bluuebunny/crossref_metadata_2025 huggingface dataset:
Free energy profiles of temozolomide crossing brain plasma membranes
Authors: Ge Yanhong , Lu Huixia , Marti Jordi
Published: July 2024

Temozolomide is an efficient small-molecule drug mostly employed for the treatment of glioblastoma, a tumor attacking both the spinal cord and the brain. Understanding the interactions of temozolomide with different lipids at the brain cell membrane can help elucidate how temozolomide permeates through cell membranes and its membrane-crossing ability. In the present work, we have constructed a simplified brain plasma membrane model to explore temozolomide’s microscopic structure and dynamics by means of all-atom microsecond scale molecular dynamics simulations. The preferential location of temozolomide is at the solvent-aqueous fluid surrounding the brain membrane, but it can access the interface with the membrane regularly, eventually binding to lipids of the choline and cerebroside classes. The free energy barriers of temozolomide related to brain-like plasma membrane crossing were investigated by adaptive biasing force methods, revealing values ranging from 18.5 to 66.5 kcal/mol at temperatures of 323 K and 310 K, respectively. Our results suggest that temozolomide cannot cross the membrane by pure diffusion at the normal human body temperature but that rising the temperature significantly increases the probability of barrier crossing. This fact is mainly due to the crucial role played by cholesterol and lipids of the cerebroside class. The findings reported in this work can be used to optimize the molecular design of temozolomide and to develop new analogs with better pharmacokinetic properties.

Author summary

Glioblastoma is a devastating tumor affecting the brain and spinal cord, which has in the FDA-approved drug temozolomide its main clinical treatment. The present study explores how temozolomide interacts with several lipids in brain-like cell membranes. Our findings show that at normal body temperature temozolomide cannot cross the membrane by pure diffusion, but that higher temperatures significantly enhance its ability to cross the membrane by reducing the free energy barriers. Temozolomide interacts differently with several lipids and sterols depending on the temperature, which affects its permeability. This implies that temozolomide will cross the outer layer of the brain membrane only with the help of driving agents, such as intermembrane proteins. Our research suggests that temozolomide may be more effective at higher temperatures and cancer patients with fever might need a lower dose. Importantly, cholesterol plays a key role in blocking temozolomide from crossing brain-like membranes, so reducing dietary intake of cholesterol and cerebroside lipids could help modify brain cell membranes, making it easier for temozolomide to target cancer cells effectively and potentially reducing side effects.
Climate-driven vegetation characteristics shape phytophagous and carnivorous insect diversity in South African savannahs
Authors: Gaona Fernando P. , Delabye Sylvain , Potocky Pavel , Govorov Valerii , Cuda Jan , Foxcroft Llewellyn C. , Garlacz Rafal , Hejda Martin , MacFadyen Sandra , Pyrcz Tomasz , Pyskova Klara , Sedlacek Ondrej , Storch David , Pysek Petr , Tropek Robert
Published: July 2024

Despite the recognized importance of insects in savannah ecosystems, the drivers of their diversity patterns remain poorly understood, particularly in the Afrotropical region. This study addresses this gap by investigating the impacts of climate, habitat, disturbance, and vegetation variables on the diversity of phytophagous moths (Lepidoptera) and carnivorous mantises (Mantodea) across 60 plots in Kruger National Park, South Africa. Based on an extensive dataset of 65,593 moth individuals representing 817 morphospecies and 3,511 mantis individuals representing 38 morphospecies, our results revealed plant communities as the fundamental driver of diversity for both insect groups. The effects of vegetation on insect diversity were indirectly influenced by climate, particularly mean temperature (negatively correlated with precipitation), through its impact on plant species richness. Additionally, a complex interplay among bedrock type, water availability, and disturbances from large herbivores and fire further shaped insect diversity. Our findings highlight the region's vulnerability to climate change, as decreasing precipitation and increasing temperatures were shown to alter vegetation composition and biomass, consequently affecting insect communities. Overall, our results emphasize the necessity of managing large herbivores and regulating fire regimes to maintain diverse vegetation, which is crucial for supporting insect diversity. Effective conservation strategies should prioritize balancing water availability and disturbance intensity, particularly in maintaining the health of seasonal rivers, to mitigate the adverse effects of climate change on these ecosystems.
Endomucin knockout leads to delayed retinal vascular development and reduced ocular pathological neovascularization
Authors: Hu Zhengping , Cano Issahy , Lennikov Anton , Wild Melissa , Gupta Urvi , Ng Yin Shan Eric , D’Amore Patricia A.
Published: July 2024

Endomucin (EMCN), an endothelial-specific glycocalyx component highly expressed in capillary and venous endothelium, plays a critical role in regulating VEGF receptor 2 (VEGFR2) endocytosis and downstream VEGF signaling. Using the first global EMCN knockout mouse model, we investigated the effects of EMCN deficiency on retinal vascularization during development and pathological angiogenesis. We found relatively high expression of EMCN in choroidal capillaries and retinal vasculature. Emcn-/-mice exhibited delayed retinal vascularization at postnatal day 5, with fewer tip cells and reduced vessel density. Ultrastructural examination revealed disrupted and reduced fenestrations in choroidal capillary endothelium. In an oxygen-induced retinopathy model, while Emcn-/-mice showed no significant difference in avascular area compared to Emcn+/+mice at postnatal day 12, there was a significant reduction in neovascular tufts in Emcn-/-mice at postnatal day 17. Similarly, in a laser-induced choroidal neovascularization model, Emcn-/-mice showed a significant reduction in vascular leakage and lesion size. These findings suggest that EMCN plays a critical role in both vascular development and pathological neovascularization, highlighting its potential as a target for anti-angiogenic therapies.
Social odors drive hippocampal CA2 place cell responses to social stimuli
Authors: Robson Emma , Donahue Margaret M. , Mably Alexandra J. , Demetrovich Peyton G. , Hewitt Lauren T. , Colgin Laura Lee
Published: July 2024

