bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of backscatter radiation on the occupational eye-lens dose
Authors: Ohno Saya , Konta Satoe , Shindo Ryota , Yamamoto Keisuke , Isobe Rio , Inaba Yohei , Suzuki Masatoshi , Zuguchi Masayuki , Chida Koichi
Published: May 2024

We quantified the level of backscatter radiation generated from physicians’ heads using a phantom. We also evaluated the shielding rate of the protective eyewear and optimal placement of the eye-dedicated dosimeter (skin surface or behind the Pb-eyewear). We performed diagnostic X-rays of two head phantoms: Styrofoam (negligible backscatter radiation) and anthropomorphic (included backscatter radiation). Radiophotoluminescence glass dosimeters were used to measure the eye-lens dose, with or without 0.07-mm Pb-equivalent protective eyewear. We used tube voltages of 50, 65 and 80 kV because the scattered radiation has a lower mean energy than the primary X-ray beam. The backscatter radiation accounted for 17.3–22.3% of the eye-lens dose, with the percentage increasing with increasing tube voltage. Furthermore, the shielding rate of the protective eyewear was overestimated, and the eye-lens dose was underestimated when the eye-dedicated dosimeter was placed behind the protective eyewear. We quantified the backscatter radiation generated from physicians’ heads. To account for the effect of backscatter radiation, an anthropomorphic, rather than Styrofoam, phantom should be used. Close contact of the dosimeter with the skin surface is essential for accurate evaluation of backscatter radiation from physician’s own heads. To assess the eye-lens dose accurately, the dosimeter should be placed near the eye. If the dosimeter is placed behind the lens of the protective eyewear, we recommend using a backscatter radiation calibration factor of 1.2–1.3.
Genetically engineered Lactococcus lactis strain constitutively expresses GABA-producing genes and produces high levels of GABA
Authors: Monteiro Marcos P , Kohl Hannah M , Roullet Jean-Baptiste , Gibson K Michael , Ochoa-Repáraz Javier , Castillo Andrea R
Published: May 2024

γ-Aminobutyric acid (GABA) is an inhibitory neurotransmitter of the central nervous system that impacts physical and mental health. Low GABA levels have been documented in several diseases, including multiple sclerosis and depression, and studies suggest that GABA could improve disease outcomes in those conditions. Probiotic bacteria naturally produce GABA and have been engineered to enhance its synthesis. Strains engineered thus far use inducible expression systems that require the addition of exogenous molecules, which complicates their development as therapeutics. This study aimed to overcome this challenge by engineering Lactococcus lactis with a constitutive GABA synthesis gene cassette. GABA synthesizing and transport genes (gadB and gadC) were cloned onto plasmids downstream of constitutive L. lactis promoters [P2, P5, shortened P8 (P8s)] of different strengths and transformed into L. lactis. Fold increase in gadCB expression conferred by these promoters (P2, P5, and P8s) was 322, 422, and 627, respectively, compared to the unmodified strain (P = 0.0325, P8s). GABA synthesis in the highest gadCB expressing strain, L. lactis-P8s-glutamic acid decarboxylase (GAD), was dependent on media supplementation with glutamic acid and significantly higher than the unmodified strain (P < 0.0001, 125 mM, 200 mM glutamic acid). Lactococcus lactis-P8s-GAD is poised for therapeutic testing in animal models of low-GABA-associated disease.
A path towards constraining the evolution of the interstellar medium and outflows in the Milky Way using APOGEE
Authors: Sharda Piyush , Ting Yuan-Sen , Frankel Neige
Published: May 2024

In recent years, the study of the Milky Way has significantly advanced due to extensive spectroscopic surveys of its stars, complemented by astroseismic and astrometric data. However, it remains disjoint from recent advancements in understanding the physics of the Galactic interstellar medium (ISM). This paper introduces a new model for the chemical evolution of the Milky Way that can be constrained on stellar data, because it combines a state-of-the-art ISM model with a Milky Way stellar disc model. Utilizing a data set of red clump stars from APOGEE, known for their precise ages and metallicities, we concentrate on the last 6 billion years – a period marked by Milky Way’s secular evolution. We examine the oxygen abundance in the low-$\alpha$ disc stars relative to their ages and birth radii, validating or constraining critical ISM parameters that remain largely unexplored in extragalactic observations. The models that successfully reproduce the radius–metallicity distribution and the age–metallicity distribution of stars without violating existing ISM observations indicate a need for modest differential oxygen enrichment in Galactic outflows, meaning that the oxygen abundance of outflows is higher than the local ISM abundance, irrespective of outflow mass loading. The models also suggest somewhat elevated ISM gas velocity dispersion levels over the past 6 billion years compared to galaxies of similar mass. The extra turbulence necessary could result from energy from gas accretion onto the Galaxy, supernovae clustering in the ISM, or increased star formation efficiency per freefall time. This work provides a novel approach to constraining the Galactic ISM and outflows, leveraging the detailed insights available from contemporary Milky Way surveys.
Voices Unveiled: Personal Reflections of Faculty of Color in Nursing Academia
Authors: Brockett-Walker Camille , Moore Erica
Published: May 2024

The presence of faculty of color (FOC) provides critical role modeling and mentorship for diverse students and thereby contributes to increasing diversity in the nursing workforce. Personal reflections of FOC within a predominantly White institution involved feelings of isolation, not belonging, and lacking support and mentorship. Addressing negative experiences of FOC supports retention and advances diversity, equity, and inclusion.
Acute Venous Thromboembolism Is Common Following Acute Necrotizing Pancreatitis and Is Associated With Worse Clinical Outcomes
Authors: Singh Ritu R. , Thandassery Ragesh B. , Chawla Saurabh
Published: May 2024

Objectives

Although splanchnic vein thrombosis (SVT) is a well-known local complication of acute pancreatitis, extrasplanchnic venous thromboembolism (ESVT) is inadequately studied. Here, we aim to explore the incidence of venous thromboembolism (VTE) in acute necrotizing pancreatitis (ANP) and the associated mortality.

