bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid and robust identification of sepsis using SeptiCyte RAPID in a heterogenous patient population
Authors: Balk Robert , Esper Annette M. , Martin Greg S. , Miller Russell R. , Lopansri Bert K. , Burke John P. , Levy Mitchell , Rothman Richard E. , D’Alessio Franco R. , Sidhaye Venkataramana K. , Aggarwal Neil R. , Greenberg Jared A. , Yoder Mark , Patel Gourang , Gilbert Emily , Parada Jorge P. , Afshar Majid , Kempker Jordan A. , van der Poll Tom , Schultz Marcus J. , Scicluna Brendon P. , Klouwenberg Peter M. C. Klein , Liebler Janice , Blodget Emily , Kumar Santhi , Mei Xue W. , Navalkar Krupa , Yager Thomas D. , Sampson Dayle , Kirk James T. , Cermelli Silvia , Davis Roy F. , Brandon Richard B.
Published: August 2024

Background/Objective

SeptiCyte RAPID is a transcriptional host response assay that discriminates between sepsis and non-infectious systemic inflammation (SIRS) with a one-hour turnaround time. The overall performance of this test in a cohort of 419 patients has recently been described [Balk et al., J Clin Med 2024, 13, 1194]. In this study we present results from a detailed stratification analysis in which SeptiCyte RAPID performance was evaluated in the same cohort across patient groups and subgroups encompassing different demographics, comorbidities and disease, sources and types of pathogens, interventional treatments, and clinically defined phenotypes. The aims were to identify variables that might affect the ability of SeptiCyte RAPID to discriminate between sepsis and SIRS, and to determine if any patient subgroups appeared to present a diagnostic challenge for the test.

Methods

1) Subgroup analysis, with subgroups defined by individual demographic or clinical variables, using conventional statistical comparison tests. 2) Principal component analysis and k-means clustering analysis, to investigate phenotypic subgroups defined by unique combinations of demographic and clinical variables.

Results

No significant differences in SeptiCyte RAPID performance were observed between most groups and subgroups. One notable exception involved an enhanced SeptiCyte RAPID performance for a phenotypic subgroup defined by a combination of clinical variables suggesting a septic shock response.

Conclusions

We conclude that for this patient cohort SeptiCyte RAPID performance was largely unaffected by key variables associated with heterogeneity in patients suspected of sepsis.
Serum fibrinogen level and fibrinogen administration in patients with traumatic brain injury: a systematic review and meta-analysis protocol
Authors: Igoli Joanne , Daniel Jeremiah Oluwatomi Itodo , Oludele Halleluyah , Alao Adedoyin Esther , Ogedegbe Idemudia Stephen , Olaniyan Adewale , Adebayo Michael Adeshola , Matthew Damilola , Oyepitan Temidayo Elizabeth , Brabi Daniel , Olukoya Olatomiwa , Osunronbi Temidayo
Published: August 2024

Introduction

Traumatic Brain Injury (TBI) is a leading cause of disability and death globally. It has a significant economic burden. Coagulopathy has been identified as one of the key factors contributing to the poor outcomes observed in TBI patients, and it has been theorised that the management of coagulopathy will improve patient outcomes. Low serum fibrinogen levels denote a coagulopathic state, and the therapeutic administration of fibrinogen has been proposed to correct this state. However, there is no consensus on its efficacy in patients with TBI.

This systematic review and meta-analysis seeks to ascertain the prognostic value of serum fibrinogen levels in patients with TBI and assess the effect of fibrinogen administration on these patients.

Methods

Using the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines, we will perform a comprehensive search of Scopus, Medline, Embase and Cochrane Library to retrieve all original articles that investigate the prognostic value of fibrinogen levels and/or the effect of fibrinogen administration in TBI patients. Primary outcomes include functional outcome and mortality assessments such as the Glasgow Outcome Score and modified Rankin Score. Secondary outcomes include progressive intracranial haemorrhage/contusion and need for surgical intervention. Data collected will encompass participant demographics, measured fibrinogen levels, dose of fibrinogen administered and specified outcome measures.

Conclusion

Findings from this study on if fibrinogen level has prognostic value and if fibrinogen administration improves patient outcomes, will help inform future TBI management and shared decision-making. Thus, TBI patient outcomes can be optimised accordingly.

PROSPERO Registration Number

CRD42024556497. Available from:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024556497
Odor source localization behavior of an insect enhanced by intermittent intake strategy
Authors: Shigaki Shunsuke , Matsushita Takumi , Ohashi Hirono , Ando Noriyasu , Hosoda Koh
Published: August 2024

This study investigated odor acquisition strategies to enhance odor plume tracking performance. Efficient odor plume tracking is a crucial ability for organisms, affecting their survival, including for insects with relatively simple nervous systems. Insects can use odor cues to locate food sources or potential mates. Odors released from a source disperse in complex patterns owing to air currents and collisions with objects, making their spread unpredictable. Organisms must therefore engage in active odor acquisition behaviors to effectively gather spatial information from this highly uncertain odor environment. This study focused on odor acquisition via wing flapping in a male silk moth and its relationship with female localization. Given the difficulty of directly intervening in wing flapping, we employed an insect-mounted robotic system to engineer interventions and investigate the relationship between wing-flapping-induced odor acquisition and localization. We found that the difference between air inflow and stoppage in odor attraction was large, and that the odor plume tracking performance was highest at 10 Hz, where odor attraction can be performed at high frequencies. Although constant strong odor acquisition improves localization performance, it increases the likelihood of movement in directions other than that of the odor source. This suggests that periodic wing flapping helps to suppress undesired movements.
Investigating microscopic angioarchitecture in the human visual cortex in 3D with angioMASH tissue clearing and labelling
Authors: Hildebrand Sven , Franz Johannes , Hoogen Hanna , Capalbo Michael , Bethge Philipp , Herrler Andreas , Helmchen Fritjof , Roebroeck Alard
Published: August 2024