Hippocampal region CA2 is essential for social memory processing. Interaction with social stimuli induces changes in CA2 place cell firing during active exploration and sharp wave-ripples during rest following a social interaction. However, it is unknown whether these changes in firing patterns are caused by integration of multimodal social stimuli or by a specific sensory modality associated with a social interaction. Rodents rely heavily on chemosensory cues in the form of olfactory signals for social recognition processes. To determine the extent to which social olfactory signals contribute to CA2 place cell responses to social stimuli, we recorded CA2 place cells in rats freely exploring environments containing stimuli that included or lacked olfactory content. We found that CA2 place cell firing patterns significantly changed only when social odors were prominent. Also, place cells that increased their firing in the presence of social odors alone preferentially increased their firing during subsequent sharp wave-ripples. Our results suggest that social olfactory cues are essential for changing CA2 place cell firing patterns during and after social interactions. These results support prior work suggesting CA2 performs social functions and shed light on processes underlying CA2 responses to social stimuli.
Deletion of the endothelial glycocalyx component endomucin leads to impaired glomerular structure and function
Authors: Hu Zhengping , Cano Issahy , Lei Fengyang , Liu Jie , Ramos Ramon Bossardi , Gordon Harper , Paschalis Eleftherios I. , Saint-Geniez Magali , Ng Yin Shan Eric , D’Amore Patricia A.
Published: July 2024

Background

Endomucin (EMCN), an endothelial-specific glycocalyx component, was found to be highly expressed by the endothelium of the renal glomerulus. We reported an anti-inflammatory role of EMCN and its involvement in the regulation of vascular endothelial growth factor (VEGF) activity through modulating VEGF receptor 2 (VEGFR2) endocytosis. The goal of this study is to investigate the phenotypic and functional effects of EMCN deficiency using the first global EMCN knockout mouse model.

Methods

Global EMCN knockout mice were generated by crossing EMCN-floxed mice with ROSA26-Cre mice. Flow cytometry was employed to analyze infiltrating myeloid cells in the kidneys. The ultrastructure of the glomerular filtration barrier was examined by transmission electron microscopy, while urinary albumin, creatinine, and total protein levels were analyzed from freshly collected urine samples. Expression and localization of EMCN, EGFP, CD45, CD31, CD34, podocin, albumin, and α-smooth muscle actin were examined by immunohistochemistry. Mice were weighed regularly, and their systemic blood pressure was measured using a non-invasive tail-cuff system. Glomerular endothelial cells and podocytes were isolated by fluorescence-activated cell sorting for RNA-seq. Transcriptional profiles were analyzed to identify differentially expressed genes in both endothelium and podocytes, followed by gene ontology analysis of up- and down-regulated genes. Protein levels of EMCN, albumin, and podocin were quantified by Western blot.

Results

EMCN-/-mice were viable with no gross anatomical defects in kidneys. The EMCN-/-mice exhibited increased infiltration of CD45+cells, with an increased proportion of Ly6GhighLy6Chighmyeloid cells and higher VCAM-1 expression. EMCN-/-mice displayed albuminuria with increased albumin in the Bowman’s space compared to the EMCN+/+littermates. Glomeruli in EMCN-/-mice revealed fused and effaced podocyte foot processes and disorganized endothelial fenestrations. We found no significant difference in blood pressure between EMCN knockout mice and their wild-type littermates. RNA-seq of glomerular endothelial cells revealed downregulation of cell-cell adhesion and MAPK/ERK pathways, along with glycocalyx and extracellular matrix remodeling. In podocytes, we observed reduced VEGF signaling and alterations in cytoskeletal organization. Notably, there was a significant decrease in both mRNA and protein levels of podocin, a key component of the slit diaphragm.

Conclusion

Our study demonstrates a critical role of the endothelial marker EMCN in supporting normal glomerular filtration barrier structure and function by maintaining glomerular endothelial tight junction and homeostasis and podocyte function through endothelial-podocyte crosstalk.
Probability of Lateral Instability While Walking on Winding Paths
Authors: Render Anna C. , Cusumano Joseph P. , Dingwell Jonathan B.
Published: July 2024