Methods

Adults with a diagnosis of ANP from January 2017 to December 2022 were identified using appropriate International Classification of Diseases, 10th Revision, Clinical Modification codes. The primary outcome was development of acute ESVT within 1 month of ANP. Secondary outcomes were 90-day mortality, 30-day rehospitalization, and oral anticoagulant (OAC) use in patients with ESVT. Propensity score matching (1:1) was performed for baseline characteristics and common comorbidities.

Results

During the study period, 17,942 (7.11%) patients were diagnosed with ANP, and about 10% (1,737) of them had a diagnosis of ESVT. Of all VTEs, 61% were ESVT with or without SVT, and 63% (n = 1799) were SVT. Ninety-day mortality (16.3% vs 5.7%; risk ratio [RR], 2.86; 95% confidence interval, 2.29–3.56) and 30-day rehospitalization (31% vs 19%; RR, 1.63; 95% confidence interval, 1.49–1.79) were higher in patients with ESVT compared with non-VTE patients. Sixty percent of patients with ESVT were on OAC, and OAC use was associated with lower 90-day mortality (8.9% vs 19.4%; RR, 0.46) without increased risk of adverse events (acute gastrointestinal bleeding, intracranial bleeding, or need for transfusion).

Conclusions

Systemic VTE is common in patients with ANP and may contribute to increased mortality and risk of readmissions. Prospective studies can confirm our findings and explore the role of aggressive VTE prophylaxis in patients with ANP during hospital stay and in the immediate ambulatory period.
ELISA for leptospiral 3-hydroxyacyl-CoA dehydrogenase in urine is a promising screening tool for acute leptospirosis
Authors: Karunadasa A.K.U.I. , Toma C. , Senaratne P. , Kumara K.G.R.A. , Herath T.M. , Pathirage M.M.K. , Gamage C.D.
Published: May 2024

Introduction. Leptospirosis is a zoonotic disease that is prevalent worldwide. Leptospiral 3-hydroxyacyl-CoA dehydrogenase (3-HADH) is excreted in the urine of infected individuals. However, the potential use of 3-HADH as a biomarker for the diagnosis of leptospirosis using enzyme-linked immunosorbent assay (ELISA) has not been investigated. A technique that identifies Leptospira in a patient in urine sample will be valuable in regular diagnostics and epidemic scenarios, as opposed to existing serological approaches. This study aimed to develop and evaluate an ELISA that can detect 3-HADH in the urine of patients with confirmed acute leptospirosis and to assess its potential as a screening test for leptospirosis.

Methods. Laboratory confirmation of acute leptospirosis was done by flaB-nested polymerase chain reaction (PCR) of plasma samples from suspected patients. ELISA-based determination of the presence of 3-HADH in the urine of PCR-positive patients versus PCR-negative patients matched for fever date was performed by coating ELISA plates with urine supernatants and using rabbit anti-3-HADH as the primary antibody. Receiver operating characteristic curve analysis was used to determine the cutoff values for the ELISA. The diagnostic measures between the PCR-positive and PCR-negative patients were compared using the Mann–Whitney U test.

Results. In total, 158 febrile patients were assessed, of whom 121 (76.6 %) were male. Of the 15 flaB-nested PCR-positive patients, 12 were in the acute phase of the febrile illness. The best cutoff was an average optical density (ODav) value of 0.2200 for febrile patients. Sensitivity and specificity were 83.33% [95 % confidence interval (CI), 51.59–97.91 %) and 83.33 % (95 % CI, 76.05–89.13 %), respectively. The ODav values for PCR-positive patients in the acute phase of the disease (≤7 days of fever) were significantly higher than those for PCR-negative patients (P<0.001, U=114.0, z=−4.946).

Conclusion. Detection of 3-HADH in urine by ELISA appears to be promising for the screening of acute leptospirosis in suspected patients.
Differential Effects of Ganglioside Lipids on the Conformation and Aggregation of Islet Amyloid Polypeptide
Authors: McCalpin Samuel D. , Mechakra Lina , Ivanova Magdalena I. , Ramamoorthy Ayyalusamy
Published: May 2024

Despite causing over 1 million deaths annually, Type 2 Diabetes (T2D) currently has no curative treatments. Aggregation of the islet amyloid polypeptide (hIAPP) into amyloid plaques plays an important role in the pathophysiology of T2D and thus presents a target for therapeutic intervention. The mechanism by which hIAPP aggregates contributes to the development of T2D is unclear but are proposed to involve disruption of cellular membranes. However, nearly all research on hIAPP-lipid interactions has focused on anionic phospholipids, which are primarily present in the cytosolic face of plasma membranes. We seek here to characterize the effects of three gangliosides, the dominant anionic lipids in the outer leaflet of the plasma membrane, on the aggregation, structure, and toxicity of hIAPP. Our results show a dual behavior that depends on the molar ratio between the gangliosides and hIAPP. For each ganglioside, a low lipid:peptide ratio enhances hIAPP aggregation and alters the morphology of hIAPP fibrils, while a high ratio eliminates aggregation and stabilizes an α-helix-rich hIAPP conformation. A more negative lipid charge more efficiently promotes aggregation, and a larger lipid headgroup improves inhibition of aggregation. hIAPP also alters the phase transitions of the lipids, favoring spherical micelles over larger tubular micelles. We discuss our results in the context of available lipid surface area for hIAPP binding and speculate on a role for gangliosides in facilitating toxic hIAPP aggregation.
Parental assigned chromosomes for cultivated cacao provides insights into genetic architecture underlying resistance to vascular streak dieback
Authors: Tobias Peri A , Downs Jacob , Epaina Peter , Singh Gurpreet , Park Robert F , Edwards Richard J , Brugman Eirene , Zulkifli Andi , Muhammad Junaid , Purwantara Agus , Guest David I
Published: May 2024