Non-invasive imaging techniques, such as ultra-high field fMRI, are intricately connected to the underlying vasculature and are approaching ever higher resolutions. For the analysis of fMRI signals over cortical depth at such high resolutions, microvascular differences might have to be taken into account. Therefore, a better understanding of the laminar distribution and interareal differences in the cortical vasculature is becoming more important. However, in comparison to cyto- and myeloarchitecture, the study of angioarchitecture has received far less attention and relatively few methods have been described to visualise the vascular network in the human brain. Here we present angioMASH, a method for double labelling angioarchitecture and cytoarchitecture in archival human brain tissue, based on the recently published MASH protocol. The double labelling and optical clearing of thick human brain slices can be accomplished within 16 days. We use this method to acquire multi-resolution 3D datasets of combined cyto- and angioarchitecture in large (∼30 mm x 10 mm x 3 mm) volumes of human samples covering visual areas V1 and V2. We demonstrate for the first time, that classical angioarchitectonic features can be visualised in the human cortex and in 3D using tissue clearing and light-sheet microscopy. Lastly, we show differences in the vessel density and orientation over cortical depth within and between the two areas. Especially in V1, the vascular density is not homogeneous over cortical depth but shows distinct layering. These layers are also determined by changes in the orientation of the blood vessels from a predominantly radial to a more tangential distribution. In V2, differences in vascular density are less pronounced, but orientation profiles follow a similar trend over cortical depth. We discuss potential consequences of these differences for the interpretation of non-invasive functional imaging modalities such as fMRI or fNIRS.

Graphical Abstract
Near-infrared spectroscopy discriminates mass-reared sterile and wild tsetse flies
Authors: Pagabeleguem Soumaïla , Da Dari F. , Somé Bernard M. , Avelessi Marx S.P. , Djègbè Nicaise D. C. , Yoda Rebecca L. , Bagayogo Abdramane , Maïga Hamidou , Churcher Thomas S. , Dabiré Roch K.
Published: August 2024

In the frame of the Pan African Tsetse and Trypanosomosis Eradication Campaign, an integrated pest management approach has been adopted to manage tsetse fly populations using a sterile insect technique (SIT).. Monitoring the efficacy of the SIT programs requires the discrimination between wild and sterile males collected in monitoring traps. The discrimination between sterile and wild males relies mainly on marking of sterile males with a fluorescent dye powder (before the releases) and their identification using a fluorescence camera and /or a fluorescence microscope. However, the accuracy of this method remains limited with defective marking and wild flies contaminated with a few dye particles in the monitoring traps. The molecular techniques developed to discriminate doubtful flies are costly for endemic countries. Here, we investigate the ability of a new generation monitoring tool, the near-infrared spectroscopy (NIRS) to discriminate between lab-rearedGlossina palpalis gambiensisand their counterparts in the field. NIRS technique discriminates wild flies males with 86% accuracy toGlossina palpalis gambiensismales reared in an insectarium. Interestingly, the prediction accuracy between wild and laboratory-reared flies improved to 88% when theGlossinalab colony flies were irradiated. In light of these results, NIRS can discriminate tsetse flies even when identification with the UV camera is doubtful. However, more investigations integrating some natural variables are required before the validation of the technical as a complementary method for potential future tsetse eradication programs.
Highjacked by a pseudoenzyme: How eudicot plants make indole
Authors: Florean Matilde , Schultz Hedwig , Grabe Veit , Luck Katrin , O’Connor Sarah E. , Köllner Tobias G.
Published: August 2024

Indole is crucial for plant defense, where it is released as a signaling volatile upon herbivore attack and also serves as a starting precursor for defensive specialized metabolites. Indole is known to be synthesized in plants from indole-3-glycerol phosphate by the enzyme indole-3-glycerol phosphate lyase. Here we report that in core eudicots, indole production for plant defense occurs via an alternative pathway. The α subunit of tryptophan synthase (TSA), an enzyme of core metabolism, normally binds to tryptophan synthase β subunit (TSB) to produce tryptophan. However, we show that a non-catalytic TSB paralogue (TSB-like) can highjack TSA to produce indole. The widespread occurrence ofTSB-likegenes in eudicots suggests that this alternative mechanism for indole formation is widespread throughout the plant kingdom.
De novo design of potent inhibitors of Clostridioides difficile toxin B
Authors: Ragotte Robert J. , Tam John , Miletic Sean , Palou Roger , Weidle Connor , Li Zhijie , Glögl Matthias , Beilhartz Greg L. , Liang Huazhu , Carr Kenneth D. , Borst Andrew J. , Coventry Brian , Wang Xinru , Rubinstein John L. , Tyers Mike , Melnyk Roman A. , Baker David
Published: August 2024

Clostridioides difficileis a major cause of secondary disease in hospitals. During infection,C. difficiletoxin B drives disease pathology. Here we use deep learning and Rosetta-based approaches to de novo design small proteins that block the entry of TcdB into cells. These molecules have binding affinities and neutralization IC50’s in the pM range and are compelling candidates for further clinical development. By directly targeting the toxin rather than the pathogen, these molecules have the advantage of immediate cessation of disease and lower selective pressure for escape compared to conventional antibiotics. AsC. difficileinfects the colon, the protease and pH resistance of the designed proteins opens the door to oral delivery of engineered biologics.

