bluuebunny/crossref_metadata_2025 huggingface dataset:
Applying Concepts of Successful Aging in Measuring and Promoting Whole Person Health
Authors: Tsai Jack , Jones Audrey L.
Published: November 2024

Countries around the world have large aging adult populations. There is wide public health concern about the health and well-being of aging adults, and a movement to transform healthcare systems to become age-friendly. The concept of “successful aging” recognizes the importance of aging and expands the goal beyond the absence of disease to functioning and well-being. In this perspective, we discuss aging as a part of life that should be considered in whole person health and cite work with the US veteran population as an example of how successful aging and age-friendly practices can be incorporated into whole person health for adult populations. We also review studies of successful aging that may offer important ways to define and measure whole person health and discuss how it might be instructive to assess successful aging with multiple indicators across the adult life span, particularly in underserved populations at-risk of premature aging and poor health. Finally, we conclude with a discussion of the “life course perspective” that may serve as a useful model for the interplay between successful aging and whole person health.
Measuring Patient Well-Being During Whole-Person Clinical Care
Authors: Etingen Bella , Cohen-Bearak Adena , Adjognon Omonyele L. , Vogt Dawne , Hogan Timothy P. , Gaj Lauren , Orner Michelle B. , Barker Anna M. , Bokhour Barbara G.
Published: November 2024

Background:

Measuring patient well-being during clinical care may enhance patient-centered communication and treatment planning. The Veterans Health Administration (VHA) piloted the use of the Well-Being Signs (WBS), a self-report measure of psychosocial well-being, in clinical care.

Objective:

To understand early WBS implementation and health care team member experiences with its use before developing detailed support materials and finalizing the measure.

Methods:

We conducted a mixed-methods evaluation of the WBS implementation pilot at 4 VHA facilities, including surveys of (n=4) Whole Health (WH) leaders/clinical leads, and semi-structured interviews with (n=11) clinical leads and team members. Survey data were characterized using descriptive statistics; interview data were analyzed using rapid qualitative analysis.

Results:

Facilities supported WBS implementation by disseminating information to clinical team members, primarily during staff meetings (3/4 facilities), individual discussions (3/4), and email (3/4); only half provided training sessions. In interviews, some care team members expressed the need for more training on using the WBS in clinical care. Some interviewees also provided suggestions for changes to the draft measure, including response option format and question look-back period.

Conclusions:

Although there have been growing calls for attention to patient well-being in clinical care, our results suggest barriers to the implementation of well-being measures in this context. Findings were used to inform the development of enhanced training materials and make modifications to enhance the acceptability of the WBS to providers. Other identified barriers will need to be addressed in future implementation efforts, including bolstering leadership support and easing the added time and burden of administration.
Veterans’ Experiences of and Preferences for Patient-Centered, Measurement-Based PTSD Care
Authors: Weber Marcela C. , Jendro Ashlyn M. , Fischer Ellen P. , Drummond Karen L. , Haltom Trenton M. , Hundt Natalie E. , Cucciare Michael A. , Pyne Jeffrey M.
Published: November 2024

Background:

Up to 50% of veterans drop out of trauma-focused evidence-based psychotherapies (TF-EBP) without completing treatment or recovering; evidence suggests this is in part because their posttraumatic stress disorder (PTSD) care is insufficiently patient-centered. There is also evidence that measurement-based care (MBC) for mental health should be personalized to the patient, yet this is not common practice in VA PTSD care.

Objectives:

To explore veterans’ experiences and preferences for aligning measurement-based PTSD care with their own treatment goals.

Method:

Qualitative interviews were conducted with veterans (n=15) with PTSD who had received at least 2 sessions of a TF-EBP.

Measures:

Survey on the administration of outcomes questionnaires and demographics and an interview about their most recent TF-EBP episode.

Results:

Half of veterans had symptom-focused goals and half did not; all had at least one treatment goal that was not symptom-focused. They typically met their goals about functioning and coping skills but not their symptom reduction goals. We found veterans overall were receptive to MBC but preferred patient-reported outcomes measures about functioning, wellbeing, coping skills, and understanding their trauma more than the commonly used PTSD symptom scale (the PCL-5).

Conclusions:

Many veterans in this sample disliked the PCL-5 because it reinforced their maladaptive cognitions. Such veterans might be more receptive to MBC if offered patient-report outcomes measures that better align with their functional and wellbeing goals. For many goal/outcome areas, psychometrically sound measures exist and require better implementation in PTSD care. For some areas, scale development is needed.
Updated diagnostic and therapeutic management for membranous nephropathy
Authors: Caravaca-Fontán Fernando , Yandian Federico , Fervenza Fernando C.
Published: November 2024

Purpose of review

Pioneering contributions in membranous nephropathy over the last decade have greatly enhanced our comprehension of its pathogenesis, diagnosis, and treatments, igniting renewed interest in this entity. This review provides an updated perspective on the diagnosis and therapeutic management of membranous nephropathy.

Recent findings

The identification of antiphospholipase A2 receptor (PLA2R) antibodies in 50–80% of membranous nephropathy patients was a key breakthrough. High or increasing PLA2R antibody levels are linked to persistent nephrotic syndrome and the need for targeted treatment. Given the high specificity of PLA2R antibodies, a kidney biopsy may not be required for pure nephrotic syndrome cases with no comorbidities. Over the years, various target antigens and associated conditions have been identified in membranous nephropathy patients, leading to a reclassification of membranous nephropathy. Treatment approaches vary based on baseline characteristics and changes in proteinuria and PLA2R titers. Rituximab has emerged as the first-line therapy for most patients without severe risk factors, with other emerging therapies under development.

