bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the impact of the Gamma variant on COVID-19 Patient admissions in a Southern Brazilian tertiary hospital - A comparison of dual pandemic phases
Authors: Domino Natalia R , Lapinscki Bruna A , Zhen Felipe , Yamaguto Guilherme , Costa Emanueli C S , Moriya Vitor L , Pereira Luciane A , Petterle Ricardo , Nogueira Meri B , Raboni Sonia M
Published: September 2023

Since the first case of COVID-19, Brazil has undergone infection waves with distinct characteristics. The description of new variants has alerted the emergence of more contagious or virulent viruses. The variant of concern Gamma emerged in Brazil and caused an epidemic wave, but its spread outside the country was limited. We report the clinical-epidemiological profile of hospitalized patients with COVID-19 by comparing two periods. A retrospective cohort study was performed. The primary outcome was to assess individuals with COVID-19 admitted in wards and intensive care units at CHC-UFPR between March 2020 and July 2021, correlating demographic, clinical-epidemiologic, and survival data with the most prevalent viral variant found in each period. We used Kaplan-Meier analysis to estimate the probability of survival and receiver operating characteristic curves to evaluate laboratory tests to find a cutoff point for poor outcomes. Data from 2,887 individuals were analyzed, 1,495 and 1,392 from the first and second periods, respectively. Hospitalization predominated among males in both periods, and the median age was significantly lower in the second one. The frequency of comorbidities was similar. Various demographic factors, clinical assessments, and laboratory tests were examined in relation to greater severity. When comparing the two studied periods, we observed predominance of the Wild virus during the first wave and the Gamma variant during the second, with no significant difference in outcomes. The findings suggest that despite the association of many factors with increased severity, the temporal variation between the two periods did not result in a notable divergence in the measured outcomes. The COVID-19 pandemic has lasted for a long time, with periods marked by peaks of cases, often caused by the emergence of viral variants, resulting in higher infection rates and rapid dissemination but, for variant Gamma, no apparent greater virulence.
Improved NAAT assay for the diagnosis of onchocerciasis and its use for detection of circulating cell free DNA
Authors: Bennuru Sasisekhar , Kodua Frimpong , Dahlstrom Eric , Nutman Thomas B
Published: September 2023

Mass drug administration (MDA) programs aimed at control and elimination of onchocerciasis relies on annual or semi-annual distribution of Ivermectin (IVM) that target the microfialarial (mf) stage of the parasiteOnchocerca volvulus. The co-endemicity of onchocerciasis with other filarial species often leads to interruptions in the control programs. A much-needed tool for the elimination efforts are sensitive diagnostic assays that can help differentiate from other co-endemic filarial infections or xenomonitoring approaches. qPCR assays targeting highly repeated elements in the genomes have allowed for increased sensitivity of detection that are pathogen-specific. Utilizing NGS data, qPCR assays were designed to target 15 highly repeated targets fromO. volvulusand 11 fromO. ochengi. The two most sensitive and specific repeats Ov15R and Ov16R fromO. volvulusand OoR1 and OoR5 fromO. ochengi, were selected for further testing.

The analytical sensitivity of both Ov15R and Ov16R were similar with limits of detection (LOD) at 1 fg ofO. volvulusgenomic DNA (gDNA), and 100% specificity and ∼32-fold sensitive than O-150 qPCR. Similarly, OoR1 and OoR5 had LOD of 100 fg ofO. ochengigDNA. Using DNA obtained previously from skin snips, Ov16R identified 17 additional samples as positive for infections when compared to O-150.

Further, to eliminate the need for time-dependent sample acquisition, we evaluated the efficiency of plasma-derived circulating cell-free DNA (ccfDNA) to detectO. volvulusinfections and as a potential modality for testing cure of infection. Plasma-derived ccfDNA failed to amplify Ov16R. In contrast using a small set of urine-derived ccfDNA samples from Ov-infected individuals had varying levels of detectability as early as 12-24 hours post-treatment. To enable processing of larger volumes of urine for better sensitivity, a modified chitosan-based filter technique was developed as proof-of-concept that efficiently captured gDNA from 1-15ml of urine.