Significance statement

C. difficileinfection (CDI) is a major public health concern with over half a million cases in the United States annually resulting in 30,000 deaths. Current therapies are inadequate and frequently result in cycles of recurrent infection (rCDI). Progress has been made in the development of anti-toxin mAb therapies that can reduce the rate of rCDI, but these remain unaffordable and out of reach for many patients. Using de novo protein design, we developed small protein inhibitors targeting two independent receptor binding sites on the toxin that drives pathology during CDI. These molecules are high affinity, potently neutralizing and stable in simulated intestinal fluid, making them strong candidates for the clinical development of new CDI therapies.
Modulation of blood-tumor barrier transcriptional programs improves intra-tumoral drug delivery and potentiates chemotherapy in GBM
Authors: Jimenez-Macias Jorge L. , Vaughn-Beaucaire Philippa , Bharati Ayush , Xu Zheyun , Forrest Megan , Hong Jason , Sun Michael , Schmidt Andrea , Clark Jasmine , Hawkins William , Mercado Noe , Real Jacqueline , Huntington Kelsey , Zdioruk Mykola , Nowicki Michal O. , Cho Choi-Fong , Wu Bin , Li Weiyi , Logan Theresa , Manz Katherine E. , Pennell Kurt D. , Fedeles Bogdan I. , Brodsky Alexander S. , Lawler Sean E.
Published: August 2024

Glioblastoma (GBM) is the most common malignant primary brain tumor. GBM has an extremely poor prognosis and new treatments are badly needed. Efficient drug delivery to GBM is a major obstacle as the blood-brain barrier (BBB) prevents passage of the majority of cancer drugs into the brain. It is also recognized that the blood-brain tumor barrier (BTB) in the growing tumor represents a challenge. The BTB is heterogeneous and poorly characterized, but similar to the BBB it can prevent therapeutics from reaching effective intra-tumoral doses, dramatically hindering their potential. Here, we identified a 12-gene signature associated with the BTB, with functions related to vasculature development, morphogenesis and cell migration. We identified CDH5 as a core molecule in this set and confirmed its over-expression in GBM vasculature using spatial transcriptomics of GBM patient specimens. We found that the indirubin-derivative, 6-bromoindirubin acetoxime (BIA), could downregulate CDH5 and other BTB signature genes, causing endothelial barrier disruption in endothelial monolayers and BBB 3D spheroidsin vitro. Treatment of tumor-bearing mice with BIA enabled increased intra-tumoral accumulation of the BBB non-penetrant chemotherapeutic drug cisplatin and potentiated cisplatin-mediated DNA damage by targeting DNA repair pathways. Finally, using an injectable BIA nanoparticle formulation, PPRX-1701, we significantly improved the efficacy of cisplatin in patient-derived GBM xenografts and prolonged their survival. Overall, our work reveals potential targets at the BTB for improved chemotherapy delivery and the bifunctional properties of BIA as a BTB modulator and potentiator of chemotherapy, supporting its further development.
Blood immunomap for prediction of responses to aPD1 immunotherapy in metastatic non-small cell lung cancer
Authors: Semitekolou Maria , Paschalidis Nikolaos , Lo Tartaro Domenico , Tsitsopoulou Aikaterini , Stamou Panagiota , Mavroudis Alexandros , Markaki Effrosyni , Varveri Athina , Morianos Ioannis , Lavigne Matthieu , Fotsitzoudis Charalampos , Magkouta Sophia , Dede Konstantina , Kalomenidis Ioannis , Samitas Konstantinos , Potaris Konstantinos , Cossarizza Andrea , Mavroudis Dimitrios , De Biasi Sara , Verginis Panayiotis
Published: August 2024

Immune checkpoint inhibitor immunotherapy has revolutionized the treatment of non-small cell lung cancer (NSCLC). Despite the immense success, still a significant proportion of patients do not develop durable responses, allowing disease progression accompanied by high mortality rates. Therefore, there is an imperative need for identification of reliable non-invasive predictive biomarkers to guide therapeutic decisions. Herein, we constructed a blood immunomap in NSCLC patients with metastatic disease, using a high-dimensional mass cytometry approach. Assessment of clinical responses to aPD1 immunotherapy revealed, among others, a significant expansion of CD8+PD-L1+T cells in individuals not responding to immunotherapy. Of interest, CD8+PD-L1+T cells were enriched in tumor biopsies and bronchoalveolar lavage of NSCLC individuals at early stages of disease as well as in pleural infusions of individuals with thoracic malignancies. Transcriptomic analysis revealed that CD8+PD-L1+T cells exhibited a regulatory/exhausted phenotype, while various transcripts associated with the overall survival of NSCLC individuals, were mapped. Overall, our findings define an immunomap in the early stage and advanced NSCLC patients and identify immune-related events which may benefit the quest for identification of predictive biomarkers of immunotherapy responses.
Long-Term Impact of Stressful Life Events on Breast Cancer Risk: A 36-Year Genetically Informed Prospective Study in the Finnish Twin Cohort
Authors: Azzi Elissar , Bode Hannes , Palviainen Teemu , Hukkanen Mikaela , Ollikainen Miina , Kaprio Jaakko
Published: August 2024