People with balance impairments often struggle performing turns or lateral maneuvers, which can increase risk of falls and injuries. Here we asked how people’s mediolateral balance is impacted when walking on non-straight winding paths. Twenty-four healthy adults (12F/12M; 25.8±3.5 yrs) participated. Each walked on each of six paths projected onto a treadmill, comprised of three pseudo-random path oscillation frequency combinations (straight, slowly-winding, quickly-winding), each presented at either wide or narrow width. We quantified stepping errors as the percent of steps taken off each path. We quantified minimum mediolateral Margin of Stability (MoSL) at each step and calculated means (μ) and standard deviations (σ) for each trial. We calculated lateral Probability of Instability (PoIL) as participants’ statistical risk of taking unstable (MoSL< 0) steps. Onnarrowerpaths, participants made more stepping errors and walked with smallerμ(MoSL) on all paths (p < 0.001), and exhibited increasedPoILon the straight and slowly-winding paths (p < 0.001). Onwindingpaths, participants made progressively more stepping errors and walked with smallerμ(MoSL) for increasingly sinuous narrow paths (all p < 0.001) and wide quickly-winding paths (all p < 0.001). They also consistently walked with largerσ(MoSL), and increasedPoILon higher sinuosity paths of both widths (all p < 0.001). Though many took numerous unstable steps, no participantfell. Our results demonstrate healthy adults’ ability both to trade off increased risk of lateral instability for greater maneuverability, and to employ highly-versatile stepping strategies to maintain balance while walking.
Pathogenic LRRK2 causes age-dependent and region-specific deficits in ciliation, innervation and viability of cholinergic neurons
Authors: Brahmia Besma , Naaldijk Yahaira , Sarkar Pallabi , Parisiadou Loukia , Hilfiker Sabine
Published: July 2024

Pathogenic activating point mutations in the LRRK2 kinase cause autosomal-dominant familial Parkinsońs disease (PD). In cultured cells, mutant LRRK2 causes a deficit inde novocilia formation and also impairs ciliary stability. In brain, previous studies have shown that in PD patients due to the G2019S-LRRK2 mutation as well as in middle-aged G2019S-LRRK2 knockin mice, striatal cholinergic interneurons show a deficit in primary cilia. Here, we show that cilia loss in G2019S-LRRK2 knockin mice is not limited to cholinergic striatal interneurons but common to cholinergic neurons across distinct brain nuclei. The lack of cilia in cholinergic forebrain neurons is accompanied by the accumulation of LRRK2-phosphorylated Rab12 GTPase and correlates with the presence of dystrophic cholinergic axons. Those deficits are already evident in young adult mutant LRRK2 mice. In contrast, the age-dependent loss of cilia in brainstem cholinergic neurons correlates with an age-dependent loss of cholinergic innervation derived from this brain area. Strikingly, we find cholinergic cell loss in mutant LRRK2 mice that is age-dependent, cell type-specific and disease-relevant. The age-dependent loss of a subset of cholinergic neurons mimics that observed in sporadic PD patients, highlighting the possibility that these particular neurons may require functional cilia for long-term cell survival.
Visual cues for moisture perception of facial skin: Enhancing high-frequency components of skin lightness increases perceived dryness
Authors: Hasegawa Yuya , Tamura Hideki , Kanematsu Tama , Yamada Yuzuka , Ishiguro Yohei , Nakauchi Shigeki , Minami Tetsuto
Published: July 2024

Facial skin texture provides crucial visual cues that reflect an individual’s impressions and health conditions. In this study, we focused on the texture attribute of “moisture” and investigated which visual cues influenced skin moisture perception. The stimuli consisted of images from three facial areas (the whole face, cheek, and eyebrow areas) with and without makeup under two lighting directions. The participants rated the presented stimuli on the three texture attributes (moisture, glossiness, and attractiveness) using a five-point scale. The results from Experiment 1 revealed correlations between the ratings and histogram statistics of each channel in the CIELAB color space, with variations depending on the conditions and facial regions. A negative correlation was observed between the cheek moisture perception and the variance in theL*channel. We subsequently obtained similar ratings by enhancing the high-frequency components of skin lightness for artificially dried stimuli (Experiment 2) and for images depicting different skin conditions due to various types of makeup (Experiment 3). Both experiments confirmed a decrease in moisture and attractiveness and an increase in glossiness; these were correlated with the degree of artificial drying. These findings indicated that the high-frequency components of skin lightness could be visual cues for determining the perceived dryness.
Alternative splicing in mechanically stretched podocytes as a model of glomerular hypertension
Authors: Mattias Francescapaola , Tsoy Olga , Hammer Elke , Gress Alexander , Simm Stefan , Lio Chit Tong , Ameling Sabine , Amann Kerstin , Dreher Leonie , Wenzel Ulrich , Kacprowski Tim , List Markus , Kalinina Olga , Endlich Karlhans , Baumbach Jan , Völker Uwe , Endlich Nicole , Kliewe Felix
Published: July 2024

Background

Alterations in pre-mRNA splicing play an important role in disease pathophysiology. However, the role of alternative splicing (AS) for podocytes in hypertensive nephropathy (HN) has not been investigated. The purpose of the Sys_CARE project was to identify AS events that play a role in the development and progression of HN.

Methods

Murine podocytes were exposed to mechanical stretch, after which proteins and mRNA were analyzed by proteomics, RNA-Seq and several bioinformatic AS tools.

Results

Based on transcriptomics and proteomics analysis we could observe significant changes in gene expression and abundance of proteins under mechanical stretch compared to unstretched conditions. By RNA-Seq, we identified over 3,000 alternative spliced genes after mechanical stretch, including all types of AS events. We found 17 genes that showed an AS event in four different splicing analysis tools. From these, we focused onMyl6, a component of the myosin protein complex, andShroom3, an actin-binding protein crucial for podocyte function. We found twoShroom3isoforms that showed significant changes in expression upon mechanical stretch, which was verified by qRT-PCR andin situhybridization. Furthermore, we observed an expression switch of twoMyl6isoforms after mechanical stretch. This switch is accompanied by a change in a C-terminally located amino acid sequence.