Interestingly, Ov15R, Ov16R and O-150 map to the same contigs ofO. volvulusgenome. This prompted the redesign of O-150 qPCR that resulted in O-150-New qPCR assay that performs on par with Ov15R/Ov16R, thus offering more sensitive and specific diagnosis ofO. volvulusthat can easily be configured to field-friendly formats such as LAMP or RPA.
Excellence is a habit: Enhancing predictions of language impairment by identifying stable features in clinical perfusion scans
Authors: Teghipco Alex , Kim Hana , Rorden Chris , Newman-Norlund Roger , Sharif Massoud , Sikorski Darek , Hillis Argye E.
Published: September 2023

Perfusion images guide acute stroke management, yet few studies have been able to systematically investigate CT perfusion collected during routine care because the measures are stored in proprietary formats incompatible with conventional research analysis pipelines. We illustrate the potential of harnessing granular data from these routine scans by using them to identify the association between specific areas of hypoperfusion and severity of object naming impairment in 43 acute stroke patients. Traditionally, similar analyses in such sample sizes face a dilemma—simple models risk being too constrained to make accurate predictions, while complex models risk overfitting and producing poor out-of-sample predictions. We demonstrate that evaluating the stability rather than out-of-sample predictive capacity of features in a nested cross-validation scheme can be an effective way of controlling model complexity and stabilizing model estimates across a variety of different regression techniques. Specifically, we show that introducing this step can determine model significance, even when the regression model already contains an embedded feature selection or dimensionality reduction step, or if a subset of features is manually selected prior to training based on expert knowledge. After improving model performance using more complex regression techniques, we discover that object naming performance relies on an extended language network encompassing regions thought to play a larger role in different naming tasks, right hemisphere regions distal to the site of injury, and regions and tracts that are less typically associated with language function. Our findings especially emphasize the role of the left superior temporal gyrus, uncinate fasciculus, and posterior insula in successful prediction of object naming impairment. Collectively, these results highlight the untapped potential of clinical CT perfusion images and demonstrate a flexible framework for enabling prediction in the limited sample sizes that currently dominate clinical neuroimaging.
Gaps in the phenotype descriptions of ultra-rare genetic conditions: review and multicenter consensus reporting guidelines
Authors: AlMail Ali , Jamjoom Ahmed , Pan Amy , Feng Min Yi , Chau Vann , D’Gama Alissa , Howell Katherine , Liang Nicole S.Y. , McTague Amy , Poduri Annapurna , Wiltrout Kimberly ,   IPCHiP Executive Committee, Bassett Anne S. , Christodoulou John , Dupuis Lucie , Gill Peter , Levy Tess , Siper Paige , Stark Zornitza , Vorstman Jacob A.S. , Diskin Catherine , Jewitt Natalie , Baribeau Danielle , Costain Gregory
Published: September 2023

Background

Genome-wide sequencing and genetic matchmaker services are propelling a new era of genotype-first ascertainment of novel genetic conditions. The degree to which reported phenotype data in discovery-focused studies address informational priorities for clinicians and families is unclear.

Methods

We identified reports published from 2017-2021 in ten genetics journals of novel Mendelian disorders ascertained genotype-first. We adjudicated the quality and detail of the phenotype data via 46 questions pertaining to six priority domains: (I) Development, cognition, and mental health; (II) Feeding and growth; (III) Medication use and treatment history; (IV) Pain, sleep, and quality of life; (V) Adulthood; and (VI) Epilepsy. For a subset of articles, all subsequent published follow-up case descriptions were identified and assessed in a similar manner. A modified Delphi approach was used to develop consensus reporting guidelines, with input from content experts across four countries.

Results

In total, 200 of 3243 screened publications met inclusion criteria. Relevant phenotypic details across each of the six domains were rated superficial or deficient in >87% of papers. For example, less than 10% of publications provided details regarding neuropsychiatric diagnoses and “behavioural issues”, or about the type/nature of feeding problems. Follow-up reports (n=95) rarely addressed the limitations of the original reports. Reporting guidelines were developed for each domain.