Advances in the diagnosis and treatment of membranous nephropathy have moved the management towards a more precision-based approach, though further studies and new therapies are needed for a comprehensive management strategy.
Efficacy of additional lateral pinhole and SPECT/CT imaging in dual-phase Tc-99m MIBI parathyroid scintigraphy for localising parathyroid pathologies in patients with primary hyperparathyroidism: a single-institution experience
Authors: Kesim Selin , Turoglu Halil Turgut , Kotan Tuncay , Balaban Genc Zeynep Ceren , Niftaliyeva Khanim , Toper Hasan , Gogas Yavuz Dilek , Ozguven Salih , Kaya Handan , Dede Fuat , Ugurlu Mustafa Umit , Oksuzoglu Kevser , Cagliyan Feyza , Gulluoglu Bahadir Mahmut , Ones Tunc , Erdil Tanju Yusuf
Published: November 2024

Purpose

Parathyroid imaging with dual-phase technetium-99m methoxyisobutrylizonitrile (Tc-99m MIBI) scintigraphy serves as an important prerequisite for the identification of hyperfunctioning parathyroid gland(s) in patients with primary hyperparathyroidism (PHPT) for a successful targeted parathyroidectomy. This study aimed to evaluate the clinical value of additional lateral imaging and single-photon emission computed tomography/computed tomography (SPECT/CT) versus conventional planar imaging for locating parathyroid pathologies in patients with PHPT.

Materials and methods

A retrospective review was performed on 105 patients who underwent dual-phase Tc-99m MIBI scintigraphy and were surgically treated by parathyroidectomy. Dual-phase Tc-99m-MIBI planar scintigraphy with additional lateral pinhole views and SPECT/CT imaging was performed on a routine basis, as per departmental protocol. Comparison study between imaging modalities was done by patient-based analysis and scintigraphy results were compared with the clinical findings, biochemical markers, and histopathological findings.

Results

Sensitivity and specificity for anterior planar dual-phase Tc-99m MIBI scintigraphy were 78.8 and 80%, respectively. In comparison, lateral pinhole scan and SPECT/CT alone were found to have sensitivities of 85.9 and 90.9%, respectively, with the same specificity. Sensitivity decreased in patients with normocalcaemia and multiglandular disease. The mean adenoma weight and size for true-positive studies were significantly higher than those for false-negative or false-positive studies.

Conclusion

SPECT/CT provided the highest diagnostic accuracy for preoperative identification of parathyroid lesions in PHPT patients. Lateral pinhole imaging offers comparable sensitivity and aids in adenoma localisation when SPECT/CT is unavailable.
Comparison of surgical effectiveness: kidney sparing surgery for upper tract urothelial carcinoma
Authors: Schuil Hugo W. , Figaroa Orlane J.A. , Baard Joyce , Lifshitz David A. , Jamaludin Faridi S. , Kamphuis Guido M.
Published: November 2024

Purpose of review

This review provides an overview of the recent publications on kidney-sparing-surgery (KSS) for upper tract urothelial carcinoma (UTUC), an alternative to radical nephroureterectomy (RNU) for an increasing number of indications

Recent findings

Recent studies highlight comparable survival outcomes between KSS [ureterorenoscopy with tumour ablation (URS) or segmental ureteral resection (SUR)] and RNU, even in high-risk UTUC patients. KSS has shown to preserve renal function without significantly compromising oncologic control in appropriately selected patients. Included literature also researched surgical complications, surveillance strategies, such as second-look ureteroscopy, and comparative cost analyses.

Over the past two and a half years, studies have emphasized the growing usage of URS and SUR in treating selected UTUC patients. Recent literature has remarkably included relatively large numbers of typically high-risk patients with features such as high-grade tumours, stage >Ta, multifocality, and hydronephrosis with acceptable results. Further research should expand on the different indications for KSS, its postoperative surveillance and comparative economic analyses.
Case report: Acute macular neuroretinopathy post–COVID-19 infection
Authors: Mohamad Nur Ain , Yong Meng Hsien , Mohd Khialdin Safinaz , Bastion Mae-Lynn Catherine
Published: November 2024

SIGNIFICANCE

Acute macular neuroretinopathy (AMN) is a rare disease that causes transient or permanent visual disturbance. The exact etiology remains unknown, but vascular compromise of the deep retinal capillary plexus was postulated as the main mechanism. Retinal vascular event post–coronavirus disease 2019 (COVID-19) infection is recently highlighted during the pandemic, which includes AMN.

PURPOSE

To report a case of AMN post–COVID-19 infection.

CASE REPORT

A 24-year-old Indian woman presented with acute-onset painless bilateral central scotoma for a day. The symptom was preceded by a history of COVID-19 infection 3 weeks prior. Ocular examination revealed a near-normal visual acuity for both eyes. Fundus examination showed bilateral dull foveal reflex with mild scattered cotton wool spot and vascular tortuosity. Optical coherence tomography macula revealed a distinct short hyperreflective band involving the outer plexiform and outer nuclear layers nasal to the fovea. The Bjerrum perimetry test revealed central scotoma temporal to the fixation. Optical coherence tomography lesions and scotomas are identical and congruous in both eyes. Serial fundus photographs are captured showing the evolving changes of near-normal macula to pigmented wedge-shaped petaloid lesions around the fovea. The patient was diagnosed as bilateral AMN and treated with oral prednisolone. On subsequent follow-up, the central scotoma improved.

