motor function alterations. Iron accumulation, detected by susceptibility-sensitive MRI, increases in certain brain regions with age, potentially contributing to neurodegenerative processes. Diffusion MRI provides detailed insights into microstructural changes such as neurite density and orientation. Neurofluid imaging, using techniques like gadolinium-based contrast agents and diffusion MRI, reveals age-related changes in cerebrospinal and interstitial fluid dynamics, crucial for brain health and waste clearance. This review offers a comprehensive overview of age-related brain changes revealed by various MRI techniques. Understanding these changes helps differentiate between normal aging and pathological conditions, aiding the development of interventions to mitigate age-related cognitive decline and other symptoms. Recent advances in machine learning and artificial intelligence have enabled novel methods for estimating brain age, offering also potential biomarkers for neurological and psychiatric disorders.
What Is the Added Value of DWI Compared With Structured Assessment of BI-RADS Criteria by the Kaiser Score? A Systematic Review and Meta-analysis
Authors: Dietzel Matthias , Vatteroni Giulia , Baltzer Pascal A.T.
Published: October 2024

Objective

This systematic review and meta-analysis investigated the added value of DWI compared with the structured assessment of BI-RADS criteria using the Kaiser score.

Materials and Methods

Articles published in English until May 2024 were included. Two independent reviewers extracted data on the characteristics of studies evaluating the added value of DWI to distinguish benign from malignant breast lesions compared with structured assessment of the BI-RADS criteria. Using bivariate random-effects models, the sensitivity and specificity were calculated. I
2 statistics, Deek's funnel plot asymmetry test for publication bias, and meta-regression were applied for the data analysis.

Results

Five studies comprising 1005 malignant and 846 benign lesions were eligible for data synthesis. The pooled sensitivity and specificity estimates of structured BI-RADS assessment were 95.7% (95% confidence interval [CI], 92.6%–97.5%) and 68.7% (95% CI, 60.9%–75.6%), respectively. Adding DWI to the structured BI-RADS assessment achieved a pooled sensitivity of 94.4% (95% CI, 90.5%–96.7%) and a pooled specificity of 74.9% (95% CI, 68.8%–80.2%). Adding DWI to the structured BI-RADS assessment significantly changed neither the sensitivity (P = 0.52) nor the specificity (P = 0.20).

Conclusions

This systematic review and meta-analysis revealed only a limited, statistically nonsignificant added value of DWI compared with the structured assessment of BI-RADS criteria using the Kaiser score.
Miniscrew-assisted Rapid Palatal Expansion Before Orthognathic Surgery for a Patient With Laterognathia
Authors: Büyükçavuş Muhammed Hilmi , Albayrak Elif , Findik Yavuz
Published: October 2024

In this case report, a 19-year-old male patient with maxillary transverse deficiency, concave profile, and facial asymmetry is presented. In the case of transversal insufficiency, nonsurgical maxillary expansion was performed with the miniscrew-assisted rapid palatal expansion (MARPE) appliance to reduce the number of surgeries and provide both dentoalveolar and skeletal expansion. The periodontal soundness and short-term stability of the maxillary expansion were confirmed both clinically and radiologically. Mandibular prognathism was later corrected with orthognathic surgery. MARPE is an effective approach to the treatment of maxillary transverse deficiencies in adult patients.
Laparoscopic Totally Extraperitoneal Inguinal Hernia Repair Under Combined Spinal Epidural Anesthesia Versus General Anesthesia
Authors: Donmez Turgut , Tulubas Evrim Kucur , Bostanci Ipek
Published: October 2024

Background:

Inguinal hernia repair is one of the most frequently used elective surgical operations in the world. General anesthesia (GA) has risks and routine postoperative complications, such as nausea, vomiting, throat irritation, and postoperative pain. Regional anesthesia (RA) has many advantages over GA, such as faster recovery, less postoperative pain, nausea, and vomiting, and less hemodynamic compromise. We aimed to investigate the efficacy and safety of combined spinal and epidural anesthesia (CSEA) in preventing shoulder pain in patients undergoing totally extraperitoneal herniorrhaphy (TEP).

Materials and Methods:

The files of patients who had undergone the TEP method under GA and CSEA due to inguinal hernia between April 2020 and November 2021 at the Bakirköy Dr. Sadi Konuk Training and Research Hospital were reviewed retrospectively.