To investigate potential interactions between stress, genetic predisposition, and breast cancer, we employed a multifaceted approach, analysing polygenic risk scores (PRS), DNA methylation (DNAm) patterns, stressful life events, and breast cancer risk using data from 10342 women in the Finnish Twin Cohort, including 719 breast cancer cases. Stressful life events data was gathered from a 1981 questionnaire while cancer and mortality data were obtained from Finnish Cancer Registry, Finnish Population Register and Statistics Finland. DNAm data from breast cancer discordant twin pairs was used to explore within-pair differences between 212 breast cancer associated CpG sites and stressful life events. A hazard ratio (HR) of 1.05 (95%CI 1.02-1.08) was observed for breast cancer per one-event increase in total stressful life events. Women exposed to over 10 stressful life events exhibited an almost two-fold increase in risk of breast cancer (HR=1.93, 95%CI 1.19-3.14). Stratifying by birth decade revealed a lower HR for those born after 1950 (HR 1.01; 95%CI 0.96-1.06) compared to those born between 1940-1949 (HR 1.07; 95%CI 1.01-1.12). In a subsample with genetic data, no association with breast cancer PRS was seen (HR = 1.03, 95%CI 0.92-1.15 per SD of PRS). Stressful life events exposure associated with breast cancer related DNAm in 42 of the 212 CpG sites. This 36-year genetically informed study highlights the long-term association between stressful life events and breast cancer risk. These findings suggest epigenetic changes, but not polygenic risk may mediate the impact the effects of stressful life events on breast cancer incidence.
Lesion distribution and network mapping in dyskinetic cerebral palsy
Authors: de Almeida Marcelino Ana Luísa , Al-Fatly Bassam , Tuncer Mehmet S. , Krägeloh-Mann Ingeborg , Koy Anne , Kühn Andrea A.
Published: August 2024

Objective

Dyskinetic cerebral palsy (DCP) encompasses a group of predominantly perinatally acquired complex motor disorders that present with dystonia and/or choreoathetosis and are frequently associated with brain lesions in neuroimaging. Recently, lesion network mapping provided a tool to redefine neurological disorders as circuitopathies. In this study, we aim to assess lesion distribution in DCP and identify a DCP-related network derived from lesions.

Methods

Here, we review the literature of MRI findings in DCP and perform literature-based lesion network mapping (LNM). Imaging findings and their anatomical distribution were extracted from literature and quantified according to an established MRI classification system for cerebral palsy. Whole-brain functional connectivity from lesions causing DCP was calculated using a pediatric resting-state functional MRI connectome. Results were contrasted with two control datasets for spatial specificity.

Results

Review of 48 selected articles revealed that grey matter injury predominated (51%), followed by white matter injury (28%). In 16% of cases MRI was normal. Subcortical lesions affected the thalamus, pallidum and putamen in >40% of reported patients, respectively. Figures available from 23 literature cases were used to calculate DCP-LNM. The LNM revealed functional connectivity to a wide network including the brainstem, cerebellum, basal ganglia, cingulate, and sensorimotor cortices. Strongest connectivity was found for the motor thalamus.

Interpretation

The neural network of DCP identified with LNM includes areas previously implicated in hyperkinetic disorders and highlights the motor thalamus as a common network node. The effects of targeting motor thalamic networks with neuromodulation in DCP should be explored in future trials.
Cost-benefit of Influenza Vaccinations in Frontline Workers: A Dynamic Modelling Study
Authors: Mortensen Peter , Gilks William , Kim Selina , Bennett Richard , Linley Matthew
Published: August 2024

Influenza significantly impacts public health, particularly among the elderly and those with underlying health conditions, but it also imposes substantial economic and operational burdens on the working-age population. This study introduces a novel machine learning-based Susceptible-Infected-Recovered (SIR) model solved as an agent-based model (ABM), designed to dynamically simulate influenza spread and assess the cost-benefit of vaccination programs specifically for frontline workers. Unlike traditional models, our approach accounts for the diverse contact rates and risk profiles across different job types, offering a more granular and accurate prediction of influenza’s impact on workforce productivity. We utilised historical influenza data from the CDC and WHO/FluMart to model the effects of varying vaccination coverage levels on infections, sick days, and associated costs within a typical workplace. The results demonstrate that higher vaccination coverage significantly reduces both the total number of infections and the peak sickness levels, leading to substantial cost savings. Additionally, higher vaccination coverage was associated with a significantly lower peak in sickness, mitigating periods of high absenteeism and operational disruptions. The model highlights the economic advantages of vaccination programs, particularly for sectors with higher salaries and absenteeism rates. It also underscores the importance of targeting frontline workers, who have higher contact rates and contribute more significantly to influenza transmission. This model’s ability to capture the dynamic nature of influenza transmission and its differential effects on various work types represents a significant advancement over previous static models. It provides a robust tool for organisations to optimise vaccination strategies, ensuring business continuity and enhancing productivity during influenza seasons.
Developmental origins of the Autism Spectrum Disorder in the Middle East and North Africa Region: A Systematic Review and Meta-Analysis of adjusted risk factors
Authors: Akomolafe Aishat F. , Mahmood Fathima R. , Abdallah Bushra M. , Elshoeibi Amgad M. , Mahmoud Elhassan , Al-Khulaifi Aisha Abdulla , Darwish Nour , Dweidri Yara , Yousif Duaa , Khalid Hafsa , Al-Theyab Majed , Azeem Muhammad Waqar , Shahwar Durre , Kamal Madeeha , Alabdulla Majid , Khaled Salma M. , Chivese Tawanda
Published: August 2024