CONCLUSIONS

This case illustrates a clear temporal and possible causal relationship of COVID-19 infection with AMN. Further studies and data are required to justify its association, but the rising cases of AMN shall be anticipated as COVID-19 infections have become endemic worldwide.
Research priorities: Establishing discipline-based education research in prosthetics and orthotics
Authors: Mullen Ashley , Spaulding Sue , Brinkmann John , Falbo Kierra , McDonald Cody , Rusaw David
Published: November 2024

Background:

Education research, as a field of study, is relatively new to the health professions. Research and scholarship in prosthetics and orthotics education is limited, and the priority areas and needs of individuals interested in pursuing this area of research and scholarship are unknown.

Objectives:

The objectives of this study were to collaboratively identify the areas in which education research in prosthetics and orthotics is needed, to prioritize these areas, and to evaluate the resources needed to support those interested in pursuing education research.

Study design:

Mixed methods.

Methods:

The researchers used a participatory action research approach. Focus group sessions were held at the 2022 International Society for Prosthetics and Orthotics (ISPO) Global Educators Meeting. Findings from the focus groups informed creation of a survey that was distributed internationally. The results of this survey were presented to attendees at the 2023 ISPO World Congress for review and ranking.

Results:

Findings from focus group discussions were used to create a 20-item survey. High priority categories included providing feedback to students, program evaluation, and clinical education and internship. Protected time and funding, faculty development, and program resources were identified as items needed to support faculty in pursuing education research. At the ISPO World Congress, participants highly rated the categories of academic v. clinical practice, program resources, and program evaluation.

Conclusions:

Many categories were identified as priorities for orthotic and prosthetic education research, and ways to support faculty pursuing this work were highlighted. This study identified opportunities for education researchers to focus their efforts on directly impacting needs of education programs and the profession.
A Multicenter Home-based Prehabilitation Intervention in Kidney Transplant Candidates
Authors: Lorenz Elizabeth C. , Bonikowske Amanda R. , David-Van Meter Ashley C. , Munson Cortney L. , Roschen Callie A. , Salstrand Rosalyn M. , Wolter Anne D. , Murthy Bhamidipati V. , Davis LaShara A. , Choi Namkee G. , Kennedy Cassie C.
Published: November 2024

Background.

Frailty is a modifiable risk factor for morbidity and mortality among kidney transplant (KT) candidates. We previously demonstrated that an 8-wk center-based exercise intervention is associated with improved frailty parameters in patients with advanced chronic kidney disease. This study aimed to adapt the intervention for home-based delivery and examine its feasibility, safety, and acceptability in a multicenter cohort of KT candidates.

Methods.

We conducted a prospective pilot study between January 2021 and November 2023 involving KT candidates from Mayo Clinic in Minnesota and Baylor St. Luke’s Medical Center in Texas. Adults approved for KT who were (1) frail or prefrail by the Physical Frailty Phenotype and/or (2) had a Short Physical Performance Battery score ≤10 were enrolled. The exercise intervention consisted of an individualized exercise prescription provided by a Mayo Clinic exercise physiologist followed by 8 weekly phone calls. Feasibility was assessed via retention rates, adverse events were recorded, and acceptability was assessed via survey.

Results.

Baseline characteristics of the 15 enrolled participants included a median age of 64 y, 73.3% were men, and 73.3% were of White race. Sixty percent of participants completed the intervention. No unanticipated adverse events occurred. Most participants strongly agreed that the exercise intervention was beneficial to their overall health.

Conclusions.

This pilot study demonstrates that a home-based 8-wk exercise intervention is a promising prehabilitation strategy in KT candidates and provides important preliminary data for future larger, randomized studies.
Bifidobacterium favimelis sp. nov., isolated from black comb honey
Authors: Li Yu , Song Qiujie , Yang Haizhu , Wei Yue , Menghe Bilege , Liu Wenjun
Published: November 2024