Results:

A total of 81 patients were included in the study. The number of patients operated on GA (group 1) was 40, and the number of patients operated under CSEA (group 2) was 41. There was no significant difference in the demographic characteristics of the patients. The surgical time was 42.9 and 42.5 minutes in groups 1 and 2, respectively (P=0.970). The mean operative time was recorded as 60.1 and 80.2 minutes in groups 1 and 2, respectively, and it was statistically significantly shorter in group 1 (P<0.001). A peritoneal tear was seen in 18 patients (43.90%) in the GA group and 16 patients (40%) in the CSEA group, but no significant difference was found between the groups (P=0.823). Mild shoulder pain that did not require intervention was observed in 1 patient (2.5%) in the CSEA group. In group 2, the VAS scores at all times and the need for postoperative analgesia were statistically significantly lower (P<0.001). In terms of anesthesia complications, headache was not observed in group 1, while it was seen in 6 (15%) patients in group 2 (P=0.012)

Conclusions:

In laparoscopic TEP surgeries, CSEA may be an alternative anesthesia method to GA anesthesia due to the low VAS score, less need for analgesia, and fewer postoperative pulmonary complications.
Damage control thoracic surgery: What you need to know
Authors: Ghneim Mira H. , O'Connor James V. , Scalea Thomas M.
Published: October 2024

Damage control surgery in trauma prioritizes patient stabilization through an initial temporizing surgical approach to rapidly control hemorrhage and contamination, minimizing intraoperative time to allow for resuscitation and the correction of hypothermia, coagulopathy, and acidosis in the intensive care unit. This is followed by definitive repair of injuries once physiological parameters have improved. While damage control techniques for traumatic intra-abdominal and extremity injuries are well established and frequently utilized, the same cannot be said for damage control thoracic surgery. The complexity of thoracic injuries, the intricate decision making process, the level of surgical expertise required, and potential complications make damage control thoracic surgery particularly challenging. However, advances in surgical techniques, improvements in perioperative care, and the emergence of adjuncts such as extracorporeal membrane oxygenation have significantly enhanced decision making and underscored the importance of timely and decisive intervention in damage control thoracic surgery to optimize patient outcomes. This review aims to provide a comprehensive overview of damage control thoracic surgery, detailing the principles, indications, operative techniques, perioperative management, and the integration of advanced therapies to improve outcomes in patients with severe thoracic injuries.
Clinical Significance of Grade A Small-for-size Syndrome After Living Donor Liver Transplantation Utilizing the New Definition of Diagnostic Criteria: An International Multicenter Study
Authors: Jo Hye-Sung , Kim Dong-Sik , Gunasekaran Vasanthakumar , Krishnamurthy Jagadeesh , Toshima Takeo , Takahashi Ryugen , Kim Jae-Yoon , Krishnan Sathish Kumar , Okumura Shinya , Hara Takanobu , Shimata Keita , Haruki Koichiro , Minnee Robert C. , Rammohan Ashwin , Gupta Subash , Yoshizumi Tomoharu , Ikegami Toru , Lee Kwang-Woong , Rela Mohamed
Published: October 2024

Background.

New diagnostic criteria have recently been established to classify small-for-size syndrome (SFSS) after living donor liver transplantation into 3 groups based on severity. This study aimed to evaluate the clinical impact of grade A SFSS and identify the mortality risk.

Methods.

We collected data from 406 patients diagnosed with grade A SFSS after living donor liver transplantation. Grade A SFSS is characterized by total bilirubin >5 mg/dL on postoperative day (POD) 7 or total bilirubin >5 mg/dL or ascites >1 L/d on POD 14. After propensity score matching, 193 patients were categorized into the up-trend group, down-trend group, and ascites group, with 43 patients (22.3%) in the up-trend group (total bilirubin on POD 7 < POD 14), 107 patients (55.4%) in the down-trend group (total bilirubin on POD 7 > POD 14), and 43 patients (22.3%) in the ascites group (only satisfying ascites criteria).

Results.

There was no significant difference in survival between patients with grade A SFSS and those without SFSS (P = 0.152). The up-trend group showed a higher 90-d mortality rate than the down-trend and ascites groups (P = 0.025). The 1-y survival rate differed significantly between the groups (87.6%, 91.9%, and 97.7%, respectively; P = 0.044). The independent risk factors for survival were up-trend of total bilirubin, recipient age (65 y and older), model for end-stage liver disease score (≥30), and ABO incompatibility. Patients with ≥2 risk factors had worse survival rates than those with none and only 1 risk factor (P < 0.001).

Conclusions.

Although the survival rate was comparable between the grade A SFSS and non-SFSS cohorts, the up-trend group showed worse survival. Aggressive interventions should be considered for up-trend patients with risk factors.
Urbanization and substance use in left-behind children and adolescents: a systematic review and meta-analysis
Authors: Lin Kelly , Buys Nicholas , Jiang Yannan , Sun Jing
Published: October 2024

Purpose of review

Inequalities in job opportunities between urban and rural regions have driven many parents to move from rural to urban regions with aims to improve household income. Financial and political barriers prevent children from moving with their parents, meaning that their children become left-behind in rural regions. This study aims to meta-analyse the risk of drinking, smoking, illicit drug use and drunk experiences in left behind children (LBC) and non-LBC.

Recent findings

Previous studies have indicated the negative effects of prolonged parental separation on children and adolescent mental health. Parental separation and poor mental health have both been identified as proximal risk factors for substance use in adolescence.