Background and Objectives

The etiology of autism spectrum disorder (ASD) is poorly understood, with sparse data from the Middle East and North Africa (MENA) region, which has a unique climate and socio-epidemiological setting. This research investigated the developmental (early life) risk factors associated with ASD in the MENA region.

Methods

In this systematic review and meta-analysis, we searched for observational studies, which carried out adjusted analyses for ASD risk factors in the MENA region, in PubMed, Embase, Scopus, and CINAHL databases. We analyzed associations between ASD and factors related to conception, inheritance, maternal morbidity during pregnancy and adverse pregnancy outcomes. After study quality assessment, meta-analyses for each risk factor were carried out using the bias-adjusted inverse variance heterogeneity model. Heterogeneity was assessed using I2and publication bias using Doi and funnel plots.

Results

The systematic review included 19 case control studies from eight countries within the MENA region. In overall synthesis, male sex (OR=3.27, 95% CI: 2.39-4.48, I2 = 40.9%), family history of ASD (OR=2.98, 95% CI: 0.51-17.31, I2 = 85.0%), and consanguinity (OR= 1.77, 95% CI: 1.38-2.28, I2 = 57.1%) were associated with ASD. Although with limited studies, a review of the literature showed some possible associations between ASD and gestational diabetes, gestational hypertension, macrosomia, NICU admission, respiratory distress syndrome, cesarean delivery, gestational age, and older maternal age.

Conclusion

These findings confirm the association between male sex, family history of ASD and consanguinity with ASD, potentially suggesting some inherited mechanism in the etiology of ASD in the MENA region. Some maternal co-morbidities during pregnancy and adverse pregnancy outcomes may contribute to ASD risk in the MENA region, although more studies are needed in the region.

Registration

The protocol for this systematic review and meta-analysis is registered on the International Prospective Register of Systematic Reviews (PROSPERO) with registration ID CRD42024499837.
Individual cases of Parkinson’s disease can be robustly classified by cortical oscillatory activity from magnetoencephalography
Authors: Roberts Gillian , Hardy Samuel , Chen Robert , Dunkley Benjamin T ,   PREVENT-AD Research Group & Quebec Parkinson Network
Published: August 2024

Parkinson’s disease (PD) is a progressive neurodegenerative disorder which causes debilitating symptoms in both the motor and cognitive domains. The neurophysiological markers of PD include ‘oscillopathies’ such as diffuse neural oscillatory slowing, dysregulated beta band activity, and changes in interhemispheric functional connectivity; however, the relative importance of these markers as determinants of disease status is not clear. In this study, we used resting state magnetoencephalography data (n = 199 participants, 78 PD, 121 controls) from the open OMEGA repository to investigate changes in spectral power and functional networks in PD. Using a Contrast of Parameter Estimates (COPE) approach, we modelled the effects of PD while controlling for population-level confounds (age, sex, brain volume). Permutation testing revealed highly significant increases in theta (p=0.0001) and decreases in gamma band spectral power (p=0.0001). Building on the group contrast results, we investigated the ability of source-resolved MEG data to distinguish PD from healthy controls. Our approach uses a Partial Least Squares (PLS)-based classifier to find linear combinations of MEG features which independently predict PD. We found MEG-based predictions to be highly sensitive and specific, reaching an optimal AUC-ROC of 0.87 ± 0.04 using a model including spectral power features with 4 independent PLS components, compared to 0.68 ± 0.04 when using functional connectivity. Interpretation of the model weights suggests that oscillatory slowing can be separated into independent posterior theta and global diffuse delta components that can robustly identify individual cases of PD with a high degree of accuracy. This suggests MEG can reveal dissociable, complementary neural processes which contribute to PD.
Stigma among people living with HIV in Northern Egypt
Authors: Magdy Mona , Zaki Adel , Osman Sherif Omar , Abd El-Wahab Ekram W. , Abd Elhameed Asmaa
Published: August 2024

Stigma involves labeling individuals, and associating them with negative behavior, leading to social isolation, stereotypes, loss of status, and discrimination. HIV stigma is considered a major barrier to effective responses to the HIV/AIDS epidemic. We aimed in this study to assess the stigma among people living with HIV (PLWH) in Alexandria, Egypt. We conducted a cross-section study on 785 PLWH attending the HIV unit in Alexandria Fever Hospital. Data collection was done through an interviewing questionnaire and an Arabic-translated version of the standardized, 12-item short version of the HIV Stigma Scale. The stigma scale was highly reliable (alpha coefficient = 0.743). About 72.4% of participants had high stigma with a total stigma score of more than 30. Men showed a higher median stigma score than women (60.8% vs 23.0% respectively recorded a median score of 33 or more). The total stigma score was significantly associated with the male sex and residing in Alexandria city (p= <0.1).