A strain of the bacterial genus Bifidobacterium, IMAU50987T, that was isolated from black comb honey from Lianghe County, Dehong Autonomous Prefecture, Yunnan Province, China, could not be accurately identified as a known species using 16S rRNA gene sequencing. In this study, the taxonomic status of strain IMAU50987T was evaluated using whole-genome sequencing combined with phenotypic analyses. Strain IMAU50987T was Gram-positive, non-motile and non-spore-forming. Comparative of 16S rRNA gene sequence similarity analysis indicated that strain IMAU50987T could be attributed to the genus Bifidobacterium and most closely related to the B. mellis Bin7NT (98.5% identity). Comparative sequence analysis of eight housekeeping genes (pyrG, thrS, glnA1, recA, tuf, dnaB, rpoC and xfp) showed that strain IMAU50987T was different from closely related species. Phylogenomic analysis based on the 88 single-copy genes in the phylogenetic tree showed that strain IMAU50987T belonged to the B. asteroides group. The highest average nucleotide identity value for strain IMAU50987T was 77.0% in comparison with B. choladohabitans B14384H11T and B. apis F753-1T. However, the highest digital DNA–DNA hybridization value was 23.1% compared with B. apis F753-1T and B. xylocopae XV2T; the highest average amino acid identity value was 73.2% compared with B. polysaccharolyticum W8117T. These values are below the accepted threshold for novel species boundaries. The draft genome size of strain IMAU50987T was 1.9 Mb, and the DNA G+C content was 63.5%. The major cellular fatty acids of strain IMAU50987T were C16 : 0, C18 : 1
 ω9c and Sum in Feature 7 (C19 : 1
 ω7c/C19 : 1
 ω6c). The cell-wall peptidoglycan was of the A3α l-Lys-Gly type. Based on data from this study, a novel species, Bifidobacterium favimelis sp. nov., is proposed with the type strain IMAU50987T (= GDMCC 1.4189T = JCM 36315T).
Spatial multi-omics defines a shared glioblastoma infiltrative signature at the resection margin
Authors: Pai Balagopal , Ramos Susana Isabel , Cheng Wan Sze , Joshi Tanvi , Price Gabrielle , Tome-Garcia Jessica , Nudelman German , Shroff Sanjana , Beaumont Kristin , Raymund Yong , Sebra Robert , Zaslavsky Elena , Tsankova Nadejda Mincheva
Published: November 2024

Glioblastoma (GBM) remains an untreatable disease. Understanding GBM’s infiltrative biology at the resection margin is limited, despite causing disease recurrence and progression. To address this, we generated a high-throughput single-nucleus (sn)RNA-seq and snATAC-seq multi-omic dataset from six tumors with distinct genomic drivers and combined it with spatial transcriptomics to characterize the unique molecular phenotype of GBM near the margin. By contrasting GBM-specific biology in matching “Core” vs. “Margin” dissections, we define unique, shared “GBM infiltration” and chromatin accessibility signatures near the margin. We prioritizeEGFRas a top differentially expressed and accessible “Margin” marker across GBM subtypes, show its dynamic expression along a core-to-margin infiltration trajectory, and validate its role in migration through CRISPR/Cas9 deletion in two patient-derived models. ChIP-seq studies furthermore corroborate preferential TEAD1 binding at EGFR’s accessible regulatory elements. This validated multi-omic dataset enables further studies into tumor and microenvironment biology in the context of residual GBM disease.
Defensive symbionts provide high protection against natural enemies at low cost to hosts: a meta-analysis
Authors: Cesar Cássia Siqueira , Santos Eduardo S. A. , Cogni Rodrigo
Published: November 2024

Defensive symbionts (i.e., symbionts that protect hosts against natural enemies) are common in nature, infecting many arthropod species. Defensive symbioses likely arose from host-symbiont interactions that are costly for hosts and evolved over time to a facultative mutualism. Hence, the role symbionts play in protecting hosts against natural enemies might be one of the reasons for their successful spread in nature. Here, we conducted a meta-analysis to investigate the costs and benefits of hosting symbionts in arthropods. We gathered approximately 3,000 effect sizes from 226 studies. Our results show that in the presence of natural enemies (i.e., hosts infected with pathogens or parasites), symbionts provide protection, positively affecting the fitness of their hosts. In the absence of natural enemies, symbionts caused little reduction in host fitness. Overall, protection was six times higher than the cost to hosts, indicating that symbionts provide high protection at low cost to hosts. We also found that natural enemies attacking hosts infected with symbionts have a significant reduction in their fitness. Moreover, the level of protection and cost for both hosts and natural enemies varies between host families, fitness components, and between natural and introduced symbionts (i.e., if the symbiont is natural of that species or if it was transinfected into a new species). Our results reveal a broad generality of protection at little cost for hosts, which may explain the successful spread of symbionts in wild arthropod populations.
Classifying Irritable Bowel Syndrome Using Spatio-Temporal Graph Convolution Networks on Brain fMRI Data
Authors: Wu Jiazhen , Zhuang Shuxin , Zhuang Zhemin , Xie Lei , Liu Mengting
Published: November 2024

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder marked by abdominal pain and changes in stool consistency or frequency. Recent studies have explored the link between IBS and various cognitive deficits using functional MRI. Despite these efforts, an effective diagnostic or predictive model for IBS remains elusive. This shortfall is twofold: firstly, the sample sizes in these studies are typically small, and secondly, the machine learning or deep learning models currently in use fail to adequately detect the subtle and dynamic pathological changes present in fMRI data for IBS. In this study, we extracted rs-fMRI of 79 subjects with IBS and 79 healthy controls, then put them into spatio-temporal graph convolution network (ST-GCN) for classification. We also incorporated a novel interpretability module into this model to identify potential regions of interest (ROI) associated with IBS. Our model outperformed other state-of-the-art ML and DL methods with the highest average accuracy of 83.51% on our dataset. Furthermore, based on the results of our interpretability module, the Inferior Parietal Lobule (IPL.R), Inferior Frontal Orbital part (ORBinf.R), Postcentral Gyrus (PCG.R), Middle Frontal Orbital part (ORBmid.R), and Superior Medial Frontal Orbital part (ORBsupmed.L) were identified as top 5 important brain regions for distinguishing IBS patients from the control group, which are consistent with the brain regions identified in previous literature reviews. We also conducted an external data-driven experiment to further validate the effectiveness of the interpretability module. The results indicate that the selected regions significantly impact IBS.
An algorithm-based investigation reveals the differential dynamics of water inside protein cavity as a function of distance from its wall
Authors: Francis Abel Xavier , Chilkoti Mansi , Atul  , Mrinal  , Sacher Sukriti , Ray Arjun
Published: November 2024