Diseases ofTheobroma cacao disruptcocoa bean supply and have economic impacts to growers. Vascular streak dieback (VSD), caused byCeratobasidium theobromae, is a new encounter disease of cacao currently contained to southeast Asia and Melanesia. Resistance to VSD has been tested with large progeny trials in Sulawesi and Papua New Guinea with the identification of informative quantitative trait loci (QTL). Using a VSD susceptible progeny tree (clone 26), derived from a resistant and susceptible parental cross, we assembled the genome to chromosome-level and discriminated alleles inherited from either resistant or susceptible parents. The parentally phased genomes were annotated for all predicted genes and then specifically for resistance genes of thenucleotide binding site leucine rich repeat class(NLR). On investigation, we determined the presence of NLR clusters at informative QTLs, as well as other potential disease response gene candidates. Understanding the genetics underlying resistance and susceptibility to VSD will accelerate the breeding cycle by providing clear targets for molecular screening. Additionally, we provide the first diploid, fully scaffolded and parentally phased genome resource forTheobroma cacaoL.
Early male and female footprints of modern humans across Eurasia and Australasia
Authors: Cabrera Vicente M.
Published: May 2024

As an alternative to a recent coastal southern route followed by modern humans to colonize Eurasia after an Out of Africa around 60 Kya, and under the premise that the evolutionary rate based coalescent ages slowdown going backwards in time, I propose a new model based on phylogenetic and phylogeographic analyses of uniparental markers in present and past modern human populations across Eurasia and Australasia.

The archaeological record favors a northern route that reached China around 120 kya and then descended latitudinally reaching Southeast Asia and islands around 70-60 kya. These ages coincide with the basal split of the mtDNA macrohaplogroup L3’4* and the origin of the Y-chromosome macrohaplogroup CT* and the subsequent splits in Eurasia of mtDNA haplogroups M and N and Y-chromosome C, D and F clades respectively.

Roughly at the same time modern humans arrived in Australasia other groups retreated southwest returning to Africa carrying with them mtDNA L3 and Y-Chromosome E lineages.

Southeast Asia and Southwest-Central Asia were the subsequent demographic centers for the respective colonization of East and northern Asia and Europe. Across the Ganges-Brahmaputra and the Indus valleys, South Asia was colonized from both migratory centers.
Kinetic Diagram Analysis: A Python Library for Calculating Steady-State Observables of Biochemical Systems Analytically
Authors: Awtrey Nikolaus Carl , Beckstein Oliver
Published: May 2024

Kinetic diagrams are commonly used to represent biochemical systems in order to study phenomena such as free energy transduction and ion selectivity. While numerical methods are commonly used to analyze such kinetic networks, the diagram method by King, Altman and Hill makes it possible to construct exact algebraic expressions for steady-state observables in terms of the rate constants of the kinetic diagram. However, manually obtaining these expressions becomes infeasible for models of even modest complexity as the number of the required intermediate diagrams grows with the factorial of the number of states in the diagram. We developedKinetic Diagram Analysis(KDA), a Python library that programmatically generates the relevant diagrams and expressions from a user-defined kinetic diagram.KDAoutputs symbolic expressions for state probabilities and cycle fluxes at steady-state that can be symbolically manipulated and evaluated to quantify macroscopic system observables. We demonstrate theKDAapproach for examples drawn from the biophysics of active secondary transmembrane transporters. For a generic 6-state antiporter model, we show how the introduction of a single leakage transition reduces transport efficiency by quantifying substrate turnover. We applyKDAto a real-world example, the 8-state free exchange model of the small multidrug resistance transporter EmrE of Hussey et al (J General Physiology152(2020), e201912437), where a change in transporter phenotype is achieved by biasing two different subsets of kinetic rates: alternating access and substrate unbinding rates.KDAis made available as open source software under the GNU General Public License version 3.
A viral vaccine design harnessing prior BCG immunization confers protection against Ebola virus
Authors: Ng Tony W. , Furuyama Wakako , Wirchnianski Ariel S. , Saavedra-Ávila Noemí A. , Johndrow Christopher T. , Chandran Kartik , Jacobs William R. , Marzi Andrea , Porcelli Steven A.
Published: May 2024