Conclusion

Phenotype information relevant to clinical management, genetic counseling, and the stated priorities of patients and families is lacking for many newly described genetic diseases. Use of the proposed guidelines could improve phenotype reporting in the genomic era.
Millimeter-sized battery-free epidural cortical stimulators
Authors: Woods Joshua E. , Singer Amanda L. , Alrashdan Fatima , Tan Wendy , Tan Chunfeng , Sheth Sunil A. , Sheth Sameer A. , Robinson Jacob T.
Published: September 2023

Refractory neurological and psychiatric disorders are increasingly treated with brain stimulation therapies using implanted neuromodulation devices. Current commercially available stimulation systems, however, are limited by the need for implantable pulse generators and wired power; the complexity of this architecture creates multiple failure points including lead fractures, migration, and infection. Enabling less invasive approaches could increase access to these therapies. Here we demonstrate the first millimeter-sized leadless brain stimulator in large animal and human subjects. This Digitally programmable Over-brain Therapeutic (or DOT) is approximately 1 cm in width yet can produce sufficient energy to stimulate cortical activity on-demand through the dura. This extreme miniaturization is possible using recently developed magnetoelectric wireless power transfer that allows us to reach power levels required to stimulate the surface of the brain without direct contact to the cortical surface. This externally powered cortical stimulation (XCS) opens the possibility of simple minimally invasive surgical procedures to enable precise, long-lasting, and at-home neuromodulation with tiny implants that never contact the surface of the brain.
Immunohistochemical Study of Histone Protein 3 Modification in Pediatric Osteosarcoma Identifies Reduced H3K27me3 as a Marker of Poor Treatment Response
Authors: Kondratowski Sebastian , Cohen Danielle , Deyell Rebecca J. , Sandhu Ash , Bush Jonathan W
Published: September 2023

Summary/Abstract

The most common pediatric primary malignant bone tumor, osteosarcoma, is often described as genetically non-recurrent and heterogeneous. Neoadjuvant chemotherapy is typically followed by resection and assessment of treatment response, which helps inform prognosis. Identifying biomarkers that may impact chemotherapy response and survival could aid in upfront risk stratification and identify patients in highest need of innovative therapies for future clinical trials. Relative to conventional genetics, little is known about osteosarcoma epigenetics. We aimed to characterize the methylation and phosphorylation status in osteosarcoma using histone markers found in primary diagnostic biopsies and their paired metastases. We constructed two tissue microarray sets from 58 primary diagnostic samples and 54 temporally-separated but related metastatic or recurrent samples, with tissue blocks available from 2002-2022. Clinical charts were reviewed for post-therapy necrosis response, presence of metastatic disease or recurrence, and overall survival. We evaluated 6 histone H3 residues using immunohistochemistry, including H3K4me3, H3K9me3, H3K27me2, H3K27me3, H3S10T11phos, and H3S28phos. Tumors were scored with low (<25%) or high (≥25%) nuclear staining of tumor cells. Diagnostic biopsies with low H3K27me3 nuclear staining were associated with poor treatment response (≤90% necrosis) at the time of definitive excision (P<0.05). We observed loss of H3S10T11phos expression in metastatic and recurrent resections specimens compared to the primary tumor (P<0.05). Expression patterns for the remaining histone markers did not show significant associations with disease parameters or survival. Although larger cohort studies are needed, these results support the expanded evaluation of histone markers, particularly H3K27me3 and H3S10T11phos, in osteosarcoma biology and risk stratification.
Dynamics of motor direction representation in the primate premotor and primary motor cortices during sensorimotor learning
Authors: Ebina Teppei , Sasagawa Akitaka , Hong Dokyeong , Setsuie Rieko , Obara Keitaro , Masamizu Yoshito , Kondo Masashi , Terada Shin-Ichiro , Ozawa Katsuya , Uemura Masato , Takaji Masafumi , Watakabe Akiya , Kobayashi Kenta , Ohki Kenichi , Yamamori Tetsuo , Murayama Masanori , Matsuzaki Masanori
Published: September 2023