Hydration forces exerted by water in the form of hydrogen bonding networks or electrostatic interactions play an essential role in protein structure and function. These interactions often govern chemical catalysis, ion transport, protein stability, and folding. While water’s role as a biological solvent and on the protein surface is widely studied, its function inside protein cavities is often neglected due to the existing challenges in its detection using experimental and computational approaches. The importance of studying these special protein-water interactions is further underscored by the fact that water spatially confined within cavities exhibits deviations from bulk behavior, directly impacting processes occurring inside protein cavities. With these challenges in mind and building upon our method that accurately identifies the protein inner cavity surface (CICLOP), we have developed a tool that can accurately distinguish water occurring within cavities from the bulk solvent around the protein. Our tool can characterize the dynamic properties of water within protein cavities, such as diffusion, residence time, and rotational and orientational relaxation, using molecular dynamics (MD) simulation trajectories as input. We demonstrate the robustness of our tool on several cavity-containing proteins and describe its applicability in characterizing the biological function of water confined within the cavity of an archaeal group II chaperonin.
Endurance Exercise Elevates Plasma Mature Brain-Derived Neurotrophic Factor through Child- and Adulthood, with Amplified Effects in Adults
Authors: Edman Sebastian , Starck Julia , Corell Linnéa , Hangasjärvi William , von Finckenstein Amelie , Reimeringer Mikael , Reitzner Stefan , Norrbom Jessica , Moberg Marcus , von Walden Ferdinand
Published: November 2024

Background

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a central role in neuronal health. BDNF exists in two primary isoforms, the mature form (mBDNF) and its precursor (proBDNF), with opposing downstream effects on neuronal function. The positive effect of exercise on plasma levels of the BDNF-isoforms has been extensively studied in adults. However, equivalent investigations are lacking in children and youth.

Methods

Twenty healthy children (9-12 years old), 19 adolescents (13-17 years old), and 39 adults (23-49 years old) donated venous blood before and after a 45-minute run. Platelet-poor plasma was analyzed for pro– and mBDNF using enzyme-linked immunosorbent assay. Maximal oxygen uptake and anthropometric data were assessed in all participants, while Tanner stage, circulating sex hormones, and accelerometry-based activity level were assessed in children and adolescents.

Results

We found that children, adolescents, and adults have similar basal levels of pro-(337-543 pg × ml−1) and mBDNF (650-1111 pg × ml−1). For children and adolescents, basal levels of mBDNF correlated with average time spent in vigorous activity (r=0.5794, p=0.0015). In response to acute endurance exercise, mBDNF increased by 701 ± 946, 1232 ± 1105, and 1557 ± 1168 pg × ml−1in children, adolescents, and adults, respectively. The acute endurance exercise did not affect proBDNF levels (p>0.05).

Conclusion

Our results demonstrate that basal plasma pro– and mBDNF levels do not depend on age and maturity. Plasma mBDNF levels increase following endurance exercise in all age groups, but to a greater extent in adults.

Highlights/Impact

We show that in children and adolescents, regular vigorous physical activity is key to increased basal levels of plasma mBDNF, a factor linked to neuroplasticity and brain health.

The ability to elevate mBDNF through exercise is present across all age groups, with the greatest increase in adults.

The mBDNF response to physical exercise seems to be independent of underlying physical fitness.

Our findings suggest that basal plasma mBDNF levels may reflect the cumulative effects of repeated exercise rather than an individual’s overall physical fitness.
Winter Survival ofCulex pipiens f. pipiens Adults in Central Greece
Authors: Ioannou Charalampos , Beleri Stavroula , Tserkezou Persa , Michaelakis Antonios , Patsoula Eleni , Hadjichristodoulou Christos , Papadopoulos Nikos T.
Published: November 2024

Winter survival consists a major component of insect vectors life history in temperate environments that is directly related with early and later population growth next season with major consequences in the epidemiology of vectored diseases. The common European mosquitoCulex pipiensis a major vector of the West Nile Virus (WNV) in Europe, including Greece. West Nile Virus outbreaks are frequently reported in Greece over the last 2 decades and Thessaly, Central Greece, is included in the affected areas. Here we report on overwintering trials conducted in three regions of Thessaly to investigate the overwintering dynamics of the subspecies of theCx. pipienscomplex,Cx. pipiens f. pipiens. Two overwintering experiments regarding adults ofCx. pipiens f. pipienscarried out in two coastal areas of Thessaly (Nea Anchialos and Volos) and an inland area (Kalamaki). Results demonstrated the successful overwintering ofCx. pipiens f. pipiensfemales, as well as the failure of males to survive in all three regions considered. Successful overwintering females were capable of initiating egg laying following a blood meal in spring onsetting the first summer generation. Nonetheless, mortality patterns differ between the coastal and the inland area as well as among different cohorts of adults.
Brain functional connectivity as a mediator between hematological metrics and cognitive decline in children with beta-thalassemia major
Authors: Xu Shumin , Wu Jiazhen , Li Yaowen , Liu Xinyi , Liu Sixi , Wang Xiaodong , Huang Gui , Liu Mengting , Zeng Hongwu
Published: November 2024