Conclusions

In summary, mechanical stretch of cultured podocytes is an excellent model to simulate hypertensive nephropathy. In depth RNA-Seq analysis disclosed alternative splicing events, such as inShroom3andMyl6, which may play a crucial role in the pathophysiology of hypertension-induced nephropathy.
Sensing endogenous RNA in living human cells using a CRISPR-activated protease
Authors: Blumenstock Katja , Hoch Alexander , Hinterlang Leo D. , Fandrey Caroline I. , Schneberger Niels , Hagelueken Gregor , Schmid-Burgk Jonathan L.
Published: July 2024

Most techniques used to detect specific mRNAs in eukaryotic cells require to extract nucleic acids and thereby kill the cells. A programmable sensor for monitoring endogenous transcripts in living cells, in contrast, would enable to enrich living cells based on a specific transcription or splicing event, and studying these cells by live microscopy or sequencing methods requiring intact cells. We have engineered CRISPR-READ, a live cell RNA detector based on the CRISPR-associated Lon protease CalpL and a cA4-producing Type III CRISPR system. Upon RNA-programmable RNA sensing, CRISPR-READ produces an orthogonal second messenger, which leads to the cleavage of a dual FRET / localization reporter compatible with FACS sorting and live microscopy. Using this genetically encoded sensing circuit as a readout for a genome-wide CRISPR perturbation screen, we identified an extended Type-I interferon signaling cascade; RNA-Seq on sensor-sorted cells enabled unbiased identification of correlated stochasticity in gene expression across single cells.
Endomucin regulates the endothelial cytoskeleton independent of VEGF
Authors: Moon Jean , Chaudhary Suman , Martinez Lorena Rodriguez , Hu Zhengping , D’Amore Patricia A.
Published: July 2024

The endothelial glycocalyx, lining the apical surface of the endothelium, is involved in a host of vascular processes. The layer contains a network of membrane-bound proteoglycans and glycoproteins. One such glycoprotein is endomucin (EMCN), which our lab has revealed is a modulator of VEGFR2 function. Intravitreal injection of siEMCN into the eyes of P5 mice impairs vascular development. In vitro silencing of EMCN suppresses VEGF-induced proliferation and migration. Signaling pathways that drive cell migration converge on cytoskeletal remodeling. By coupling co-immunoprecipitation with liquid chromatography/mass spectrometry, we identified interactions between EMCN, and proteins associated with actin cytoskeleton organization. The aim of the study was to investigate the influence of EMCN on cytoskeleton dynamics in angiogenesis. EMCN depletion resulted in reduction of F-actin levels, whereas overexpression of EMCN induced membrane protrusions in cells that were rich in stress fibers. The reorganization of the actin filaments did not depend on VEGFR2 signaling, suggesting that EMCN is a potential connection between the cytoskeleton and the glycocalyx.
Temporal dynamics analysis reveals that concurrent working memory load eliminates the Stroop effect through disrupting stimulus-response mapping
Authors: Li Yafen , Lin Yixuan , Li Qing , Chen Yongqiang , Li Zhifang , Chen Antao
Published: July 2024

Concurrent verbal working memory task can eliminate the color-word Stroop effect. Previous research, based on specific and limited resources, suggested that the disappearance of the conflict effect was due to the memory information preempting the resources for distractors. However, it remains unclear which particular stage of Stroop conflict processing is influenced by working memory loads. In this study, electroencephalography (EEG) recordings with event-related potential (ERP) analyses, time-frequency analyses, multivariate pattern analyses (MVPA), and representational similarity analyses (RSA) were applied to provide an in-depth investigation of the aforementioned issue. Subjects were required to complete the single task (the classical manual color-word Stroop task) and the dual task (the Sternberg working memory task combined with the Stroop task), respectively. Behaviorally, the results indicated that the Stroop effect was eliminated in the dual-task condition. The EEG results showed that the concurrent working memory task did not modulate the P1, N450, and alpha bands. However, it modulated the sustained potential (SP), late theta (740-820 ms), and beta (920-1040 ms) power, showing no difference between congruent and incongruent trials in the dual-task condition but significant difference in the single-task condition. Importantly, the RSA results revealed that the neural activation pattern of the late theta was similar to the response interaction pattern. Together, these findings implied that concurrent working memory task eliminated the Stroop effect through disrupting stimulus-response mapping.
Microbial metabolomics’ latest SICRIT: Soft ionization by Chemical Reaction in-Transfer mass spectrometry
Authors: McAtamney Allyson , Ferranti Allison , Ludvik Denise A. , Yildiz Fitnat H. , Mandel Mark J. , Hayward Taylor , Sanchez Laura M.
Published: July 2024