Sensorimotor learning requires reorganization of neuronal activity in the premotor cortex (PM) and primary motor cortex (M1). However, how PM- and M1-specific reorganization occurs in primates remains unclear. We conducted calcium imaging of these areas in common marmosets while they learned a two-target reaching (pull/push) task. Throughout learning, the dorsorostral PM (PMdr) showed peak activity earlier than the dorsocaudal PM (PMdc) and M1. PMdr showed decreased representation of newly introduced (push) movement, whereas PMdc and M1 maintained high representation. Many task-related neurons in PMdc and M1 exhibited a strong preference to either movement direction. PMdc neurons dynamically switched their preferred direction, whereas M1 neurons stably retained their preferred direction. Differences in preferred direction between adjacent neurons in PMdc increased during learning. These results suggest that in primate sensorimotor learning, dynamic motor representation in PMdc converts the cognitive sensorimotor signals of PMdr to stable and specific motor representation of M1.
Representation of Protein Dynamics Disentangled by Time-structure-based Prior
Authors: Ishizone Tsuyoshi , Matsunaga Yasuhiro , Fuchigami Sotaro , Nakamura Kazuyuki
Published: September 2023

Representation learning (RL) is a universal technique for deriving low-dimensional disentangled representations from high-dimensional observations, aiding a multitude of downstream tasks. RL has been extensively applied to various data types, including images and natural language. Here, we analyze molecular dynamics (MD) simulation data of biomolecules in terms of RL to obtain disentangled representations related to their conformational transitions. Currently, state-of-the-art RL techniques, which are mainly motivated by the variational principle, try to capture slow motions in the representation (latent) space. Here, we propose two methods based on alternative perspective on thedisentanglementin the representation space. The methods introduce a simple prior that imposes temporal constraints in the representation space, serving as a regularization term to facilitate capturing disentangled representations of dynamics. The introduction of this simple prior aids in characterizing the conformational transitions of proteins. Indeed, comparison with other methods via the analysis of MD simulation trajectories for alanine dipeptide and chignolin validates that the proposed methods construct Markov state models (MSMs) whose implied time scales are comparable to state-of-the-art methods. By coarse-graining MSMs, we further show the methods aid to detect physically important interactions for conformational transitions. Overall, our methods provide good representations of complex biomolecular dynamics for downstream tasks, allowing for better interpretations of conformational transitions.
Whole blood mitochondrial copy number in clinical populations with mood disorders: a meta-analysis
Authors: Calarco Cali A. , Keppetipola Swarnapali M. , Kumar Gautam , Shipper Andrea G. , Lobo Mary Kay
Published: September 2023

Background

Major depressive disorder (MDD) and bipolar disorder (BD), are globally prevalent, contributing to significant disease burden and adverse health outcomes. These mood disorders are associated with changes in many aspects of brain reward pathways, yet cellular and molecular changes in the brain are not readily available in clinical populations. Therefore, the use of biomarkers as proxies for changes in the brain are necessary. The proliferation of mitochondria in blood has emerged as a potentially useful biomarker, yet a clear consensus on how these mood disorders impact mitochondrial DNA copy number (mtDNAcn) has not been reached.

Methods

Following PRISMA guidelines for a systematic search, 22 papers met inclusion criteria for meta-analysis (10 MDD, 10 BD, 2 both MDD and BD). We extracted demographic, disorder, and methodological information with mtDNAcn. Using the metafor package for R, calculated effect sizes were used in random effects or meta regression models for MDD and BD.

Results

Our results show a trending increase in mtDNAcn in patients with MDD, which reaches significance when one study with outlying demographic characteristics is excluded. Overall, there was no effect of BD on mtDNAcn, however, further subgroup and meta-regression analysis indicated the effects on mtDNAcn are dependent on BD type.

Conclusions

Together our data suggest whole blood/leukocyte mtDNAcn may be a useful biomarker for mood disorders, with MDD and BD Type II associated with higher mtDNAcn, and BD Type I associated with lower mtDNAcn. Further study of blood mtDNAcn could predict downstream health outcomes or treatment responsivity in individuals with mood disorders.
Sensation and expectation are embedded in mouse motor cortical activity
Authors: Holey Brooke E. , Schneider David M.
Published: September 2023