Children with beta-thalassemia major (β -TM) are at risk of cognitive impairment, particularly in learning and memory. While cognitive deficits in the general population have been extensively studied, brain-based predictors for β-TM children remain unexplored. This study used connectome-based predictive modeling (CPM) to examine whole-brain functional connectivity in 60 participants to predict cognitive performance. β-TM children showed impaired cognitive abilities, as evidenced by lower Wechsler Intelligence Scale scores compared to controls. The identified brain regions, though not typically linked to cognitive performances, exhibited functional connectivity patterns associated with β-TM, as confirmed by network-based statistics. Correlations between task performance, functional connectivity identified by the CPM, and hematological metrics were also examined. Significant correlations were found between the strength of functional network identified by CPM and hematological metrics, particularly hemoglobin levels and red blood cell distribution width. The study demonstrates that hematological factors influence cognitive performance indirectly through specific functional connectivity, providing new insights into the neural underpinnings of cognitive deficits in children with beta-thalassemia major.
Disentangling folding from energetic traps in simulations of disordered proteins
Authors: Lotthammer Jeffrey M. , Holehouse Alex S.
Published: November 2024

Protein conformational heterogeneity plays an essential role in a myriad of different biological processes. Extensive conformational heterogeneity is especially characteristic of intrinsically disordered proteins and protein regions (collectively IDRs), which lack a well-defined three-dimensional structure and instead rapidly exchange between a diverse ensemble of configurations. An emerging paradigm recognizes that the conformational biases encoded in IDR ensembles can play a central role in their biological function, necessitating understanding these sequence-ensemble relations. All-atom simulations have provided critical insight into our modern understanding of the solution behavior of IDRs. However, effectively exploring the accessible conformational space associated with large, heterogeneous ensembles is challenging. In particular, identifying poorly sampled or energetically trapped regions of disordered proteins in simulations often relies on qualitative assessment based on visual inspection of simulations and/or analysis data. These approaches, while convenient, run the risk of masking poorly-sampled simulations. In this work, we present an algorithm for quantifying per-residue local conformational heterogeneity in protein simulations. Our work builds on prior work and compares the similarity between backbone dihedral angle distributions generated from molecular simulations in a limiting polymer model and across independent all-atom simulations. In this regime, the polymer model serves as a statistical reference model for extensive conformational heterogeneity in a real chain. Quantitative comparisons of probability vectors generated from these simulations reveal the extent of conformational sampling in a simulation, enabling us to distinguish between situations in which protein regions are well-sampled, poorly-sampled, or folded. To demonstrate the effectiveness of this approach, we apply our algorithm to several toy, synthetic, and biological systems. Accurately assessing local conformational sampling in simulations of IDRs will help better quantify new enhanced sampling methods, ensure force field comparisons are equivalent, and provide confidence that conclusions drawn from simulations are robust.
Human xenobiotic metabolism proteins have full-length and split homologs in the gut microbiome
Authors: Rendina Matthew , Turnbaugh Peter J. , Bradley Patrick H.
Published: November 2024

Xenobiotics, including pharmaceutical drugs, can be metabolized by both host and microbiota, in some cases by homologous enzymes. We conducted a systematic search for all human proteins with gut microbial homologs. Because gene fusion and fission can obscure homology detection, we built a pipeline to identify not only full-length homologs, but also cases where microbial homologs were split across multiple adjacent genes in the same neighborhood or operon (“split homologs”). We found that human proteins with full-length gut microbial homologs disproportionately participate in xenobiotic metabolism. While this included many different enzyme classes, short-chain and aldo-keto reductases were the most frequently detected, especially in prevalent gut microbes, while cytochrome P450 homologs were largely restricted to lower-prevalence facultative anaerobes. In contrast, human proteins with split homologs tended to play roles in central metabolism, especially of nucleobase-containing compounds. We identify twelve specific drugs that gut microbial split homologs may metabolize; two of these, 6-mercaptopurine by xanthine dehydrogenase (XDH) and 5-fluorouracil by dihydropyrimidine dehydrogenase (DPYD), have been recently confirmed in mouse models. This work provides a comprehensive map of homology between the human and gut microbial proteomes, indicates which human xenobiotic enzyme classes are most likely to be shared by gut microorganisms, and finally demonstrates that split homology may be an underappreciated explanation for microbial contributions to drug metabolism.

Article Summary

We develop a pipeline to systematically find human proteins with gut microbial homologs, including those split across multiple microbial genes (e.g., operons). This reveals thousands of proteins with full-length gut homologs, especially reductases and hydrolases that metabolize xenobiotics. Nearly two dozen split homologs are also observed for central metabolic enzymes, many of which can transform substrate analogs; in two cases, previous studies verify that microbial split homologs enable the expected drug to be metabolizedin vivo. These results, which we provide as a resource, map out homology and shed light on parallel drug metabolism between host and microbiome.
Efficient and Versatile Rapeseed Transformation for New Breeding Technologies
Authors: Ille Kea , Melzer Siegbert
Published: November 2024