Microbial metabolomics studies are a common approach to identifying microbial strains that have a capacity to produce new chemistries bothin vitroandin situ. A limitation to applying microbial metabolomics to the discovery of new chemical entities is the rediscovery of known compounds, or “known unknowns.” One contributing factor to this rediscovery is the majority of laboratories use one ionization source–electrospray ionization (ESI)–to conduct metabolomics studies. Although ESI is an efficient, widely adopted ionization method, its widespread use may contribute to the re-identification of known metabolites. Here, we present the use of a dielectric barrier discharge ionization (DBDI) for microbial metabolomics applications through the use of soft ionization chemical reaction in-transfer (SICRIT). Additionally, we compared SICRIT to ESI using two differentVibriospecies–Vibrio fischeri,a symbiotic marine bacterium, andVibrio cholerae, a pathogenic bacterium. Overall, we found that the SICRIT source ionizes a different set of metabolites than ESI, and it has the ability to ionize lipids more efficiently than ESI in positive mode. This work highlights the value of using more than one ionization source for the detection of metabolites.
STK19 is a transcription-coupled repair factor that participates in UVSSA ubiquitination and TFIIH loading
Authors: Tan Yuanqing , Gao Meng , Huang Yanchao , Zhan Delin , Wu Sizhong , An Jiao , Zhang Xiping , Hu Jinchuan
Published: July 2024

Transcription-coupled repair (TCR) is the major pathway to remove transcription-blocking lesions. Although discovered for nearly 40 years, the mechanism and critical players of mammalian TCR remain unclear. STK19 is a factor affecting cell survival and recovery of RNA synthesis in response to DNA damage, however, whether it is a necessary component for TCR is unknown. Here we demonstrated that STK19 is essential for human TCR. Mechanistically, STK19 is recruited to damage sites through direct interaction with CSA. It can also interact with RNA polymerase IIin vitro. Once recruited, STK19 plays an important role in UVSSA ubiquitination which is needed for TCR. STK19 also promotes TCR independent of UVSSA ubiquitination by stimulating TFIIH recruitment through its direct interaction with TFIIH. In summary, our results suggest that STK19 is a key factor of human TCR that links CSA, UVSSA ubiquitination and TFIIH loading, shedding light on the molecular mechanisms of TCR.
Systemic Review of Health Disparities in Access and Delivery of Care for Geriatric Diseases in the United States
Authors: Thomas Mony , Hussein Muhammad R , Utterman Sonia , Jushua Jackline
Published: July 2024

Background

The U.S. population continues to age, and the identification of disparities in geriatric care -so that they may be understood and solutions addressed - is ever more critical. A systematic review is presented on current disparities found in access to care for geriatric diseases as well as in the delivery of care within the United States.

Methods

A comprehensive search for the available literature from 2010 to 2024 was carried out through the PubMed, CINAHL, and Scopus databases in peer-reviewed journals. Studies that focused on disparities in access and provision of geriatric care for adults aged 65 years and above within the U.S. health system were included in this study. The Joanna Briggs Institute critical appraisal tools were used in the quality appraisal of studies included.

Results

Of the total number of 5,218 studies that were identified initially, 132 studies were eligible for inclusion. Our analysis uncovered continued inequity in geriatric care across racial, ethnic, socioeconomic, and geographic lines. Findings include: (1) low rates of early diagnosis and delayed treatment of dementia and Alzheimer’s among minority seniors, who were found to be 2.3 times more likely for African Americans and 1.9 times more likely for Hispanics than their white counterparts; (2) inability to access high-level geriatric care in regions outside of metropolitan areas, where it was identified that older adults had to commute, on average, 3.2 times farther to the nearest provider; (3) socioeconomic factors found to present obstacles to home health and long-term care, with seniors from a lower income bracket 1.8 times more likely to be placed in a poor-quality nursing home; and (4) disparities in the quality of end-of-life care for elders of lower socioeconomic status, with African Americans and Hispanics being respectively 38% and 51% less likely to use hospice care.

Conclusion

This review has demonstrated that important and persistent disparities exist in the availability and delivery of geriatric care in the United States. Of the 132 studies, 34 directed their efforts toward reducing interventions to have such disparities with salutary results coming from culturally tailored community-based approaches. Multipronged interventions that include policy revision, workforce development, and community-based initiatives hold promise for reducing these disparities. This should be an area of focus for future targeted interventions, which should, therefore, be evaluated for effectiveness in reducing disparities in health outcomes for all older adults.
Do amyloid cerebral deposits influence the long-term post-stroke cognitive outcome? The IDEA3 study
Authors: Godefroy Olivier , Trinchard Niels , Marchal Etienne , Lamy Chantal , Canaple Sandrine , Meyer Marc-Etienne , Roussel Martine , Wollenweber Frank A ,   the IDEA3 study group
Published: July 2024

Background

Although the presence of amyloid deposits is associated with a more severe cognitive status in stroke patients at baseline, its influence on the subsequent cognitive outcome has not been extensively assessed. The primary objective of the present study of the IDEA3 cohort was to determine the influence of amyloid PET status on the 5-year cognitive outcome.

Methods

The 91 stroke patients (ischemic stroke: 89%; hemorrhagic stroke: 11%) with florbetapir PET data at baseline (positive: n=14) underwent comprehensive clinical and cognitive assessments for 5 years after the PET scan.

Results

A survival analysis (mean post-stroke follow-up: 80.4 ±27 months) showed that the incidence of dementia was higher in the PET-positive patients (OR=5.89, 95% CI: 1.24-22.7, p=0.02), as was the incidence of cognitive impairment (OR=10, 95% CI: 1.9-52.3, p=0.003). A Cox regression analysis showed that the association between amyloid status and the incidences of dementia (p=0.006) and CI (p=0.04) was still significant after adjustment for age. Considering the overall prevalence at last follow-up in the whole study population (n=91 patients), PET positivity was associated with an elevated risk of post-stroke cognitive impairment (OR=6.25, 95%CI: 1.77-22, p=0.002) or dementia (OR= 6, 95%CI: 1.76-20.5, p=0.002). The final Rankin score did not differ according to PET status (p=0.3).