During behavior, the motor cortex sends copies of motor-related signals to sensory cortices. It remains unclear whether these corollary discharge signals strictly encode movement or whether they also encode sensory experience and expectation. Here, we combine closed-loop behavior with large-scale physiology, projection-pattern specific recordings, and circuit perturbations to show that neurons in mouse secondary motor cortex (M2) encode sensation and are influenced by expectation. When a movement unexpectedly produces a sound, M2 becomes dominated by sound-evoked activity. Sound responses in M2 are inherited partially from the auditory cortex and are routed back to the auditory cortex, providing a path for the dynamic exchange of sensory-motor information during behavior. When the acoustic consequences of a movement become predictable, M2 responses to self-generated sounds are selectively gated off. These changes in single-cell responses are reflected in population dynamics, which are influenced by both sensation and expectation. Together, these findings reveal the rich embedding of sensory and expectation signals in motor cortical activity.
Single-cell optogenetics reveals attenuation-by-suppression in visual cortical neurons
Authors: LaFosse Paul K. , Zhou Zhishang , O’Rawe Jonathan F. , Friedman Nina G. , Scott Victoria M. , Deng Yanting , Histed Mark H.
Published: September 2023

The relationship between neurons’ input and spiking output is central to brain computation. Studiesin vitroand in anesthetized animals suggest nonlinearities emerge in cells’ input-output (activation) functions as network activity increases, yet how neurons transform inputsin vivohas been unclear. Here, we characterize cortical principal neurons’ activation functions in awake mice using two-photon optogenetics. We deliver fixed inputs at the soma while neurons’ activity varies with sensory stimuli. We find responses to fixed optogenetic input are nearly unchanged as neurons are excited, reflecting a linear response regime above neurons’ resting point. In contrast, responses are dramatically attenuated by suppression. This attenuation is a powerful means to filter inputs arriving to suppressed cells, privileging other inputs arriving to excited neurons. These results have two major implications. First, somatic neural activation functionsin vivoaccord with the activation functions used in recent machine learning systems. Second, neurons’ IO functions can filter sensory inputs — not only do sensory stimuli change neurons’ spiking outputs, but these changes also affect responses to input, attenuating responses to some inputs while leaving others unchanged.

Significance statement

How neurons transform their inputs into outputs is a fundamental building block of brain computation. Past studies have measured neurons’ input-output (IO) functionsin vitroor in anesthetized states. Here, we measure neurons’ IO functions in the awake and intact brain, where ongoing network activity can influence neurons’ responses to input. Using state-of-the-art optogenetic methods to deliver precise inputs to neurons near the cell body, or soma, we discover neurons have a supralinear-to-linear IO function, contrary to previous findings of threshold-linear, strongly saturating, or power law IO functions. This supralinear-to-linear somatic IO function shape allows neurons to decrease their responses to, or filter, inputs while they are suppressed below their resting firing rates, a computation we term attenuation-by-suppression.
Bacterial composition changes in canine plaque over periodontal disease severity and daily care practices
Authors: Watanabe Ayano , Okada Junichi , Niwa Ryo , Inui Yukiko , Ito Kohei , Shimokawa Yutaka , Kihira Miho
Published: September 2023

Background

Periodontal disease (PD) is a common oral disease in dogs and humans. Dogs have distinctly different oral environments from humans. Although common bacteria are observed in both species, profiling of the causative bacteria for the progression of PD in dogs is limited compared to humans.

Results

Our study examined the shifts in the bacterial community within canine plaque as PD intensifies, analyzing plaque samples from 48 dogs at various PD stages. Additionally, we examined the impact of a tooth-brushing regimen using a dental gel on twelve dogs. We revealed a correlation between the age of the dogs and the severity of PD. As PD advanced, we noted a marked increase inPorphyromonasabundance, a key pathogenic genus. Conversely,Conchiformibiusprevalence diminished in higher PD levels. Furthermore, a regimen of two week brushing with a dental gel resulted in a notable decrease inPorphyromonaslevels and five of the twelve dogs improve severity.

Conclusions

Our findings suggest the potential efficacy of daily brushing with dental gels, incorporating compounds proven effective in humans, for managing PD in dogs. This study demonstrates a distinct disease progression in dogs compared to humans, underscoring the need for continued research and innovation in veterinary oral healthcare.
A novel, scenario-based approach to comparing non-pharmaceutical intervention strategies across nations
Authors: Calabrese Justin M. , Schüler Lennart , Fu Xiaoming , Gawel Erik , Zozmann Heinrich , Bumberger Jan , Quaas Martin , Wolf Gerome , Attinger Sabine
Published: September 2023