In conclusion, PLWH in Egypt experience a significant degree of stigma. These data can guide future health interventions to provide psychological and social support for PLWH.
HIF-α signaling regulates the macrophage inflammatory response duringLeishmania majorinfection
Authors: Fry Lucy G. , Washam Charity L. , Roys Hayden , Bowlin Anne K. , Venugopal Gopinath , Bird Jordan T. , Byrum Stephanie D. , Weinkopff Tiffany
Published: August 2024

Cutaneous leishmaniasis (CL) contributes significantly to the global burden of neglected tropical diseases, with 12 million people currently infected withLeishmaniaparasites. CL encompasses a range of disease manifestations, from self-healing skin lesions to permanent disfigurations. Currently there is no vaccine available, and many patients are refractory to treatment, emphasizing the need for new therapeutic targets. Previous work demonstrated macrophage HIF-α-mediated lymphangiogenesis is necessary to achieve efficient wound resolution during murineL. majorinfection. Here, we investigate the role of macrophage HIF-α signaling independent of lymphangiogenesis. We sought to determine the relative contributions of the parasite and the host-mediated inflammation in the lesional microenvironment to myeloid HIF-α signaling. Because HIF-α activation can be detected in infected and bystander macrophages in leishmanial lesions, we hypothesize it is the host’s inflammatory response and microenvironment, rather than the parasite, that triggers HIF-α activation. To address this, macrophages from mice with intact HIF-α signaling (LysMCreARNTf/+) or mice with deleted HIF-α signaling (LysMCreARNTf/f) were subjected to RNASequencing afterL. majorinfection and under pro-inflammatory stimulus. We report thatL. majorinfection alone is enough to induce some minor HIF-α-dependent transcriptomic changes, while infection withL. majorin combincation with pro-inflammatory stimuli induces numerous transcriptomic changes that are both dependent and independent of HIF-α signaling. Additionally, by coupling transcriptomic analysis with several pathway analyses, we found HIF-α suppresses pathways involved in protein translation duringL. majorinfection in a pro-inflammatory environment. Together these findings showL. majorinduces a HIF-α-dependent transcriptomic program, but HIF-α only suppresses protein translation in a pro-inflammatory environment. Thus, this work indicates the host inflammatory response, rather than the parasite, largely contributes to myeloid HIF-α signaling duringLeishmaniainfection.
Rate of force development is correlated with corticospinal excitability during explosive voluntary contractions
Authors: Castelli Federico , Mian Omar S. , Bruton Adam , Chembila Valappil Ashika C. , Hannah Ricci , Tillin Neale A.
Published: August 2024

Objective

To investigate the relationship between rate of torque development (RTD) and corticospinal excitability (denoted by motor-evoked potential; MEP) during explosive voluntary contractions. Also, to assess differences in MEP and silent period duration between different phases of explosive contraction and at maximum voluntary contraction (MVC) plateau.

Methods

In 14 adults, quadriceps muscle MEP and silent period duration were measured at ∼45 (early), ∼115 (middle), and ∼190 ms (late) from EMG onset during knee-extensor isometric explosive contractions, and at MVC plateau with superimposed transcranial magnetic stimulation (TMS). RTD was measured immediately prior to early-phase MEP during the same contractions, and these two variables were correlated across separate contractions, within participants, via repeated measures correlation (RmCorr). RTD was also measured in explosive contractions without TMS over early-, middle-, and late-phases and correlated to MEP averaged across the corresponding and preceding phases, via Pearson’s r correlations, assessing relationships across participants. MEP and silent period duration were compared (ANOVA) between the different phases and at MVC plateau.

Results

MEP and RTD were correlated across separate contractions within participants (RmCorr r=0.43), and in the middle phase across participants (Pearson’s r=0.56). MEP and RTD were not correlated in other phases (r≥0.09). Silent period duration increased throughout the different phases of contraction and up to MVC plateau (ANOVA, p=0.001) but MEP remained constant (ANOVA, p=0.42).

Conclusion

The correlations between MEP and RTD suggests corticospinal excitability is an important determinant of RTD. During rapid torque development and up to MVC plateau, corticospinal inhibition increases but excitability remains constant.
Genome-wide Search for Gene Mutations likely Conferring Insecticide Resistance in the Common Bed Bug,Cimex lectularius
Authors: Toga Kouhei , Kimoto Fumiko , Fujii Hiroki , Bono Hidemasa
Published: August 2024

Insecticide resistance in the bedbugCimex lectulariusis poorly understood due to the lack of genome sequences for resistant strains. In Japan, we identified a resistant strain ofC. lectulariusthat exhibits a higher pyrethroid resistance ratio compared to many previously discovered strains. We sequenced genomes of the pyrethroid resistant and susceptible strains using long-read sequencing, resulting in the construction of highly contiguous genomes (N50 of resistant strain: 2.1Mb and N50 of susceptible strain: 1.5 Mb). Gene prediction was performed by BRAKER3 and Functional annotation was performed by Fanflow4insects workflow. Next, we compared their amino acid sequences to identify gene mutations, identifying 729 mutated transcripts that were specific to the resistant strain. Among them, those defined previously as resistance genes were included. Additionally, enrichment analysis implicated DNA damage response, cell cycle regulation, insulin metabolism, and lysosomes in the development of pyrethroid resistance. Genome editing of these genes can provide insights into the evolution and mechanisms of insecticide resistance. This study expanded the target genes to monitor allele distribution and frequency changes, which will likely contribute to the assessment of resistance levels. These findings highlight the potential of genome-wide approaches to understand insecticide resistance in bed bugs.