The results indicated that LBC were at significantly greater risk of drinking, smoking, using illicit drugs, and having drunk experiences. Positive psychology interventions are required to help provide LBC with positive coping strategies against psychological distress. Policy changes to reduce inequalities in job opportunities between urban and rural regions are required to reduce the prevalence of LBC.
Elephants develop wrinkles through both form and function
Authors: Schulz Andrew K. , Kaufmann Lena V. , Reveyaz Noemie , Ritter Cindy , Hildebrandt Thomas , Brecht Michael
Published: October 2024

The trunks of elephants have prominent wrinkles from their base to the very tip. But neither the obvious differences in wrinkles between elephant species nor their development have been studied before. In this work, we characterize the lifelong development of trunk wrinkles in Asian and African elephants. Asian elephants have more dorsal major, meaning deep and wide, trunk wrinkles (approx. 126 ± 25 s.d.) than African elephants (approx. 83 ± 13 s.d.). Both species have more dorsal than ventral major trunk wrinkles and a closer wrinkle spacing distally than proximally. In Asian elephants, wrinkle density is high in the ‘trunk wrapping zone’. Wrinkle numbers on the left and right sides of the distal trunk differed as a function of trunk lateralization, with frequent bending in one direction causing wrinkle formation. Micro-computed tomography (microCT) imaging and microscopy of newborn elephants’ trunks revealed a constant thickness of the putative epidermis, whereas the putative dermis shrinks in the wrinkle troughs. During fetal development, wrinkle numbers double every 20 days in an early exponential phase. Later wrinkles are added slowly, but at a faster rate in Asian than African elephants. We discuss the relationship of species differences in trunk wrinkle distribution and number with behavioural, environmental and biomechanical factors.
Stable coexistence in indefinitely large systems of competing species
Authors: Mooij M. N. , Baudena M. , von der Heydt A. S. , Kryven I.
Published: October 2024

The Lotka–Volterra system is a set of ordinary differential equations describing growth of interacting ecological species. One of the debated questions is understanding how the number of species in the system influences the stability of the model. Robert May studied how large systems may become unstable when species–species interactions do not vanish. This outcome has frequently been interpreted as a universal phenomenon and summarized as ‘large systems are unstable’. By exploring general interaction networks, we show that the competitive Lotka–Volterra system may maintain stability even for large networks, despite non-vanishing interaction strength. We establish sufficient conditions for stability as a threshold on the interspecific interaction strength, formulated in terms of the maximum and minimum degrees (or weights) rather than the network’s size. For values below this threshold, coexistence of all species is attained, regardless of the system size. Our finding generalizes May’s result by showing that it is the outlier nodes with large degree that cause instability rather than the large number of species in the system.
Long-term anti-predator learning and memory differ across populations and sexes in an intertidal snail
Authors: Neylan Isabelle P. , Longman Emily K. , Sanford Eric , Stachowicz John J. , Sih Andrew
Published: October 2024

Anti-predator behaviours in response to predator cues can be innate, or they can be learned through prior experience and remembered over time. The duration and strength of continued anti-predator behaviour after predator cues are no longer present, and the potential for an enhanced response when re-exposed to predator cues later is less known but could account for the observed variation in anti-predator responses. We measured the carryover effects of past predation exposure and the potential for anti-predator learning and memory in the marine snail
Nucella canaliculata
from six populations distributed over 1000 km of coastline. We exposed lab-reared snails to cues associated with a common crab predator or seawater control in two serial experiments separated by over seven months. Responses were population- and sex-dependent, with some populations retaining anti-predator behaviours while others showed a capacity for learning and memory. Male snails showed a strong carryover of risk aversion, while females were able to return to normal feeding rates and grow more quickly. These behavioural differences culminated in strong impacts on feeding and growth rates, demonstrating that this variation has implications for the strength of trait-mediated indirect interactions, which can impact entire ecosystems.
Asymmetric arms races between predators and prey: a tug of war between the life–dinner principle and the rare-enemy principle
Authors: McLean Donald James , Herberstein Marie E. , Kokko Hanna
Published: October 2024

Antagonistic co-evolution can be asymmetric, where one species lags behind another. Asymmetry in a predator–prey context is expressed by the ‘life–dinner principle’, a classic informal model predicting that prey should be in some sense ahead in this arms race, since prey are running for their lives, while predators lag as they only run for their dinner. The model has undergone surprisingly little theoretical scrutiny. We derive analytical models that show coevolutionary outcomes do not always align with the life–dinner principle. Our results show that other important asymmetries can easily reverse the outcome, especially the rare-enemy principle: predators are usually outnumbered by their prey, sometimes substantially (trophic asymmetry), which can make selection on prey relatively weak. We additionally show that the antagonists typically exhibit different evolutionary responses to a situation where both predator and prey start out as equally fast runners. Although predators sometimes become so efficient that attacks always succeed, attack success often reaches a stable intermediate value. We conclude that the life–dinner principle has some validity as a metaphor, but its effect is of an ‘all else being equal’ type, which is surprisingly easily overridden by other features of the evolutionary dynamics.
Coral responses to a catastrophic marine heatwave are decoupled from changes in total coral cover at a continental scale
Authors: Mellin Camille , Stuart-Smith Rick D. , Heather Freddie , Oh Elizabeth , Turak Emre , Edgar Graham J.
Published: October 2024