Comparing COVID-19 non-pharmaceutical intervention (NPI) strategies across nations is a key step in preparing for future pandemics. Conventional comparisons, which rank individual NPI effects, are limited by: 1) vastly different political, economic, and social conditions among nations, 2) NPIs typically being applied as packages of interventions, and 3) an exclusive focus on epidemiological outcomes of interventions. Here, we develop a coupled epidemiological-behavioural-macroeconomic model that allows us to transfer NPI strategies from a reference nation to a focal nation while preserving the packaged nature of NPIs, controlling for differences among nations, and quantifying epidemiological, behavioural and economic outcomes. As a demonstration, we take Germany as our focal nation during Spring 2020, and New Zealand and Switzerland as reference nations with contrasting NPI strategies. We show that, while New Zealand’s more aggressive strategy would have yielded modest epidemiological gains in Germany, it would have resulted in substantially higher economic costs while dramatically reducing social contacts. In contrast, Switzerland’s more lenient NPI strategy would have prolonged the first wave in Germany, but would have also have increased relative costs. Our results demonstrate that Germany’s intermediate strategy was effective in quelling the first wave while mitigating both economic and social costs.
Diagnostic testing and the evolution of detection avoidance by pathogens
Authors: Wood Jason , Ashby Ben
Published: September 2023

Diagnostic testing is a key tool in the fight against many infectious diseases. The emergence of pathogen variants that are able to avoid detection by diagnostic testing therefore represents a key challenge for public health. In recent years, variants for multiple pathogens have emerged which escape diagnostic testing, including mutations inPlasmodium falciparum(malaria),Chlamydia trachomatis(chlamydia) and SARS-CoV-2 (COVID-19). However, little is currently known about when and the extent to which diagnostic test escape will evolve. Here we use a mathematical model to explore how the frequency of diagnostic testing, combined with variation in compliance and efficacy of quarantining, together drive the evolution of detection avoidance. We derive key thresholds under which a testing regime will (i) select for diagnostic test avoidance, or (ii) drive the pathogen extinct. Crucially, we show that imperfect compliance with diagnostic testing regimes can have marked effects on selection for detection avoidance, and consequently, for disease control. Yet somewhat counterintuitively, we find that an intermediate level of testing can select for the highest level of detection avoidance. Our results, combined with evidence from various pathogens, demonstrate that the evolution of diagnostic testing avoidance should be carefully considered when designing diagnostic testing regimes.
Transcutaneous auricular vagus nerve stimulation enhanced inhibitory control via increasing intrinsic prefrontal couplings
Authors: Zhu Siyu , Liu Qi , Zhang Xiaolu , Zhou Menghan , Zhou Xinqi , Ding Fangyuan , Zhang Rong , Becker Benjamin , Kendrick Keith M , Zhao Weihua
Published: September 2023

Inhibitory control represents a core executive function that critically facilitates adaptive behavior and survival in an ever-changing environment. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has been hypothesized to improve behavioral inhibition performance, however the neurocomputational mechanism of taVNS-induced neuroenhancement remain elusive. In the current study, we investigated the effect of taVNS on inhibitory control in a pre-registered sham-controlled between-subject functional near infrared spectroscopy (fNIRS) experiment with an emotional face Go/No-Go paradigm in ninety subjects. After data quality check, eighty-two subjects were included in the final data analysis. Behaviorally, the taVNS improved No-Go response accuracy, together with computational modeling using Hierarchical Bayesian estimation of the Drift Diffusion Model (HDDM) indicating that it specifically reduced the information accumulation rate for Go responses, and this was negatively associated with increased accuracy of No-Go responses. On the neural level, taVNS enhanced engagement of the bilateral inferior frontal gyrus (IFG) during inhibition of angry expression faces and modulated functional couplings (FCs) within the prefrontal inhibitory control network. Mediation models revealed that taVNS-induced facilitation of inhibitory control was critically mediated by a decreased information accumulation for Go responses and concomitantly enhanced neurofunctional coupling between the inferior and orbital frontal cortex. Our findings demonstrate a striking potential for taVNS to improve inhibitory control via reducing pre-potent responses and enhancing FCs within prefrontal inhibitory control networks, suggesting a promising therapeutic role in treating specific disorders characterized by inhibitory control deficits.
bistro: An R package for vector bloodmeal identification by short tandem repeat overlap
Authors: Lapp Zena , Abel Lucy , Mangeni Judith , Obala Andrew A. , O’Meara Wendy , Taylor Steve M. , Markwalter Christine F.
Published: September 2023

Measuring vector-human contact in a natural setting can inform precise targeting of interventions to interrupt transmission of vector-borne diseases. One approach is to directly match human DNA in vector bloodmeals to the individuals who were bitten using genotype panels of discriminative short tandem repeats (STRs). Existing methods for matching STR profiles in bloodmeals to the people bitten preclude the ability to match most incomplete profiles and multi-source bloodmeals to bitten individuals.