Many gene functions are widely studied and understood in Arabidopsis; however, the lack of efficient transformation systems often limits the application and verification of this knowledge in crop plants.Brassica napusL., a member of the Brassicaceae family, is usually transformed byAgrobacterium-mediated hypocotyl transformation, but not all growth types are equally amenable to transformation. In particular, winter-type rapeseed, which requires vernalization to initiate flowering, is recalcitrant toin vitroregeneration and transformation. The analysis of gene functions in rapeseed is further complicated by the allotetraploid nature of its genome and the genome triplication within theBrassicagenus, which has led to the presence of a large number of gene homologs for each Arabidopsis ortholog. We have established a transformation method that facilitates the regeneration of winter-type rapeseed by using theWUSCHELgene fromBeta vulgaris. This allowed us to efficiently transform winter-type and spring-type rapeseed in small-scale experiments. As proof of principle, we targetedBna.CLV3andBna.SPL9/15with CRISPR/Cas9 and showed that entire gene families are effectively edited using this transformation protocol. This allowed us to simultaneously study many redundantly acting homologous genes in rapeseed. We observed mutant phenotypes forBna.CLV3andBna.SPL9/15in primary transformants, indicating that biallelic knockouts were obtained for up to eight genes. This allowed an initial phenotypic characterization to be performed already a few months after starting the experiment.
An mRNA Display Approach for Covalent Targeting of aStaphylococcus aureusVirulence Factor
Authors: Wang Sijie , Woods Emily C. , Jo Jeyun , Zhu Jiyun , Hansel-Harris Althea , Holcomb Matthew , Pedowitz Nichole J. , Upadhyay Tulsi , Bennett John , Fellner Matthias , Park Ki Wan , Zhang Anna , Valdez Tulio A. , Forli Stefano , Chan Alix I , Cunningham Christian N. , Bogyo Matthew
Published: November 2024

Staphylococcus aureus (S. aureus) is an opportunistic human pathogen that causes over one million deaths around the world each year. We recently identified a family of serine hydrolases termed fluorophosphonate binding hydrolases (Fphs) that play important roles in lipid metabolism and colonization of a host. Because many of these enzymes are only expressed inStaphylococcusbacteria, they are valuable targets for diagnostics and therapeutics. Here we developed and screened highly diverse cyclic peptide libraries using mRNA display with a genetically encoded oxadiazolone (Ox) electrophile that was previously shown to potently and covalently inhibit multiple Fph enzymes. By performing multiple rounds of counter selections with WT and catalytic dead FphB, we were able to tune the selectivity of the resulting selected cyclic peptides containing the Ox residue towards the desired target. From our mRNA display hits, we developed potent and selective fluorescent probes that label the active site of FphB at single digit nanomolar concentrations in liveS. aureusbacteria. Taken together, this work demonstrates the potential of using direct genetically encoded electrophiles for mRNA display of covalent binding ligands and identifies potent new probes for FphB that have the potential to be used for diagnostic and therapeutic applications.
A Single Chimeric Spike Antigen Induces Pan-Sarbecovirus Immunity
Authors: Counoupas Claudio , Pino Paco , Armitano Joshua , Johansen Matt D , Smith Lachlan J , Chan Elizabeth , Ashley Caroline , Estapé Eva , Troyon Jean , Alca Sibel , Miem-czyk Stefan , Hansbro Nicole G. , Gabriella Scandurra , Britton Warwick J. , Courant Thomas , Dubois Patrice M. , Collin Nicolas , Mohan V Krishna , Hansbro Philip M , Wurm Maria J , Wurm Florian M. , Steain Megan , Triccas James A.
Published: November 2024

Next-generation vaccines are required to address the evolving nature of SARS-CoV-2 and to protect against emerging pandemic threats from other coronaviruses. These vaccines should aim to elicit broad-protection, provide long-lasting immunity and facilitate equitable access for all populations. In this study, a panel of chimeric, full-length spike antigens were developed that incorporate mutations from previous, circulating and predicted SARS-CoV-2 variants. The lead candidate (CoVEXS5) was obtained from a high-yield production process in stable CHO cells with purity of >95%, long-term stability and elicitation of broadly cross-reactive neutralising antibodies when delivered to mice in a squalene emulsion adjuvant (Sepivac SWE™). In both mice and hamsters, CoVEXS5 immunisation reduced clinical disease signs, lung inflammation and organ viral titres after SARS-CoV-2 infection, including challenge with the highly immunoevasive Omicron XBB.1.5 subvariant. In mice previously primed with a licenced protein vaccine (NVX-CoV2373), CoVEXS5 could boost T cell immunity, as well as neutralising antibodies levels against viruses from three sarbecoviruses clades. The breadth of sarbecovirus cross-reactivity elicited by CoVEXS5 exceeded that observed after boosting with the NVX-CoV2373 vaccine. These findings highlight the potential of a chimeric spike antigen, formulated in an open-access adjuvant, as a next-generation vaccine candidate to enhance cross-protection against emerging sarbecoviruses in vaccinated populations globally.
Predictors of Response and Rational Combinations for the Novel MCL-1 Inhibitor MIK665 in Acute Myeloid Leukemia
Authors: Saad Joseph , Newman Rhiannon , Khabusheva Elmira , Aakko Sofia , Durand Eric , Tambe Mahesh , Kuusanmäki Heikki , Parsons Alun , Miettinen Juho J. , Javarappa Komal Kumar , Ikonen Nemo , Kontro Mika , Porkka Kimmo , Maacke Heiko , Woo Janghee , Halilovic Ensar , Heckman Caroline A.
Published: November 2024