The services provided by the world’s coral reefs are threatened by increasingly frequent and severe marine heatwaves. Heatwave-induced degradation of reefs has often been inferred from the extent of the decline in total coral cover, which overlooks extreme variation among coral taxa in their susceptibility and responses to thermal stress. Here, we provide a continental-scale assessment of coral cover changes at 262 shallow tropical reef sites around Australia, using ecological survey data on 404 coral taxa before and after the 2016 mass bleaching event. A strong spatial structure in coral community composition along large-scale environmental gradients largely dictated how coral communities responded to heat stress. While heat stress variables were the best predictors of change in total coral cover, the pre-heatwave community composition best predicted the temporal beta-diversity index (an indicator of change in community composition over time). Indicator taxa in each coral community differed before and after the heatwave, highlighting potential winners and losers of climate-driven coral bleaching. Our results demonstrate how assessment of change in total cover alone may conceal very different responses in community structure, some of which showed strong regional consistency, and may provide a telling outlook of how coral reefs may reorganize in a warmer future.
Cell-based high-content approach for SARS-CoV-2 neutralization identifies unique monoclonal antibodies and PI3K pathway inhibitors
Authors: Cabel Carly R. , Guzman Briana A. , Alizadeh Elaheh , Li Shuaizhi , Holberg Cameron , Wichaidit Chonlarat , Cusanovich Darren A. , Paek Andrew L. , Thatcher Gregory R. J. , Doorslaer Koenraad Van , Nargi Rachel S. , Sutton Rachel E. , Suryadevara Naveenchandra , Crowe James E. , Carnahan Robert H. , Campos Samuel K. , Thorne Curtis A.
Published: October 2024

The sudden rise of the SARS-CoV-2 virus and the delay in the development of effective therapeutics to mitigate it made evident a need for ways to screen for compounds that can block infection and prevent further pathogenesis and spread. Yet, identifying effective drugs efficacious against viral infection and replication with minimal toxicity for the patient can be difficult. Monoclonal antibodies were shown to be effective, yet as the SARS-CoV-2 mutated, these antibodies became ineffective. Small molecule antivirals were identified using pseudovirus constructs to recapitulate infection in non-human cells, such as Vero E6 cells. However, the impact was limited due to poor translation of these compounds in the clinical setting. This is partly due to the lack of similarity of screening platforms to the in vivo physiology of the patient and partly because drugs effective in vitro showed dose-limiting toxicities. In this study, we performed two high-throughput screens in human lung adenocarcinoma cells with authentic SARS-CoV-2 virus to identify both monoclonal antibodies that neutralize the virus and clinically useful kinase inhibitors to block the virus and prioritize minimal host toxicity. Using high-content imaging combined with single-cell and multidimensional analysis, we identified antibodies and kinase inhibitors that reduce virus infection without affecting the host. Our screening technique uncovered novel antibodies and overlooked kinase inhibitors (i.e. PIK3i, mTORi, multiple RTKi) that could be effective against SARS-CoV-2 virus. Further characterization of these molecules will streamline the repurposing of compounds for the treatment of future pandemics and uncover novel mechanisms viruses use to hijack and infect host cells.
Compression andk-mer based Approach For Anticancer Peptide Analysis
Authors: Ali Sarwan , Ali Tamkanat E , Chourasia Prakash , Patterson Murray
Published: October 2024

Our research delves into the imperative realm of anti-cancer peptide sequence analysis, an essential domain for biological researchers. Presently, neural network-based methodologies, while exhibiting precision, encounter challenges with a substantial parameter count and extensive data requirements. The recently proposed method to compute the pairwise distance between the sequences using the compression-based approach [26] focuses on compressing entire sequences, potentially overlooking intricate neighboring information for individual characters (i.e., amino acids in the case of protein and nucleotide in the case of nucleotide) within a sequence. The importance of neighboring information lies in its ability to provide context and enhance understanding at a finer level within the sequences being analyzed. Our study advocates an innovative paradigm, where we integrate classical compression algorithms, such as Gzip, with a pioneeringk-mersbased strategy in an incremental fashion. Diverging from conventional techniques, our method entails compressing individualk-mers and incrementally constructing the compression for subsequences, ensuring more careful consideration of neighboring information for each character. Our proposed method improves classification performance without necessitating custom features or pre-trained models. Our approach unifies compression, Normalized Compression Distance, andk-mers-based techniques to generate embeddings, which are then used for classification. This synergy facilitates a nuanced understanding of cancer sequences, surpassing state-of-the-art methods in predictive accuracy on the Anti-Cancer Peptides dataset. Moreover, our methodology provides a practical and efficient alternative to computationally demanding Deep Neural Networks (DNNs), proving effective even in low-resource environments.
Modeling Thoracic Aortic Dissection Using Patient-Specific iPSCs Reveals VSMC Dysfunction and Extracellular Matrix Dysregulation
Authors: Jin Peifeng , Xu Yubin , Wang Sixian , Ding Lu , Chen Yuhao , Zhou Miqi , Chen Xiufang , Fang Xiaofang , Gong Yongsheng , Li Ming , Wang Yongyu
Published: October 2024