We developed bistro, an R package that implements 3 preexisting STR matching methods as well as the package’s namesake, bistro, a new algorithm described here. bistro employs forensic analysis methods to calculate likelihood ratios and match human STR profiles in bloodmeals to people using a dynamic threshold. We evaluated the algorithm’s accuracy and compared it to existing matching approaches using a publicly-available panel of 188 single-source and 100 multi-source samples containing DNA from 50 known human sources. Then we applied it to match 777 newly field-collected mosquito bloodmeals to a database of 645 people.

The R package implements four STR matching algorithms in user-friendly functions with clear documentation. bistro correctly matched 99% (184/185) of profiles in single-source samples, and 63% (225/359) of profiles from multi-source samples, resulting in a sensitivity of 0.75 (vs < 0.51 for other algorithms). The specificity of bistro was 0.9998 (vs. 1 for other algorithms). Furthermore, bistro identified 80% (729/909) of all possible matches for field-derived mosquitoes, yielding 1.4x more matches than existing algorithms.

bistro identifies more correct bloodmeal-human matches than existing approaches, enabling more accurate and robust analyses of vector-human contact in natural settings. The bistro R package and corresponding documentation allow for straightforward uptake of this algorithm by others.
Differential LRRK2 signalling and gene expression in WT-LRRK2 and G2019S-LRRK2 mouse microglia treated with zymosan and MLi2
Authors: Nazish Iqra , Mamais Adamantios , Mallach Anna , Bettencourt Conceicao , Kaganovich Alice , Warner Tom , Hardy John , Lewis Patrick A. , Pocock Jennifer , Cookson Mark R , Bandopadhyay Rina
Published: September 2023

Introduction

Mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene cause autosomal dominant Parkinson’s disease (PD) with the most common causative mutation being theLRRK2p.G2019S within the kinase domain. LRRK2 protein is highly expressed in the human brain and also in the periphery, and high expression of dominant PD genes in immune cells suggest involvement of microglia and macrophages in inflammation related to PD. LRRK2 is known to respond to extracellular signalling including TLR4 resulting in alterations in gene expression, with the response to TLR2 signalling through zymosan being less known.

Methods

Here, we investigated the effects of zymosan, a TLR2 agonist and the potent and specific LRRK2 kinase inhibitor MLi-2 on gene expression in microglia fromLRRK2-WTandLRRK2p.G2019S knock-in mice by RNA-Sequencing analysis.

Results

We observed both overlapping and distinct zymosan and MLi-2 mediated gene expression profiles in microglia. At least two candidate Genome-Wide Association (GWAS) hits for PD, CathepsinB (Ctsb) and Glycoprotein-nmb (Gpnmb), were notably downregulated by zymosan treatment. Genes involved in inflammatory response and nervous system development were up and downregulated respectively with zymosan treatment while MLi-2 treatment particularly exhibited upregulated genes for ion transmembrane transport regulation. Furthermore, we observed the top twenty most significantly differentially expressed genes inLRRK2p.G2019S microglia show enriched biological processes in iron transport and response to oxidative stress.