Previous studies have demonstrated the efficacy and feasibility of an anti-viral vaccine strategy that takes advantage of pre-existing CD4+helper T (Th) cells induced byMycobacterium bovisbacille Calmette-Guérin (BCG) vaccination. This strategy uses immunization with recombinant fusion proteins comprised of a cell surface expressed viral antigen, such as a viral envelope glycoprotein, engineered to contain well-defined BCG Th cell epitopes, thus rapidly recruiting Th cells induced by prior BCG vaccination to provide intrastructural help to virus-specific B cells. In the current study, we show that Th cells induced by BCG were localized predominantly outside of germinal centers and promoted antibody class switching to isotypes characterized by strong Fc receptor interactions and effector functions. Furthermore, BCG vaccination also upregulated FcγR expression to potentially maximize antibody-dependent effector activities. Using a mouse model of Ebola virus (EBOV) infection, this vaccine strategy provided sustained antibody levels with strong IgG2c bias and protection against lethal challenge. This general approach can be easily adapted to other viruses, and may be a rapid and effective method of immunization against emerging pandemics in populations that routinely receive BCG vaccination.
Identification of Respiratory Diseases using Peak Energy Analysis of Acoustic Cough
Authors: Chandy Sujith Thomas , Thangakunam Balamugesh , Rudraraju Gowrisree , Sripada Narayana Rao , Govindaraj Jayanthy , Gottipulla Charishma , Mamidgi Baswaraj , Palreddy Shubha Deepti , Bhoge Nikhil kumar Reddy , Narreddy Harsha Vardhan Reddy , P Prasanna Samuel , Christopher Devasahayam Jesudas , Yechuri Venkat
Published: May 2024

Background and Objectives

Cough is a common symptom of respiratory diseases and change in the cough sound can reflect a pathological condition in the lungs. Recent advancement on the analysis of the cough sound has suggested that it has the potential to be used as a non-invasive marker for screening respiratory conditions, such as Asthma, Chronic Pulmonary Obstructive Disease (COPD), Interstitial Lung Disease (ILD) and Bronchiectasis. The energy envelope is distinguishable for normal subjects versus subjects with respiratory conditions. Peak analysis of the energy envelope helps in quantifying the feature variation for these conditions.

This study provides the variation of the peak energy features on the Root Mean Square Energy (RMSE) envelope of cough sounds using machine learning tools. Peak properties of energy contours like peak height, peak prominence, base distance (distance between left and right base of a peak) help in quantifying cough patterns.

Methods and Materials

Patients presenting with respiratory symptoms to the hospital were recruited to the study. Their cough sounds were recorded through a mobile application. The cough sounds were labeled with corresponding pathologies from spirometry. From every subject three audio recordings were collected before taking a spirometry test. Peak analysis is performed on the features extracted from cough audio signals. Peak features are extracted using the function “scipy.signal.find_peaks” from python’s Scipy library. The comparison of these features are done against the clinical diagnosis which the physician finally arrives at after going through the history, spirometry and radiology as per the standard of practice.

Results

The peak analysis in Asthma shows higher base distance and peak height than that of Normal because of prolonged expulsion and airways constriction. The base distance is observed high in Bronchiectasis but peak height and prominence are less when compared with Normal due to loss of elasticity in the airways. Whereas in COPD the base distance and prominence are found to be less than Normal, Asthma and Bronchiectasis which is attributed to multiple narrowing of the glottis. Additionally, the energy peak heights of the cough were observed to be very close due to conditions like excess mucus, airways inflammation, destruction of lung tissue in COPD.

Conclusion

Peak analysis of cough provides inferences which can be used as descriptors to differentiate coughs related to respiratory diseases. This study helps us to enhance the performance of Machine Learning models by including the peak energy related features. This peak analysis along with frequency spectral analysis can also be further used in detecting other respiratory conditions.
Unveiling the role of mosquito and human diel activity patterns in the risk of mosquito-borne disease infection
Authors: Ventura Paulo C. , Wilke Andre B.B. , Chitturi Jagadeesh , Kummer Allisandra G. , Agrawal Snigdha , Vasquez Chalmers , Gonzalez Yaziri , Litvinova Maria , Mutebi John-Paul , Ajelli Marco
Published: May 2024

Background

Mosquito-borne pathogens are transmitted through bites of female mosquito vectors that are actively seeking hosts for a blood meal and hosts, when either of them is infectious. Different mosquito species have different preferences for the time of the day/night when they actively seek blood meals. In the United States, the encounters between mosquito vectors and human hosts primarily take place outdoors. Socioeconomic factors such as occupation and income are major determinants of the hour of the day and total amount of time spent outdoors by different population groups. The aim of this study is to quantify: i) diel variations in the level of human exposure to mosquito vectors, and ii) exposure heterogeneities by human population group.

Methods

We collected both diel activity data for two mosquito vector species (Aedes aegyptiandCulex quinquefasciatus) and time-use data for the United States. Then, we analyzed the diel overlap between the two at the population level and by human population group.

Results

For both mosquito species, we found a substantial heterogeneity in their diel overlap with human outdoors activities. We estimated that the time periods with the highest risk of exposure to bites ofAe. aegyptiare 7am-11am and 5pm-8pm, while the highest risk forCx. Quinquefasciatusis 6am-7am and 6pm-9pm. Moreover, we found disparities in the exposure to mosquito vector species across different demographic groups. Workers with primarily outdoor occupations, males, and Hispanics/Latinos were shown to have higher levels of exposure as compared to the general population. In particular, we estimated that workers with primarily outdoor occupations were 7.50-fold (95%CI: 7.18-7.84) and 6.63-fold (95%CI: 6.09-7.35) more exposed toAe. aegyptiandCx. quinquefasciatusthan the general population, respectively.