Simple Summary

Bedbugs have expanded globally over the past two decades, causing several health risks. Mutations in their genes allow bed bugs to develop insecticide resistance. However, the extent to which gene mutations exist in the bug genome remains largely unknown because the genomes of resistant strains have not been determined. We accurately sequenced the genomes of both susceptible and resistant strains and compared the gene sequences between the two strains. Several genes with resistance-specific mutations have been identified. These mutations can alter gene function and lead to insecticide resistance.
Early steps of the biosynthesis of the anticancer antibiotic pleurotin
Authors: Weaver Jack A. , Alkhder Duha , Prasongpholchai Panward , Tadesse Michaël D. , de los Santos Emmanuel L. , Song Lijiang , Corre Christophe , Alberti Fabrizio
Published: August 2024

Pleurotin is a meroterpenoid specialised metabolite made by the fungusHohenbuehelia grisea, and it is a lead anticancer molecule due to its irreversible inhibition of the thioredoxin-thioredoxin reductase system. Total synthesis of pleurotin has previously been achieved, including through a stereoselective route, however its biosynthesis has not been characterised. In this study, we used isotope-labelled precursor feeding to show that the non-terpenoid quinone ring of pleurotin and its congeners is derived from phenylalanine. We sequenced the genome of the pleurotin-producing fungus and used comparative transcriptomics to identify putative genes involved in pleurotin biosynthesis. Additionally, the heterologous expression of a UbiA-like prenyltransferase fromH. grisearesulted in the isolation and characterisation of the first predicted pleurotin biosynthetic intermediate, 3-farnesyl-4-hydroxybenzoic acid. This work sets the foundation to fully elucidate the biosynthesis of pleurotin and its congeners, with long-term potential to optimise their production for therapeutic use and engineer the pathway towards the biosynthesis of valuable analogues.
Artificial selection for adult predation survival impacts life history and morphology in guppies (Poecilia reticulata)
Authors: De Waele Hannah , Vega-Trejo Regina , Vila-Pouca Catarina , Noordenbos Jori , Phillips Elizabeth , Pollux Bart J.A. , Kotrschal Alexander
Published: August 2024

Predation is accepted as a major evolutionary driver of life history and morphology. However, whether these traits evolve directly via predation or via indirect effects is largely unresolved. We used artificial selection over three generations to experimentally test the impact of adult predation on the evolution of life history and morphology in guppies (Poecilia reticulata). We found that, compared to control fish, predation-selected fish produced larger offspring and larger broods early in life. However, other life history parameters, such as interbrood interval and total number of offspring, showed no response. We also found that predation-selected for smaller and lighter females and for shorter tails and gonopodia in males, with no effect on body colouration. Our results show that while several traits evolve fast under selection on adult predation, several ‘classic’ predation-dependent traits seem unaffected by predation selection. By comparing our experimental results to those from natural populations we can disentangle the contribution of direct and indirect effects on trait evolution under predation pressure.
Development of a highly-sensitive method to detect the carriage of carbapenem-resistantPseudomonas aeruginosain humans
Authors: Shahab Selvi N. , van Veen Anneloes , Kempenaars Nikita , Rijfkogel Amber , Schmitt Heike , Saharman Yulia R. , Vos Margreet C. , Karuniawati Anis , Severin Juliëtte A.
Published: August 2024

Carbapenem-resistantPseudomonas aeruginosa(CRPA) causes severe and potentially life-threatening infections in hospitalized patients with mortality rates of more than 40%. To detect CRPA carriage in humans for surveillance purposes or to prevent spread and outbreaks in hospitals, a highly-sensitive culture method for CRPA carriage in humans is needed. We aimed to develop such a highly-sensitive method, that would be feasible in laboratories with limited resources. In this study, seven well-defined CRPA strains belonging to high-risk clones were used, including one CRPA without a carbapenemase gene and six carbapenem-resistant isolates with carbapenemase genes. We applied a stepwise approach wherein we included four enrichment broths and eightPseudomonas aeruginosa-selective culture media. Spiking experiments were performed to further evaluate the combination of the most sensitive enrichment broths and selective agar plates in human samples. The two most sensitive enrichments broths were TSB-vancomycin and TSB-vancomycin with 2 mg/L imipenem and the most sensitive selective agar plates werePseudomonasisolation agar Becton Dickinson,Pseudomonasisolation agar Sigma-Aldrich, and M-PA-C (Becton Dickinson). After the spiking experiment, the best method for detecting CRPA based on the sensitivity and the selectivity was the combination of TSB-vancomycin with 2 mg/L imipenem as an enrichment broth for overnight incubation, followed by subculturing the broth on M-PA-C agar plate. We have thus developed a highly-sensitive selective method to detect CRPA carriage in humans, which can also be applied in limited-resource laboratories. This may contribute to an overall effort to control CRPA.
The city and forest bird flock together in a common garden: genetic and environmental effects drive urban phenotypic divergence
Authors: Thompson M.J. , Réale D. , Chenet B. , Delaitre S. , Fargevieille A. , Romans M. , Caro S.P. , Charmantier A.
Published: August 2024