Thoracic aortic dissection (TAD) is a life-threatening condition characterized by medial degeneration and vascular smooth muscle cell (VSMC) dysfunction, with no effective medical therapy currently available. The underlying pathological mechanisms of TAD remain incompletely understood. In this study, we used a non-integrated episomal vector-based reprogramming system to generate induced pluripotent stem cells (iPSCs) from TAD patients and healthy controls. Both TAD and normal iPSCs expressed key pluripotency markers and were capable of differentiating into the three germ layers in vitro. These iPSCs were differentiated into VSMCs through a mesodermal intermediate for disease modeling. VSMCs derived from both TAD and normal iPSCs expressed smooth muscle α-actin (α-SMA), calponin, and SM22α. However, TAD-iPSC-derived VSMCs exhibited significantly reduced contraction in response to carbachol stimulation compared to their normal counterparts. Whole-exome sequencing identified a mutation in the COL4A2 gene (c.392G>T, p. R131M) in TAD-iPSCs. This mutation was associated with reduced collagen IV expression and increased expression of collagen I and III in TAD-VSMCs, both with and without TGF-β stimulation. Furthermore, noncanonical TGF-β signaling was hyperactivated in TAD-VSMCs, accompanied by elevated MMP9 expression. This patient-specific iPSC model reveals key dysfunctions in VSMC contractility, extracellular matrix protein expression, and dysregulated TGF-β signaling, which may contribute to TAD pathogenesis. Our findings provide new insights into the molecular mechanisms driving TAD and offer a platform for future therapeutic development.
Primosomal protein PriC rescues replication initiation stress by bypassing the DnaA-DnaB interaction step for DnaB helicase loading atoriC
Authors: Yoshida Ryusei , Korogi Kazuma , Wu Qinfei , Ozaki Shogo , Katayama Tsutomu
Published: October 2024

InEscherichia coli, replisome and replication fork assembly are initiated by DnaB helicase loading at the chromosomal originoriCvia its interactions with the DnaA initiator and the DnaC helicase loader. Upon replication fork arrest, the replisome including DnaB dissociates from the stalled fork. Replication fork progression is rescued by primosomal protein PriA- or PriC-dependent pathway in which PriA and PriC promote reloading of DnaB in different mechanisms. However, the mechanism responsible for rescue of blocked replication initiation atoriCremains unclear. Here, we found that PriC rescued blocked replication initiation in cells expressing an initiation-specific DnaC mutant, in mutant cells defective in DnaA-DnaB interactions, and in cells containing truncatedoriCsequence variants. PriC rescued DnaB loading atoriCeven in the absence of Rep helicase, a stimulator of the PriC-dependent replication fork restart pathway. These and results ofin vitroreconstituted assays concordantly suggest that this initiation-specific rescue mechanism provides a bypass of the DnaA-DnaB interaction for DnaB loading by PriC-promoted loading of DnaB to the unwoundoriCregion. These findings expand understanding of mechanisms sustaining the robustness of replication initiation and specific roles for PriC in the genome maintenance.
A quantitative multi-parameter mapping protocol standardized for clinical research in autoimmune neuroinflammatory diseases with white matter abnormalities
Authors: Trang Henri , Hartung Tim J. , Chen Qianlan , Hetzer Stefan , Chien Claudia , Sperber Pia S. , Schmitz-Hübsch Tanja , Asseyer Susanna , Rust Rebekka , Mewes Darius , Anderhalten Lina , Sy Michael , Brandt Alexander U. , Finke Carsten , Paul Friedemann
Published: October 2024

Quantitative magnetic resonance imaging (qMRI) involves mapping microstructure in standardized units sensitive to histological properties and supplements conventional MRI, which relies on contrast weighted images where intensities have no biophysical meaning. While measuring tissue properties such as myelin, iron or water content is desired in a disease context, qMRI changes may typically reflect mixed influences from aging or pre-clinical degeneration. We used a fast multi-parameter mapping (MPM) protocol for clinical routine at 3T to reconstruct whole-brain quantitative maps of magnetization transfer saturation (MT), proton density (PD), longitudinal (R1), and transverse relaxation rate (R2*) with 1.6 mm isotropic resolution. We report reference MPM values from a healthy population with age and gender distributions typical of neuroimmunology studies in whole brain white matter (WM), T2-weighted WM hyperintensities, cortical grey matter and deep grey matter regions and present post-processing optimizations including integration of lesions and normalization of PD maps against cerebrospinal fluid (CSF) for standardized research in multiple sclerosis (MS) and related disorders. PD maps were affected by WM abnormalities in MS using WM calibration. The results acknowledge the impact of non-linear age effects on MPM and suggest using CSF calibration for future clinical application in autoimmune neuroinflammatory diseases with WM abnormalities.
Characterization and Racial Stratification of Social Determinants of Health for Individuals with Type 2 Diabetes as Recorded in Electronic Health Records: Implications for Artificial Intelligence Development
Authors: Kukhareva Polina V. , O’Brien Matthew J. , Malone Daniel C , Kawamoto Kensaku , Gouripeddi Ramkiran , Reddy Deepika , Zhang Mingyuan , Deshmuch Vikrant G. , Facelli Julio C.
Published: October 2024

Background

Accurate documentation of social determinants of health (SDoH) in electronic health records (EHRs) is critical for developing equitable AI models for diabetes management. This study investigates SDoH data in a cross-institutional EHR database.