Conclusion

This study serves as a steppingstone to quantify the risk of exposure to mosquito vector species in the United States. The obtained results can be instrumental for the design of public health interventions such as education campaigns, which could contribute to improve health and health equity.
Gray matter morphology and pain-related disability in young adults with low back pain
Authors: Armour Smith Jo , Tain Rongwen , Chrisman Isaac , Sharp Kelli G. , Glynn Laura M , Van Dillen Linda R. , Jacobs Jesse V. , Cramer Steven C.
Published: May 2024

Structural neuroplasticity in the brain may contribute to the persistence of low back pain (LBP) symptoms and the disability associated with them. It is not known if structural adaptations are evident early in the lifespan in young adults with LBP. This study compared gray matter in cortical sensorimotor regions in young adults with and without persistent LBP and identified gray matter and clinical predictors of pain-related disability. Eighty-two individuals with and without a history of LBP participated. Peak and average gray matter density in cortical sensorimotor regions of interest was quantified using voxel-based morphometry. Pain-related disability, pain intensity, pain duration, and pain-related fear were also assessed. Multiple linear regression was used to determine independent predictors of pain-related disability. We document significantly greater peak gray matter density in individuals with LBP in the primary somatosensory cortex, angular gyrus, and the midcingulate cortex. Pain-related disability positively correlated with average gray matter density in the posterior cingulate cortex. The most robust predictors of disability were average gray matter in the posterior cingulate, pain intensity, and pain-related fear. We demonstrate that in young adults, persistent LBP, and pain-related disability, are linked with structural neuroplasticity in regions forming part of the brain network termed the pain matrix. In contrast with studies of LBP in older adults, our findings of increased rather than decreased gray matter in young adults with LBP suggest that gray matter may increase initially in response to nociceptive pain.
Modeling disease progression in spinocerebellar ataxias
Authors: Georgii Elisabeth , Klockgether Thomas , Jacobi Heike , Schmitz-Hubsch Tanja , Ashizawa Tetsuo , Kuo Sheng-Han , Elter Tim , Piraud Marie ,   ESMI study group,   EUROSCA study group,   RISCA study group,   CRC-SCA study group,   SCA-Registry study group, Faber Jennifer
Published: May 2024

Background and objectives

The most common autosomal-dominantly inherited spinocerebellar ataxias (SCA), SCA1, SCA2, SCA3 and SCA6, account for more than half of all SCA families. Disease course is characterized by progressive ataxia and additional neurological signs. Each of these SCAs is caused by a CAG repeat expansion, leading to an expanded polyglutamine stretch in the resulting type-specific protein. To comparatively investigate determinants of disease progression, we analyzed demographic and genetic data and three-year clinical time courses of neurological symptoms. The aim was to provide tailored marker candidates and prediction models to support type-specific clinical monitoring and trial design.

Methods

To analyze relationships among the different neurological symptoms, we examined co-occurrence patterns of deterioration events. Predicting disease progression was treated as a survival analysis problem.

Results

The data set contained 1538 subjects from five different longitudinal cohorts and 3802 visits. The pattern of neurological symptoms that showed progression varied with the SCA type. Mining of the progression data revealed the Scale for the Assessment and Rating of Ataxia (SARA) sum score to be the most representative descriptor of disease progression, reflecting progression of the majority of the other included symptoms. We trained models for predicting the progression of each neurological symptom for each SCA type from genetic features, age and symptoms at the baseline visit. The most universal predictors included the SARA sum score, gait and the CAG repeat length of the expanded allele. Finally, deterioration in disease staging was studied in detail: For the milestones of deterioration, (i) the need to use walking aids and (ii) the requirement to use a wheelchair, we discovered common as well as diverging predictive markers. For clinical interpretability, a decision tree was built to indicate the probability of progression within 3 years in dependence of the top predictive features.

Discussion

Data-driven approaches are potent tools to identify the main contributing features of progression prediction. Progression events for the disease stage were predictable from the baseline neurological status. Remarkably, a limited number of features had predictive importance, and only few were shared among all four SCA types, including gait and the SARA sum score, confirming the need for type-specific models.
Preventing CpG island hypermethylation in oocytes safeguards mouse development
Authors: Kawamura Yumiko K. , Ozonov Evgeniy A. , Papasaikas Panagiotis , Kondo Takashi , Nguyen Nhuong V. , Stadler Michael B. , Smallwood Sebastien A. , Koseki Haruhiko , Peters Antoine H.F.M
Published: May 2024

In mammalian somatic and male germline cells, genomes are extensively DNA methylated (DNAme). In oocytes, however, DNAme is largely limited to transcribed regions only. Regulatory CpG-island (CGI) sequences are also devoid of repressive DNAme in somatic and germ cells of both sexes. The mechanisms restrictingde novoDNAme acquisition in developing oocytes, at CGIs and globally, and the relevance thereof for regulating zygotic gene expression and embryo development after fertilization are largely unknown. Here we show that the histone H3 lysine 36 dimethyl (H3K36me2) demethylases KDM2A and KDM2B prevent genome-wide accumulation of H3K36me2, thereby impeding global DNMT3A-catalyzedde novoDNAme, including at CGI gene promoters. By recruiting variant Polycomb Repressive Complex 1 (vPRC1), they further control H2A mono-ubiquitin deposition and vPRC1-dependent gene repression. Through genetic perturbations, we demonstrate that aberrantDnmt3a-dependent DNAme established inKdm2a/Kdm2bdouble mutant oocytes represses transcription from maternal loci in two-cell embryos. The lethality ofKdm2a/Kdm2bmaternally deficient pre-implantation embryos is suppressed byDnmt3adeficiency during oogenesis. Hence, KDM2A/KDM2B are essential for confining the oocyte DNA methylome, conferring competence for early embryonic development. Our research implies that the reprogramming capacity eminent to early embryos is insufficient to erase aberrant DNAme from maternal chromatin, and that early development is vulnerable to gene dosage haplo-insufficiency effects.