Conclusions

Our results demonstrated the major impact of amyloid deposition on the stroke outcome and emphasized the need for comprehensive etiologic work-up in patients with post-stroke cognitive impairment.

Clinical Trial Registration

NCT 02813434
Multidrug-resistant organism bloodstream infections in solid organ transplant recipients and impact on mortality: a systematic review
Authors: Liu Alice , Dennis Adelaide , Fariha Zarin , Pai Mangalore Rekha , Macesic Nenad
Published: July 2024

Background

Bloodstream infections (BSI) cause significant morbidity and mortality in solid organ transplant (SOT) recipients. There are few data regarding the contribution of multidrug-resistant organisms (MDROs) to these infections.

Objectives

We evaluated the resistance-percentage of MDRO BSIs in SOT recipients and assessed associated mortality.

Methods

A systematic review

Data sources

MEDLINE and Embase databases up to January 2024.

Study eligibility criteria

Studies of adult SOT recipients that quantify MDRO BSI resistance-percentage and/or associated crude mortality. MDROs studied were carbapenem-resistant Enterobacterales (CRE),Acinetobacter baumannii(CRAB) andPseudomonas aeruginosa(CRPA), third-generation-cephalosporin-resistant Enterobacterales (3GCR-E), methicillin-resistantStaphylococcus aureus(MRSA) and vancomycin-resistantEnterococcus faecium(VRE).

Participants

Adult SOT recipients with a microbiologically confirmed BSI.

Interventions

Not applicable.

Risk of bias assessment

Newcastle Ottawa Scale.

Methods of data synthesis

MDRO BSI resistance-percentage and mortality outcomes were reported as median (IQR) and crude mortality (%), respectively.

Results

Of 945 studies identified, 52 were included. Most were retrospective (41/52) and/or single centre (37/52), and liver transplantation was the most studied SOT type (22/52). High resistance-percentages of BSIs were noted, ranging from 13.6% CRE for Enterobacterales to 59.2% CRAB forAcinetobacter baumannii. Resistance-percentage trends decreased over time, but these changes were not statistically significant. Asia had highest resistance-percentages for MRSA (86.2% [IQR 77.3-94.6%]), 3GCR-E (59.5% [IQR 40.5-66.7%]) and CRE (35.7% [IQR 8.3-63.1%]). North America had highest VRE resistance-percentages (77.7% [IQR 54.6-94.7%]). Crude mortality was 15.4-82.4% and was consistently higher than non-MDRO BSIs.

Conclusions

MDRO BSIs resistance-percentages were high for all pathogens studied (IQR 24.6-69.4%) but there was geographical and temporal heterogeneity. MDRO BSIs were associated with high mortality in SOT recipients. Microbiological and clinical data in this vulnerable population were incomplete, highlighting the need for robust international multi-centre studies.
A conjugative plasmid exploits flagella rotation as a cue to facilitate its transfer
Authors: Bhattacharya Saurabh , Bejerano-Sagie Michal , Ravins Miriam , Zeroni Liat , Kaur Prabhjot , Gopu Venkadesaperumal , Rosenshine Ilan , Ben-Yehuda Sigal
Published: July 2024

Conjugation-mediated DNA delivery is the primary mode for antibiotic resistance spread; yet, molecular mechanisms regulating the process remain largely unexplored. While conjugative plasmids typically rely on solid surfaces to facilitate donor-to-recipient proximity, the pLS20 conjugative plasmid, prevalent among Gram-positiveBacillusspp., uniquely requires fluid environments to motivate its transfer. Here we unveiled that pLS20, carried byB. subtilis, induces adhesin-promoted multicellular clustering, which can accommodate various species, offering a stable platform for DNA delivery in liquid milieu. We further discovered that induction of pLS20 promoters, governing crucial conjugative genes, hinges on the presence of donor cell flagella, the major bacterial motility organelle. Moreover, pLS20 regulatory circuit is strategically integrated into a mechanosensing signal transduction pathway responsive to flagella rotation, harnessing propelled flagella to activate conjugation genes exclusively during the host motile phase. This flagella-conjugation coupling strategy, provides the plasmid with the benefit of disseminating into remote destinations, infiltrating new niches.
A development-specific POLX essential for programmed genome rearrangement inParamecium tetraurelia
Authors: Verron Baptiste , Arnaiz Olivier , Zangarelli Coralie , Mathy Nathalie , Bétermier Mireille , Bischerour Julien
Published: July 2024