Urban phenotypic divergences are documented across diverse taxa, but the underlying genetic and environmental drivers behind these phenotypic changes are unknown in most wild urban systems. We conduct a common garden experiment using great tit (Parus major) eggs collected along an urbanization gradient to: 1) determine whether documented morphological, physiological, and behavioural shifts in wild urban great tits are maintained in birds from urban and forest origins reared in a common garden (N = 73) and 2) evaluate how different sources of genetic, early maternal investment, and later environmental variation contributed to trait variation in the experiment. In line with the phenotypic divergence in the wild, common garden birds from urban origins had faster breath rates (i.e., higher stress response) and were smaller than birds from forest origins, while wild differences in aggression and exploration were not maintained in the experiment. Differences between individuals (genetic and environmentally induced) explained the most trait variation, while variation among foster nests and captive social groups was limited. Our results provide trait-specific evidence of evolution in an urban species where genetic change likely underlies urban differences in morphology and stress physiology, but that urban behavioural divergences are more strongly driven by plasticity.
Inpp5e Is Critical for Photoreceptor Outer Segment Maintenance
Authors: Gupta Mohona , Lewis Tylor R. , Stuck Michael W. , Spencer William J. , Klementieva Natalia V. , Arshavsky Vadim Y. , Pazour Gregory J.
Published: August 2024

In humans, inositol polyphosphate-5-phosphatase e (INPP5E) mutations cause retinal degeneration as part of Joubert and MORM syndromes and can also cause non-syndromic blindness. In mice, mutations cause a spectrum of brain, kidney, and other anomalies and prevent the formation of photoreceptor outer segments. To further explore the function of Inpp5e in photoreceptors, we generated conditional and inducible knockouts of mouseInpp5ewhere the gene was deleted either during outer segment formation or after outer segments were fully formed. In both cases, the loss of Inpp5e led to severe defects in photoreceptor outer segment morphology and ultimately photoreceptor cell loss. The primary morphological defect consisted of outer segment shortening and reduction in the number of newly forming discs at the outer segment base. This was accompanied by structural abnormalities of the Golgi apparatus, mislocalized rhodopsin, and an accumulation of extracellular vesicles. In addition, knockout cells showed a reduction in the size and prevalence of the actin network at the site of new disc morphogenesis and the occasional formation of membrane whorls instead of discs in a subset of cells. Together, these data demonstrate that Inpp5e plays a critical role in maintaining the outer segment and the normal process of outer segment renewal depends on the activity of this enzyme.
Microbiome diversity, intra-mucosal bacteria and immune integration within normal and asthmatic airway mucosa
Authors: Moffatt Miriam F. , Nishimura Tamiko , Cox Michael J. , McBrien Claire , Burke Conor , Cuthbertson Leah , Lewis Keir , Attanoos Richard , Davies Gwyneth , Chung Kian Fan , Robertus Jan Lukas , Ish-Horowicz Jonathan , O’Carroll Orla , Bozeman John M. , McGowan Aisling , Hopkin Julian M. , Lathrop G. Mark , Riazalhosseini Yasser , Cookson William O.C.
Published: August 2024

Asthma is characterized by reduced bronchial bacterial diversity and airway mucosal disruption. We examined spatial distributions of microbial sequences and host mucosal transcripts in bronchial biopsies from healthy controls and adult asthmatics. Bacteria were discovered by 16S ribosomal RNA staining in the lamina propria of all biopsies, with counts positively associated to lumenal bacterial diversity. Weighted correlation network analysis identified fifteen co-expression networks, including distinct programs of adaptive and innate immunity in differing spatial distributions. Stromal bacterial counts correlated significantly with eight of the network eigenvectors in directions compatible with beneficial relationships. The results suggest that dysbiosis may affect mucosal immunity through impaired interactions beneath the epithelial border. Intra-mucosal companion bacteria may be a potential substrate for selective management of immunity in a wide range of diseases.

One-Sentence Summary

The lung microbiome extends within the airway mucosa and associates spatially and functionally with immune networks.
Tracing active members in microbial communities by BONCAT and click chemistry-based enrichment of newly synthesised proteins
Authors: Hellwig Patrick , Kautzner Daniel , Heyer Robert , Dittrich Anna , Wibberg Daniel , Busche Tobias , Winkler Anika , Reichl Udo , Benndorf Dirk
Published: August 2024

A comprehensive understanding of microbial community dynamics is fundamental to the advancement of environmental microbiology, human health, and biotechnology. Metaproteomics, i.e. the analysis of all proteins in a microbial community, provides insights into these complex systems. Microbial adaptation and activity depend to an important extent on newly synthesized proteins (nP), however, the distinction between nP and bulk proteins is challenging. The application of bioorthogonal non-canonical amino acid tagging (BONCAT) with click chemistry has demonstrated efficacy in the enrichment of nP in pure cultures. However, the transfer of this technique to microbial communities has proven challenging and has therefore not been used on microbial communities before. To address this, a new workflow with efficient and specific nP enrichment was developed using a laboratory-scale mixture of labelledE. coliand unlabelled yeast. This workflow was successfully applied to an anaerobic microbial community with initially low BONCAT efficiency. A substrate shift from glucose to ethanol selectively enriched nP with minimal background. The identification of bifunctional alcohol dehydrogenase and a syntrophic interaction between an ethanol-utilizing bacterium and two methanogens (hydrogenotrophic and acetoclastic) demonstrates the potential of metaproteomics targeting nP to trace microbial activity in complex microbial communities.