HIGHLIGHTS

Demethylation of H3K36me2 by KDM2A and KDM2B prevents aberrant de novo DNA methylation in mouse oocytes.

Sequence composition and H3K4me3 modulate the probability for aberrant H3K36me2 and DNA methylation at CpG islands.

Aberrant oocyte DNA methylation is not reprogrammed in early embryos and suppresses maternal gene transcription.

Aberrant oocyte DNA methylation causes embryonic lethality during pre-implantation development.

GRAPHICAL SUMMARY
Real-time optimization to enhance noninvasive cortical excitability assessment in the human dorsolateral prefrontal cortex
Authors: Parmigiani Sara , Cline Christopher C. , Sarkar Manjima , Forman Lily , Truong Jade , Ross Jessica M. , Gogulski Juha , Keller Corey J.
Published: May 2024

Objective

We currently lack a robust noninvasive method to measure prefrontal excitability in humans. Concurrent TMS and EEG in the prefrontal cortex is usually confounded by artifacts. Here we asked if real-time optimization could reduce artifacts and enhance a TMS-EEG measure of left prefrontal excitability.

Methods

This closed-loop optimization procedure adjusts left dlPFC TMS coil location, angle, and intensity in real-time based on the EEG response to TMS. Our outcome measure was the left prefrontal early (20-60 ms) and local TMS-evoked potential (EL-TEP).

Results

In 18 healthy participants, this optimization of coil angle and brain target significantly reduced artifacts by 63% and, when combined with an increase in intensity, increased EL-TEP magnitude by 75% compared to a non-optimized approach.

Conclusions

Real-time optimization of TMS parameters during dlPFC stimulation can enhance the EL-TEP.

Significance

Enhancing our ability to measure prefrontal excitability is important for monitoring pathological states and treatment response.

Highlights

We developed a real-time closed-loop optimization procedure to obtain high amplitude early local TEPs (EL-TEPs) from dlPFC TMS.

Sequential optimization of coil angle and brain target reduced artifacts by 63%.

Sequential optimization of coil angle, brain target, and intensity increased EL-TEP amplitude by 75%.
Development of non-β-Lactam covalent allosteric inhibitors targeting PBP2a in Methicillin-ResistantStaphylococcus aureus
Authors: Benin Bogdan M. , Kharel Rupak , Hillyer Trae , Sun Chuanqi , Cmolik Anna , Kuebler Taylor , Sham Yuk Yin , Bonomo Robert , Mighion Jeffrey D. , Shin Woo Shik
Published: May 2024

Methicillin-resistantStaphylococcus aureus(MRSA), a Gram-positive bacterial pathogen, continues to pose a serious threat to the current public health system in our society. The high level of resistance to β-lactam antibiotics in MRSA is attributed to the expression of penicillin-binding protein 2a (PBP2a), which catalyzes cell wall cross-linking. According to numerous research reports, the activity of the PBP2a protein is known to be regulated by an allosteric site distinct from the active site where cell wall cross-linking occurs. Here, we conducted a screening of 113 compounds containing a 1,3,4-oxadiazole core to design new covalent inhibitors targeting the allosteric site of PBP2a and establish their structural-activity relationship. The stereochemically selective synthesis of sulfonyl oxadiazole compounds identified in the initial screening resulted in a maximum eightfold enhancement in cell inhibition activity. The sulfonyl oxadiazole-based compounds formulated as PEG-based ointments, with low toxicity test results on human cells (CC50: >78μM), demonstrated potent antimicrobial effects not only in a mouse skin wound infection model but also against oxacillin-resistant clinical isolate MRSA (IC50≈ 1μM), as evidenced by the results. Furthermore, additional studies utilizing LC-MS/MS and in-silico approaches clearly support the allosteric site covalent binding mechanism through the nucleophilic aromatic substitution (SNAr) reaction, as well as its association with the closure of the major active site of PBP2a.
CCR2 silencing in sensory neurons blocks bone cancer progression
Authors: Midavaine Élora , Côté Jérôme , Trépanier Alexandra , Kashem Sakeen W. , Dansereau Marc-André , Longpré Jean-Michel , Charbonneau Martine , Dubois Claire , Jacobi Ashley M. , Rose Scott D. , Belkhe Mark A. , Sarret Philippe
Published: May 2024

The peripheral nervous system has been shown to contribute to cancer growth by expanding the immunological niche. How the nervous system affects bone cancer progression and how neuroimmune pathways can be targeted for cancer treatment are not yet clear. Here, we demonstrate a profound influence of the peripheral nervous system on tumor progression, which can be targeted by silencing neuronal chemokine receptor signaling. We show that axotomy in animals with bone cancer inhibits tumor progression. Conversely, intrathecal injection of a known tumor-associated proinflammatory chemokine, CCL2, promotes tumor growth and allodynia. Silencing CCR2 in DRG neurons through a newly developed gene therapy successfully impedes tumor progression and bone remodeling and relieves bone cancer-associated pain. We demonstrate that the mechanism underlying CCR2-mediated tumor progression involves decreased neuropeptide secretion by peripheral nerves that promote expansion of the tumor-associated macrophage population. Silencing the CCR2 receptor in DRG neurons successfully normalizes the neuropeptide milieu and ameliorates altered bone remodeling. Thus, we have developed a novel therapeutic pathway for targeting a neuroimmune axis that contributes to cancer progression.

Highlights

Cancer progression activates sensory neurons, inducing pain hypersensitivity and neuropeptide release.

Axotomy impedes tumor progression.

CCL2 signaling in DRG neurons induces pain sensitivity and cancer growth.