During the sexual cycle, programmed genome rearrangement (PGR) inParamecium tetraureliainvolves the non-homologous end joining (NHEJ) DNA repair pathway to eliminate specific germinal Internal Eliminated Sequences (IESs) from the newly developing somatic nucleus. In addition to the core NHEJ factors Ku70/80 and Xrcc4/Lig4, additional enzymes are required to process the 4-base 5’-protruding ends generated following DNA cleavage at IES boundaries, prior to their ligation. Here, we report that PolX (a,b,c,d), fourP. tetraureliadistant orthologs of the human Polλ DNA polymerase, are involved in repair of IES excision junctions. During rearrangements, PolX-depleted cells accumulate genome-wide errors, such as unrepaired double-strand breaks, 1-nucleotide deletions and IES retention. Although all PolX paralogs can process DNA ends, two of them (PolXa&b) are induced during PGR and have acquired tight nuclear anchoring properties through their N-terminal region, which contains a predicted BRCT domain. Finally, we show that PolXa accumulates in nuclear foci together with other NHEJ proteins and the Dicer-like enzyme Dcl5, which is involved in the biogenesis of IES-specific small RNAs. We propose that these “DNA repair foci” correspond to the sites where IES concatemers, a by-product of IES excision, are ligated together to produce the precursors of iesRNAs.
Shape that matters: Yolk geometry spatially modulates developing vascular networks within chick chorioallantoic membrane
Authors: Padmanaban Prasanna , Wanders Dirk , Katovich Oryan Karni , Salehi-Nik Nasim , Levenberg Shulamit , Rouwkema Jeroen
Published: July 2024

Controlling the multiscale organization of vasculature within diverse geometries is essential for shaping tissue-specific and organ-specific architectures. Nevertheless, how geometrical characteristics of surrounding tissues influence vessel morphology and blood flow remains unclear. Where the regulation of vascular organization by mechanical signals associated with fluid flow is well known, this study postulates that the organization of developing vasculature can also be regulated by mechanical signals connected to the confinement and thus the deformation of surrounding tissues. To test the Shape-Induced Vascular Adaptation (SIVA) concept, fertilized chicken egg contents containing developing vasculature were cultured within engineered eggshell platforms of different shapes. Our findings demonstrate that the vascularized chick chorioallantoic membrane (CAM) adapts to the shape of engineered eggshell, long before reaching its boundaries. This adaptation affects the organization of the vascular network within the CAM, affecting parameters such as vessel area, branching, orientation, length, diameter and endpoints. Specifically, we observed that sharp corners in the engineered eggshell led to more elongated vascular structures. To further explore the dynamic nature of this phenomenon, a proof-of-concept experiment was performed using a shape-shifting engineered eggshell that deforms the egg content from circle to square shape. Using this shape-shifting prototype, we observed a direct effect of eggshell deformation on the vessel morphology and flow dynamics in a time-dependent manner. Overall, our exovo experimental platform provides a unique opportunity to study how mechanical stimuli such as shape influence the spatial and temporal organization of developing vascularized tissues. By subjecting these tissues to various static and dynamic conditions, we induced both local and global changes in their organization. This class of perturbation provides us with an additional tool which can be used for shaping vascular organization within developing tissues and to engineer tissues with geometrically tunable vessel structures.
Histone Tetrasome Dynamics Affects Chromatin Transcription
Authors: Shi X. , Fedulova A.S. , Kotova E.Y. , Maluchenko N.V. , Armeev G.A. , Chen Q. , Prasanna C. , Sivkina A.L. , Feofanov A.V. , Kirpichnikov M.P. , Nordensköld L. , Shaytan A. K. , Studitsky V.M.
Published: July 2024

During various DNA-centered processes in the cell nucleus, the minimal structural units of chromatin organization, nucleosomes, are often transiently converted to hexasomes and tetrasomes missing one or both H2A/H2B histone dimers, respectively. However, the structural and functional properties of the subnucleosomes and their impact on biological processes in the nuclei are poorly understood. Here, using biochemical approaches, molecular dynamics simulations, single-particle Förster resonance energy transfer (spFRET) microscopy and NMR spectroscopy, we have shown that, surprisingly, removal of both dimers from a nucleosome results in much higher mobility of both histones and DNA in the tetrasome. Accordingly, DNase I footprinting shows that DNA-histone interactions in tetrasomes are greatly compromised, resulting in formation of a much lower barrier to transcribing RNA polymerase II than nucleosomes. The data suggest that tetrasomes are remarkably dynamic structures and their formation can strongly affect various biological processes.
Global survey of secondary metabolism inAspergillus nigervia activation of specific transcription factors
Authors: Semper Cameron , Pham Thi Thanh My , Ram Shane , Palys Sylvester , Evdokias Gregory , Ouedraogo Jean-Paul , Moisan Marie-Claude , Geoffrion Nicholas , Reid Ian , Di Falco Marcos , Bailey Zachary , Tsang Adrian , Benoit-Gelber Isabelle , Savchenko Alexei
Published: July 2024

Genomics analysis confirmed the status of the filamentous fungi as a rich source of novel secondary metabolites; however, the discovery of these compounds is hampered by the cryptic nature of their biosynthetic pathways under laboratory conditions. Consequently, despite substantial research effort over the past decades, much of the secondary metabolome remains uncharacterized in fungal organisms. Our manual curation of biosynthetic gene clusters (BGCs) in theAspergillus nigerNRRL3 genome revealed that only 13 of 86 BGCs have had their cognate secondary metabolite products confirmed or reliably inferred. We also identified 60 transcription factors associated with cryptic BGCs. To further characterizeA. nigersecondary metabolism, we created a collection of strains each overexpressing a single BGC-associated transcription factor. We analyzed the strain collection using a standardized pipeline where we monitored phenotypic changes and compound production using mass spectrometry. Strains showing evidence of secondary metabolism activation were selected for gene expression analysis. Our approach resulted in the production of multiple potentially novel secondary metabolites and linked a specific BGC to tensidol production inA. niger.More broadly, this study found evidence counter to the existing paradigm of BGC expression controlled by co-localized transcription factors, lending credence to the emerging picture of a complex regulatory network governing fungal secondary metabolism.