Methods

We analyzed neighborhood-level (i.e., social vulnerability index [SVI], Rural-Urban Community Area [RUCA]) and individual-level SDoH (e.g., preferred language, marital status, tobacco, alcohol, and substance use) within the Epic Cosmos database, focusing on adults diagnosed with T2D (E11.*) who had encounters between 2021 and 2023. We measured data completeness (i.e., the proportion of individuals who have a non-missing value) and the prevalence of non-canonical values (e.g., preference for language other than English) for each available SDoH variable.

Findings

The study included 12,696,680 individuals with T2D. SVI, RUCA and preferred language were available for all individuals, while marital status, and smoking data were available for over 90%. However, financial needs, interpersonal violence, social activity, and physical activity were present in EHRs for 7.6%-24.6% of the population depending on race/ethnicity. Minority groups experienced lower data completeness and higher burden of non-canonical values compared to White individuals.

Interpretation

Neighborhood-level and some individual-level SDoH have potential for use in AI development and evaluation. Other SDoH data cannot be used without additional analysis to address high amounts of missing data. Significant disparities in completeness exist across racial/ethnic groups. Addressing these data gaps may require government and payer mandates, standardized SDoH screening tools, and personnel training.

Highlights

This study examined social determinants of health (SDoH) data for adults with type 2 diabetes in a cross-institutional electronic health record (EHR) database to support equitable AI model development.

Neighborhood-level SDoH data and some individual-level SDoH data (individual-level SDoH (i.e., race/ethnicity, preferred language, marital status) were highly complete.

Disparities in SDoH data completeness by race/ethnicity underscore the need for standardized SDoH documentation.
Association of RDoC dimensions with post-mortem brain transcriptional profiles in Alzheimer’s Disease
Authors: Jiang Weiqian , Vogelgsang Jonathan , Dan Shu , Durning Peter , McCoy Thomas H. , Berretta Sabina , Klengel Torsten
Published: October 2024

INTRODUCTION

Neuropsychiatric symptoms are common in people with Alzheimer’s disease (AD) across all severity stages. Their heterogeneous presentation and variable temporal association with cognitive decline suggest shared and distinct biological mechanisms. We hypothesized that specific patterns of gene expression associate with distinct NIMH Research Domain Criteria (RDoC) domains in AD.

METHODS

Post-mortem bulk RNAseq on the insula and anterior cingulate cortex from 60 brain donors representing the spectrum of canonical AD neuropathology combined with natural language processing approaches based on the RDoC Clinical Domains.

RESULTS

Distinct sets of >100 genes (pFDR<0.05) were specifically associated with at least one clinical domain (Cognitive, Social, Negative, Positive, Arousal). In addition, dysregulation of immune response pathways was shared across domains and brain regions.

DISCUSSION

Our findings provide evidence for distinct transcriptional profiles associated with RDoC domains suggesting that each dimension is characterized by specific sets of genes providing insight into the underlying mechanisms.
Predictors and outcomes of pulmonary hypertension after mitral valve replacement in severe mitral regurgitation
Authors: Rocío García-Orta , Mercedes González Molina , Inés Uribe Morales , Lucía Torres Quintero , Diego J. Rodríguez Torres , Diego Segura Rodríguez , Eduardo Moreno Escobar
Published: October 2024

Background

The objective of the study was to determine perioperative clinical and echocardiographic factors associated with pulmonary hypertension (PH) during long-term follow-up of patients with severe primary mitral regurgitation (MR) after mitral valve replacement surgery and its prognostic repercussions.

Methods

Prospective cohort of consecutive patients undergoing mitral valve replacement between January 2005 and January 2015 and followed for ≥3 years. Main exclusion criteria were receipt of mitral repair surgery and the presence of mitral stenosis. The main outcome was a systolic pulmonary pressure (SPAP) by echocardiography >50 mmHg at least 12 months’ post-surgery.

Results

106 patients, 46% male, mean age of 61.7±11 yrs. and median follow-up of 8.8 [6- 16] yrs. SPAP was >50 mmHg in 33% of patients. Predictors identified by multivariate analysis were diabetes (OR 8.3, 95%CI 1.1-73.9), persistent atrial fibrillation (OR 4.2, 95%CI 1.1-20.6), non-rheumatic MR (OR 7.3, 95%CI 1.1-45.5), prosthesis gradient, (OR 2.8, 95%CI 1.3-5.7), patient-prosthesis mismatch (OR 16.9, 95%CI 1.2-234), and preoperative SPAP ≥50 mmHg (OR 19.3, 95%CI 3.4-107). Patients with PH had higher hospitalization (78.8 % vs. 37%, p<0.001) and mortality (72,4% vs. 19,7%, p<0.001) rates. The 10-year survival rate was 83% in patients without PHversus30% in those with PH (p<0.001).