Despite promising anti-leukemic activity of MCL-1 inhibitors in preclinical studies of acute myeloid leukemia (AML), their progress through clinical evaluation has in part been challenged by limited knowledge of patient subgroups suitable for treatment. To stratify patients with AML for MCL-1 inhibitor-based treatment, we evaluated the sensitivity of 42 primary AML samples to MCL-1 inhibitor MIK665 (S64315) and contrasted their molecular profiles. We observed that MIK665 sensitive samples had a more differentiated phenotype, whereas resistant samples displayed higher levels of ABCB1 (MDR1) and the anti-apoptotic protein BCL-XL. Further evaluation revealed thatABCB1expression has good predictive performance in identifying MIK665 primary resistant samples. To induce sensitivity, we treated MIK665-resistant samples with ABCB1 inhibitor elacridar, BCL-XL inhibitor A1331852, or BCL-2 inhibitor venetoclax in combination with MIK665. While combinations with elacridar and A1331852 were not effective, the combination of MIK665 and venetoclax effectively eliminated AML blasts compared to either of the agents alone. Additionally, the combination restored sensitivity of samples with primary venetoclax resistance. Overall, this study indicates that elevatedABCB1expression is a potential predictor of resistance to MIK665 in AML, and that a combination of MIK665 with venetoclax may be effective for overcoming resistance to either MCL-1 or BCL-2 inhibition.
Autophagic stress activates distinct compensatory secretory pathways in neurons
Authors: Palumbos Sierra D. , Popolow Jacob , Goldsmith Juliet , Holzbaur Erika L.F.
Published: November 2024

Autophagic dysfunction is a hallmark of neurodegenerative disease, leaving neurons vulnerable to the accumulation of damaged organelles and proteins. However, the late onset of diseases suggests that compensatory quality control mechanisms may be engaged to delay the deleterious effects induced by compromised autophagy. Neurons expressing common familial Parkinson’s disease (PD)-associated mutations in LRRK2 kinase exhibit defective autophagy. Here, we demonstrate that both primary murine neurons and human iPSC-derived neurons harboring pathogenic LRRK2 upregulate the secretion of extracellular vesicles. We used unbiased proteomics to characterize the secretome of LRRK2G2019Sneurons and found that autophagic cargos including mitochondrial proteins were enriched. Based on these observations, we hypothesized that autophagosomes are rerouted toward secretion when cell-autonomous degradation is compromised, likely to mediate clearance of undegraded cellular waste. Immunoblotting confirmed the release of autophagic cargos and immunocytochemistry demonstrated that secretory autophagy was upregulated in LRRK2G2019Sneurons. We also found that LRRK2G2019Sneurons upregulate the release of exosomes containing miRNAs. Live-cell imaging confirmed that this upregulation of exosomal release was dependent on hyperactive LRRK2 activity, while pharmacological experiments indicate that this release staves off apoptosis. Finally, we show that markers of both vesicle populations are upregulated in plasma from mice expressing pathogenic LRRK2. In sum, we find that neurons expressing pathogenic LRRK2 upregulate the compensatory release of secreted autophagosomes and exosomes, to mediate waste disposal and transcellular communication, respectively. We propose that this increased secretion contributes to the maintenance of cellular homeostasis, delaying neurodegenerative disease progression over the short term while potentially contributing to increased neuroinflammation over the longer term.

SIGNIFICANCE

A hallmark feature of many neurodegenerative diseases is autophagy dysfunction, resulting in the accumulation of damaged proteins and organelles that is detrimental to neuronal health. The late onset of neurodegenerative diseases, however, suggests alternative quality control mechanisms may delay neuronal degeneration. Here, we demonstrate that neurons expressing a Parkinson’s Disease-causing mutation upregulate the release of two extracellular vesicle populations. First, we observe the increased expulsion of secreted autophagosomes to mediate cellular waste disposal. Second, we observe the increased release of exosomes, likely to facilitate transcellular communication. Thus, we propose that increases in secretory autophagy and exosome release are a homeostatic response in neurons undergoing chronic stress.
Competition strategies driving resource partitioning in chitin degrading communities
Authors: Pontrelli Sammy , Guessous Ghita , Trouillon Julian , Krishna Aswin , Hwa Terence , Sauer Uwe
Published: November 2024

Resource competition strongly shapes microbial community dynamics and function. In polysaccharide-degrading communities, primary degraders secrete monomer-releasing enzymes and exploiters consume released products without investing in enzymes. By investigating competitive strategies between chitin degraders and N-acetylglucosamine (GlcNAc) exploiters, we uncover several interacting factors, including GlcNAc liberation rates, diffusive loss, and resource partitioning between competitors, which determine community viability and growth dynamics at early stages of degradation. Aside from cases involving antibiotic secretion or aggregation on particles to privatize degrading enzymes, exploiters also inhibit degraders by siphoning away limiting GlcNAc flux during early stages of particle degradation, when degraders must overcome diffusive GlcNAc loss to sustain chitinase production. Analogous to the Allee effect in population biology, these effects lead to sensitive dependences on initial species densities for a community to thrive. This study elucidates how metabolic competition at early stages of particle degradation shapes species interactions, resource partitioning, and ultimately community viability.