Silencing CCR2 in the DRG reduces pain sensitivity, tumor-associated macrophage numbers and cancer growth.
Epidemiology ofBurkholderia pseudomallei, Streptococcus suis, Salmonellaspp.,Shigellaspp. andVibriospp. infections in 111 hospitals in Thailand, 2022
Authors: Jitpeera Charuttaporn , Kripattanapong Somkid , Klaytong Preeyarach , Rangsiwutisak Chalida , Wannapinij Prapass , Doungngern Pawinee , Pinyopornpanish Papassorn , Chamawan Panida , Srisuphan Voranadda , Tuamsuwan Krittiya , Boonyarit Phairam , Sripichai Orapan , Hinjoy Soawapak , Stelling John , Turner Paul , Bhunyakitikorn Wichan , Iamsirithaworn Sopon , Limmathurotsakul Direk
Published: May 2024

The information on notifiable diseases in low- and middle-income countries is often incomplete, limiting our understanding of their epidemiology. Our study addresses this knowledge gap by analyzing microbiology laboratory and hospital admission data from 111 of 127 public referral hospitals in Thailand, excluding Bangkok, from January to December 2022. We evaluated factors associated with the incidence of notifiable bacterial diseases (NBDs) caused by 11 pathogens; includingBrucellaspp.,Burkholderia pseudomallei,Corynebacterium diphtheriae,Neisseria gonorrhoeae,Neisseria meningitidis, non-typhoidalSalmonellaspp. (NTS),Salmonella entericaserovar Paratyphi,Salmonella entericaserovar Typhi,Shigellaspp.,Streptococcus suis, andVibriospp.. We used multivariable Poisson random-effects regression models. Additionally, we compared their yearly incidence rates in 2022 with those from 2012-2015 in hospitals where paired data were available. In 2022, the NBD associated with the highest total number of deaths wasB. pseudomallei(4,407 patients; 1,219 deaths) infection, followed by NTS (4,501 patients; 461 deaths) andS. suis(867 patients, 134 deaths) infection. The incidence rate ofB. pseudomalleiandS. suisinfection was highest in the northeast and upper central, respectively. The incidence rate of NTS infection was not associated with geographical region. The yearly incidence rate ofB. pseudomalleiandS. suisinfection in 2022 were higher than those between 2012-2015, while those of fecal-oral transmitted NBDs including NTS infection, typhoid, shigellosis and vibriosis were lower. Overall,B. pseudomalleiandS. suisinfection are emerging and associated with a high number of deaths in Thailand. Specific public health interventions are warranted.
Deep Learning Model of Diastolic Dysfunction Risk Stratifies the Progression of Early-Stage Aortic Stenosis
Authors: Tokodi Márton , Shah Rohan , Jamthikar Ankush , Craig Neil , Hamirani Yasmin , Casaclang-Verzosa Grace , Hahn Rebecca T. , Dweck Marc R. , Pibarot Philippe , Yanamala Naveena , Sengupta Partho P.
Published: May 2024

Background

The development and progression of aortic stenosis (AS) from aortic valve (AV) sclerosis is highly variable and difficult to predict.

Objectives

We investigated whether a previously validated echocardiography-based deep learning (DL) model assessing diastolic dysfunction (DD) could identify the latent risk associated with the development and progression of AS.

Methods

We evaluated 898 participants with AV sclerosis from the Atherosclerosis Risk in Communities (ARIC) cohort study and associated the DL-predicted probability of DD with two endpoints: (1) the new diagnosis of AS and (2) the composite of subsequent mortality or AV interventions. We performed validation in two additional cohorts: 1) patients with mild-to-moderate AS undergoing cardiac magnetic resonance (CMR) imaging and serial echocardiographic assessments (n=50), and (2) patients with AV sclerosis undergoing18F-sodium fluoride (18F-NaF) and18F-fluorodeoxyglucose positron emission tomography (PET) combined with computed tomography (CT) to assess valvular inflammation and calcification (n=18).

Results

In the ARIC cohort, a higher DL-predicted probability of DD was associated with the development of AS (adjusted HR: 3.482 [2.061 – 5.884], p<0.001) and subsequent mortality or AV interventions (adjusted HR: 7.033 [3.036 – 16.290], p<0.001). The multivariable Cox model (incorporating the DL-predicted probability of DD) derived from the ARIC cohort efficiently predicted the progression of AS (C-index: 0.798 [0.648 – 0.948]) in the CMR cohort. Moreover, the predictions of this multivariable Cox model correlated positively with valvular18F-NaF mean standardized uptake values in the PET/CT cohort (r=0.62, p=0.008).

Conclusions

Assessment of DD using DL can stratify the latent risk associated with the progression of early-stage AS.

CONDENSED ABSTRACT

We investigated whether DD assessed using DL can predict the progression of early-stage AS. In 898 patients with AV sclerosis, the DL-predicted probability of DD was associated with the development of AS. The multivariable Cox model derived from these patients also predicted the progression of AS in an external cohort of patients with mild-to-moderate AS (n=50). Moreover, the predictions of this model correlated positively with PET/CT-derived valvular18F-NaF uptake in an additional cohort of patients with AV sclerosis (n=18). These findings suggest that assessing DD using DL can stratify the latent risk associated with the progression of early-stage AS.
Running acceleration correlates with T2 magnetic resonance imaging values of the lumber intervertebral disc
Authors: Hakkaku Takayoshi , Kubo Yoshiaki , Koyama Koji , Nakazato Koichi , Okada Takashi , Hiranuma Kenji
Published: May 2024

Background

Running can contribute to both beneficial and detrimental responses in the intervertebral discs (IVDs). To better understand these effects, we investigated the relationship between loading directions during slow running and the rapid changes in T2 times occurring in the lumbar IVDs before and after running.