Conclusions

Persistent PH is a frequent and serious long-term complication of valve replacement for severe mitral regurgitation. It is associated with a poor prognosis and is related to preoperative pulmonary pressure. Surgery could be considered in candidates for mitral valve replacement with moderate PH, especially in the presence of atrial fibrillation.

Clinical perspective

What is already known on this topic

Pulmonary hypertension is not reversed in an important subset of patients with severe mitral regurgitation after mitral valve replacement surgery and it is associated with a poor prognosis.

No prospective study has been published on preoperative factors associated with this condition. The prevalence and prognosis of postoperative PH has not been precisely described.

What this study adds

Persistent PH after valve replacement for severe mitral regurgitation is common and its prognosis is ominous.

Preoperative SPAP ≥50 mmHg and persistent atrial fibrillation are the main predictive factors. The results of this study might affect clinical practice suggesting considering surgery in this population (not only in mitral valve repair) when SPAP ≥50 mmHg, especially if persistent atrial fibrillation.

Graphical abstract
Giant virus creates subcellular environment to overcome codon– tRNA mismatch
Authors: Zhang Ruixuan , Mayer Lotte , Hikida Hiroyuki , Shichino Yuichi , Mito Mari , Willemsen Anouk , Iwasaki Shintaro , Ogata Hiroyuki
Published: October 2024

Codon usage consonant with the cellular tRNA pool is important for efficient translation. However, many eukaryotic viruses, including amoeba-infecting mimiviruses, have codon usage that is largely deviated from that of their host, despite using the host machinery for translation. This raises the question of how these viruses cope with the mismatch between tRNA supply and demand. Here we show that Acanthamoeba castellanii mimivirus generates a subcellular area in the host cells to translate virus mRNAs. A combination of genome-wide ribosome profiling and RNA sequencing showed that ribosomes traversed along viral mRNAs with fewer pausing events than were observed on amoeba mRNAs. Frequently used codons in viral mRNAs had higher tRNA accessibility than the same type of codons in amoeba mRNAs. tRNA sequencing showed that the tRNA pool was not greatly altered during the infection even though the virus encodes tRNA genes. Instead, byin situlabelling, we found that viral mRNAs and newly synthesized proteins were localized at the periphery region of the viral factory, likely creating a unique environment to facilitate viral translation. Our data provide a perspective on how local translation assists the virus in overcoming the mismatch between tRNA supply and demand.
Modular cloning of multigene vectors for the baculovirus system and yeast
Authors: Lai Zhihao , Flanigan Sarena F. , Boudes Marion , Davidovich Chen
Published: October 2024

Recombinant macromolecular complexes are often produced by the baculovirus system, using multigene expression vectors. Yet, the construction of baculovirus-compatible multigene expression vectors is complicated and time-consuming. Furthermore, while the baculovirus and yeast are popular protein expression systems, no single method for multigene vector construction is compatible with both. Here we present the modular cloning (MoClo) Baculo toolkit for constructing multigene expression vectors for the baculovirus system and, through compatibility with the MoClo Yeast toolkit, also for yeast. Vector construction by MoClo Baculo utilises Golden Gate assembly, which does not require PCR, primers or the sequencing of intermediate products. As a proof of principle, MoClo Baculo was used to construct baculovirus and yeast multigene vectors expressing the four- and five-subunit human Polycomb Repressive Complex 2. We show that MoClo Baculo simplifies and expedites the construction of multigene expression vectors for the baculovirus system and provides compatibility with yeast as an alternative expression system.
The structural scaffold of the TPLATE complex deforms the membrane during plant endocytosis
Authors: Kraus Julia Michaela , Neubergerova Michaela , Furones Cuadrado Alvaro , Schilling Neeltje , Eeckhout Dominique , De Winne Nancy , Van De Slijke Eveline , Vandorpe Michael , Yperman Klaas , Mylle Evelien , Fislage Marcus , De Jaeger Geert , Pleskot Roman , Van Damme Daniel
Published: October 2024

Eukaryotic cells maintain homeostasis of their outer membrane by controlled internalization of lipid and protein constituents via endocytosis. Endocytosis is evolutionary conserved and utilizes similar structural folds. How these structural folds are combined into proteins and protein complexes however differs between eukaryotic kingdoms. The TPLATE complex in plants is an evolutionary ancient protein module that combines several endocytic folds into a single octameric protein complex. Its molecular architecture, lipid-nucleated condensate formation, and its requirement for clathrin cage curvature revealed its function in endocytosis initiation in plants. Mechanistic understanding of how this complex drives membrane deformation during plant endocytosis is, however, lacking. Here, we used an integrative structural approach to obtain a precise molecular structure of the TPLATE complex. In addition, our approach allowed visualizing the structural flexibility that hallmarks this enigmatic complex. We prove that the intrinsic structural flexibility is required for its functionality and membrane recruitment. The membrane binding interface consists of several domains with differential lipid preferences. Finally, we show that the crescent shape of the structured part of the complex is sufficient for membrane curvature generation. Our mechanistic insight answers the long-standing question of how plants execute endocytosis without cytoskeletal-based force generation.
Cardiomyopathic mutations of lamin A perturb mutual interactions of lamin, nuclear membrane, and chromatin leading to LLPS
Authors: Nath Subhradip , Dutta Shuvadip , Sarkar Shreyasi Dey , Sengupta Duhita , Mitra Mithun K. , Sengupta Kaushik
Published: October 2024