Significance Statement

Fungi produce an array of chemically diverse compounds that are routinely found to harbour valuable bioactivity. The products of secondary metabolism, these compounds have been a source of antimicrobials, anti-cancer agents, and other biopharmaceutical compounds termed natural products. Despite their demonstrated economic value, much is still unknown about the biosynthesis, regulation, and identities of these compounds. This study adopted a genome-wide approach to improve our understanding of the regulatory mechanisms that control fungal secondary metabolism, improving our ability to investigate the pathways responsible for natural product production.
Proposed Peking University muon experiment for muon tomography and dark matter search
Authors: Yu Xudong , Wang Zijian , Liu Cheng-en , Feng Yiqing , Li Jinning , Geng Xinyue , Zhang Yimeng , Gao Leyun , Jiang Ruobing , Wu Youpeng , Zhou Chen , Li Qite , Wang Siguang , Ban Yong , Mao Yajun , Li Qiang
Published: July 2024

A set of new methods are proposed here to directly detect light mass dark matter through its scattering with abundant atmospheric muons or accelerator beams. A first plan is to use the free cosmic-ray muons interacting with dark matter in a volume surrounded by tracking detectors, to trace the possible interaction between dark matter and muons. Secondly, the same device can be interfaced with domestic or international muon beams. Due to the much larger muon intensity and focused beam, it is anticipated that the detector can be made further compact, and the resulting sensitivity on dark matter searches will be improved. Furthermore, it may also be possible to measure precisely directional distributions of cosmic-ray muons, either at mountain or sea level, and the differences may reveal possible information about dark matter distributed near the Earth. Specifically, methods described here can have advantages over “exotic” dark matters that are either muonphilic or slowed down due to some mechanism, and the sensitivity on dark matter and muon scattering cross section can reach as low as microbarn level.

Published by the American Physical Society
2024
One-loop calculations in the chirality-flow formalism
Authors: Lifson Andrew , Sjödahl Malin , Plätzer Simon
Published: July 2024

In a few recent papers we introduced the chirality-flow formalism, which builds on the spinor-helicity formalism, but incorporates the Fierz identity into the Feynman rules. Calculations at tree level are thereby trivial, often to the extent that it is possible to immediately write down a tree-level Feynman diagram in terms of spinor inner products. This simplification persists in tree-level computer implementations, giving very sizable speedups. In the present paper, we argue that there is also a significant simplification of the Lorentz structure at the one-loop level when using the four-dimensional formulation of the four-dimensional helicity scheme. As at tree level, the gauge reference vector for external gauge bosons, and the simplified Lorentz structure lead to significant shortening of the calculations. Additionally, we find that the possible terms in a tensor decomposition of loop integrals are highly constrained, and therefore the tensor reduction procedure is simplified.

Published by the American Physical Society
2024
Existence of thermodynamically stable asymptotically flat black holes
Authors: Astefanesei Dumitru , Ballesteros Romina , Cabrera Paulina , Casanova Gonzálo , Rojas Raúl
Published: July 2024

We use the quasilocal formalism of Brown and York, supplemented with counterterms, to investigate the thermodynamics of asymptotically flat black holes. We consider two families of exact regular black hole solutions, which are thermodynamically stable. The first one consists of four-dimensional static charged hairy black holes in extended supergravity. The second family consists of five-dimensional static charged black holes in Gauss-Bonnet (GB) gravity. Despite the fact that their characteristics are completely different, we found a striking similarity between their thermodynamic behavior.

Published by the American Physical Society
2024
Axionlike quasiparticles and topological states of matter: Finite density corrections of the chiral anomaly vertex
Authors: Corianò Claudio , Cretì Mario , Lionetti Stefano , Tommasi Riccardo
Published: July 2024

We investigate the general structure of the chiral anomaly AVV/AAA and (LLL,RRR) vertices, in the presence of chemical potentials in perturbation theory. The study finds application in anomalous transport, whenever chirally unbalanced matter is present, with propagating external currents that are classically conserved. Examples are topological materials and the chiral magnetic effect in the plasma state of matter of the early universe. We classify the minimal number of form factors of the AVV parametrization, by a complete analysis of the Schouten identities in the presence of a heat bath. We show that the longitudinal (anomaly) sector in the axial-vector channel, for on-shell and off-shell photons, is protected against corrections coming from the insertion of a chemical potential in the fermion loop. When the photons are on-shell, we prove that the transverse sector, in the same channel, is also μ-independent and vanishes. The related effective action is shown to be always described by the exchange of a massless anomaly pole, as in the case of vanishing chemical potentials. The pole is interpreted as an interpolating axionlike quasiparticle generated by the anomaly. In each axial-vector channel, it is predicted to be a correlated fermion/antifermion pseudoscalar (axionlike) quasiparticle appearing in the response function, once the material is subjected to an external chiral perturbation. The cancellation of the μ dependence extends to any chiral current within the Standard Model, including examples such as B (baryon), L (lepton), and B−L. This holds true irrespective of whether these currents exhibit anomalies.

Published by the American Physical Society
2024