Method

Sixteen healthy male students were fitted with a triaxial accelerator and ran on a treadmill at 8 km/h for one minute. Three lumbar T2 times from the L3/L4 to L5/S1 levels were measured before, immediately after, and 30 minutes post-exercise via magnetic resonance imaging (MRI). The analysis focused on five regions of interest within each disc.

Result

Acceleration was 0.23 ± 0.06 root mean square in the mediolateral (X-axis), 1.37 ± 0.08 in the vertical (Y-axis), and 0.30 ± 0.06 in the anteroposterior (Z-axis) direction. A strong correlation was observed between the T2 relaxation times and acceleration, particularly in the Z-axis. At L3/L4, a positive correlation was observed for the posterior nucleus (r = 0.72, p = 0.002, R2 = 0.59). At L4/L5, a positive correlation was observed for the central nucleus (r = 0.73, p = 0.003, R2 = 0.49). At L5/S1, a negative correlation was observed for the anterior annulus fibrosus (r = -0.73, p = 0.01, R2 = 0.48).

Conclusion

These results suggest that anteroposterior loading may play a significant role in the response of the IVDs to running.
BRCA1 Interaction with Non-Canonical DNA Structures: Insights into Genome Maintenance and Disease Mechanisms
Authors: Lowran Kaitlin , Campbell Laura , Cismas Emma , Wu Colin G
Published: May 2024

Breast Cancer Susceptibility Gene 1 (BRCA1) plays a crucial role in the homologous recombination (HR) pathway to repair double-stranded breaks (DSBs) in human cells. Interactions between BRCA1 protein and DNA have been mapped to the central region, which could be further divided as two DNA binding domains (DBDs); however, the relative substrate preferences of the DBDs and their functional role in HR remain poorly understood. We hypothesize that the DBDs have distinct binding preferences for DNA repair intermediates, and we have measured the DNA binding affinities of DBD1 (amino acids (aa) 330-554), DBD2 (aa894-1057), and the BRCA1 C-terminal repeats (BRCT) for single-stranded (ssDNA), double-stranded (dsDNA), and G-quadruplex (G4) DNA using biolayer interferometry. Our results indicate that DBD1 has the highest affinity for dsDNA, while DBD2 and BRCT bound tightest to G4 and ssDNA. Based on these findings, we propose a model in which DBD1 targets BRCA1 to DSBs for the promotion of DNA end resection, whereas DBD2 and BRCT target BRCA1 to telomeres to function in chromatin remodeling and telomere regulation.
The Mia40 substrate Mix17 exposes its N-terminus to the cytosolic side of the mitochondrial outer membrane
Authors: Resch Moritz , Frickel Johanna S. , Dischinger Korbinian , Wen Rachel Choo Shen , Hell Kai , Harner Max E.
Published: May 2024

Mitochondrial architecture and the contacts between the outer and the inner mitochondrial membrane depend on the mitochondrial contact site and cristae organizing system (MICOS) that is highly conserved from yeast to human. Mutations in the mammalian MICOS subunit Mic14/CHCHD10 have been linked to amyotrophic lateral sclerosis and frontotemporal dementia, indicating the importance of this protein. Mic14/CHCHD10 has a yeast ortholog, Mix17, a protein of unknown function, which has not been shown to interact with MICOS so far. As a first step to elucidate the function of Mix17 and its orthologs, we analyzed its interactions, biogenesis and mitochondrial sublocation.

We report that Mix17 is no stable MICOS subunit in yeast. Our data suggest that Mix17 is the first Mia40 substrate in the mitochondrial outer membrane. Unlike all other Mia40 substrates, Mix17 spans the outer membrane and exposes its N-terminus to the cytosol. The insertion of Mix17 is likely to be mediated by its interaction with Tom40, the pore of the TOM complex. Moreover, we show that the exposure of Mix17 to the cytosolic side of the membrane depends on its N-terminus.
Unveiling Stimulus Transduction Artifacts in Auditory Steady-State Response Experiments: Characterization, Risks, and Mitigation Strategies
Authors: Strobl Jan , Viktorin Vojtech , Piorecky Marek , Griskova-Bulanova Inga , Hubeny Jan , Brunovsky Martin , Palenicek Tomas , Koudelka Vlastimil
Published: May 2024

This scientific paper addresses the potential risk of spurious responses in neuroscientific auditory steady-state response (ASSR) experiments attributed to transduction artifacts. The focus is particularly on click train stimuli, given their spectral content in the frequency range of interest (e.g., 40 Hz). Building upon a pilot experiment demonstrating the existence of the artifact in a phantom head, this study focuses on the characterization of stimulus artifacts in extended measurements with phantoms and the evaluation of associated risks in experiments involving human subjects. The investigation is divided into two parts: the first part scrutinizes stimulus artifact properties crucial for mitigation, while the second part assesses risks in ASSR experiments with human subjects based on the characterized artifact. The discussion covers stimulus characterization, experimental setups with phantoms, and experiments with human subjects, exploring potential sources of the artifact, its spatial properties, and the influence of re-referencing. The results reveal the role of headphone cables as a source of stimulus artifacts, along with the surprising impact of headphone transducers. The study emphasizes the need for careful experimental design and data analysis to avoid misinterpretations of stimulus artifacts as genuine brain responses in ASSR experiments.