Lamins are nuclear intermediate filaments constituting the nuclear lamina which maintains the structural integrity of the nucleus and play a key role in the spatial organisation of the genome. Mutations in the lamin protein have been associated with diverse diseases collectively known as laminopathies. In this study, we focused on two lamin A mutants - E161K and K97E - associated with dilated cardiomyopathy (DCM). Through confocal imaging, we established that these mutations cause large scale disruption of the peripheral lamin and consequent heterochromatin organisation, along with the formation of lamin aggregates inside the nucleoplasm. Using coarse-grained polymer simulations, we uncovered the role of lamin-lamin, lamin-membrane and lamin-chromatin interactions in maintaining wild-type lamin and chromatin organisation and showed that disruptions in these interactions can reproduce the experimental observations in the lamin mutants. These predictions were verified using 3D-FISH experiments to quantify the reorganisation of chromosome territories in these mutants. Using advanced imaging methods, we characterised the dynamical properties of the lamin aggregates in the mutants to show for the first time a liquid-like state of the lamin aggregates through a liquid-liquid phase separation. The altered lamin and chromatin interactions in the mutants thus manifest as liquid-like aggregates in the nucleoplasm leading to disruption of the spatial organisation of the genome in these laminopathy-associated mutants.
Mutators can increase both the rate of occurrence and specificity of nitrofurantoin resistance mutations
Authors: Kettlewell Riannah , Forsyth Jessica H. , Gifford Danna R.
Published: October 2024

Antimicrobial resistance is a significant global health crisis, with many antibiotics losing effectiveness within a decade of their introduction. The antibiotic nitrofurantoin, however, counters this trend, as it has sustained low resistance rates despite prolonged and widespread use. A key factor behind nitrofurantoin’s success is that resistance requires two independent inactivating mutations in separate genes,nfsAandnfsB. However, this inherent safeguard may be undermined by elevated mutation rates, a risk that remains unquantified for this antibiotic. Here, we investigated how mutation rates influence nitrofurantoin resistance inEscherichia coliusing experimental evolution with both low-level and high-level mutator strains, alongside genomic analyses of uropathogenic nitrofurantoin-resistant clinical isolates. Under experimental conditions, increasing mutation rates increased the development of nitrofurantoin resistnace. Moreover, changes in the mutations that occurred also shifted the spectrum of resistance mutations from broad-impact frameshifts and indels to specific amino acid substitutions in the proteins’ active sites. Of the nitrofurantoin-resistant clinical isolates we analysed, nearly 40% harboured disruptive variants in DNA replication fidelity and repair genes—a prevalence at the higher end of what is typically observed in uropathogenicE. coli. These findings indicate that elevated mutation rates pose a risk to the continued efficacy of nitrofurantoin, highlighting the need for increased monitoring of mutator-driven resistance.
Distinct Virulence Mechanisms ofBurkholderia gladioliin Onion Foliar and Bulb Scale Tissues
Authors: Paudel Sujan , Franco Yaritza , Zhao Mei , Dutta Bhabesh , Kvitko Brian H.
Published: October 2024

Slippery skin of onion caused byBurkholderia gladiolipv.alliicola(Bga) is a common bacterial disease reported from onion growing regions around the world. Despite the increasing attention in recent years, our understanding of the virulence mechanisms of this pathogen remains limited. In this study, we characterized the predicted genetic determinants of virulence in Bga strain 20GA0385 using reverse genetics approach. Using the closely related rice pathogen,B. glumaeas a reference, comparative genomics analysis was performed to identify Bga candidate virulence factors and regulators. Marked and unmarked deletion mutants were generated using allelic exchange and the mutants were functionally validated usingin vitroandin vivoassays. The role of mutants in pathogenic phenotypes was analyzed using onion foliar/seedling necrosis assays, the Red Scale Necrosis (RSN) assay andin plantabacterial population counts. The phytotoxin toxoflavin was a major contributor to foliar necrosis and bacterial populations whereas the type II and type III secretion system (T2SS/T3SS) were dispensable for foliar symptoms. In onion scale tissue, the T2SS single mutantgspCand its double and triple mutant derivatives all contributed to scale lesion area. Neither the lipocyclopeptide icosalide, toxoflavin, nor T3SS were required for scale symptoms. Our results suggest the quorum sensingtofIMRsystem in Bga regulates, toxoflavin, T2SS, and T3SS, contributing to onion symptom production. We show different virulence factors contribute to onion tissue-specific virulence patterns in Bga and that decreases in scale symptoms often do not result in decreased Bga populations in onion tissue.