Discussion

Overall, these results suggest that microglial LRRK2 may contribute to PD pathogenesis through altered inflammatory pathways. Our findings should encourage future investigations of these putative avenues in the context of PD pathogenesis.
A taxonomically informed DNA reference library to facilitate future biodiversity assessments and monitoring: a case study using seaweeds along a tropical-temperate transition zone in South Africa
Authors: Reddy Maggie M. , du Plessis Jamie , Anderson Robert J. , Roodt-Wilding Rouvay , Bolton John J.
Published: September 2023

The role of seaweeds in the blue bioeconomy has stimulated research efforts around the world but proper species identification and biodiversity assessments, remain a challenge. The South African coast hosts the confluence of the Indian Ocean and Atlantic Ocean, creating a dynamic evolutionary environment that has over time yielded a rich diversity of seaweeds with the highest seaweed diversity occurring along the Agulhas Marine Province. Although South Africa harbours one of the richer seaweed floras in the world, only 24% of the known species are represented by DNA barcodes. We therefore initiated the construction of a taxonomically guided DNA reference library for seaweeds in South Africa with the aim of continuously adding to it in the future. To do this, a seaweed biodiversity survey of the Rhodophyta occurring along a temperate-tropical biogeographic transition zone situated within the Agulhas Marine Province (AMP) in South Africa was carried out. Seaweeds were identified in the field using available field or taxonomic guides and herbarium vouchers were prepared. Subsamples were preserved for DNA analyses and three DNA barcodes (LSU D2-D3;rbcL-3P; COI 5P) were amplified. Sequences were verified on BLAST and preliminary phylogenetic analyses or comparison with the literature were carried out where necessary. A total of 220 barcodes was generated for 88 species and one species variety, including 17 species from or near their type localities and eight generitypes. Novel barcodes were generated for 73 species, nearly half of which were species endemic to Southern Africa. In addition, 21 taxa representing new, potentially new, or reinstated species and at least two new genera were identified as well as one new distribution recorded, all of which require further study. This study significantly adds to the foundational biodiversity knowledge of the South African seaweed flora and highlights new avenues for further research.
Legionella felix sp. - A novel Legionella species isolated in Israel from hot tap water
Authors: Valenci Gal Zizelski , Ohad Shosanit , Robinstein Mor , Assaly Shereen , Kutikov Ina , Groisman Ludmila , Murik Omer , Zeevi David A. , David Ravid Ben , Farber Alona , Dveyrin Zeev , Rorman Efrat , Nissan Israel
Published: September 2023

Bacteria of the genusLegionellaare natural pathogens of the environment that can cause legionellosis, which can result in severe human pneumonia called Legionnaires’ disease. Here we describe a novelLegionellaspecies isolated from hot tap water. High quality complete genome was generated using a combination of Nanopore and Illumina sequencing approaches. Our novelLegionellaisolate possesses a 3,913,681 bp chromosome, (GC content 38.78% Mol) and a single novel largeincFconjugative plasmid of 160,500 bp (GC content 37.97%). Interestingly, the chromosome encodes for 14 secondary metabolites biosynthetic gene clusters, more than any known otherLegionellasp. The novel plasmid encodes for multiple genes that confer resistance to heavy metals. Bioinformatics analysis including average nucleotide identity (ANI) and genome-based taxonomy computation revealed that the genome of the new isolate differs from any previously describedLegionellaspecies. The closest related species to our isolate isLegionella cherrii. The name proposed for the new specie isLegionella felixin honor of Dr. Arthur Felix (1887-1956), a pioneering microbiologist, and member of the Royal Society of UK, who established the National Public Health Laboratory in Tel Aviv.
The ALDH1A3 Reporter Construct: A Novel Mechanism of Identifying and Tracking the Breast Cancer Stem Cell Population
Authors: Philbin Nick , Laurie Ellen M. , Fifield Bre-Anne , Porter Lisa Ann
Published: September 2023

Cancer stem cells lie at the heart of progression and relapse for many solid tumours including breast cancers. The Breast Cancer Stem Cell (BCSC) population is typically isolated via a combination of markers utilizing various staining techniques which prevents the ability to track dynamic changes in expression and to dissect the role in pathogenesis overtime. Here we report the development of a reporter for the expression of Aldehyde Dehydrogenase 1A3 (ALDH1A3), a marker of high clinical importance in many breast cancers, and other solid tumours. BCSCs displaying increased transcriptional activation of ALDH1A3 demonstrate an increase in self-renewal capabilities. This tool improves the ability to reliably follow select cancer stem cell populations over time.
Understanding Neuromodulation Pathways in tDCS: Brain Stem Recordings in Rat During Trigeminal Nerve Direct Current Stimulation
Authors: Majdi Alireza , Asamoah Boateng , Mc Laughlin Myles
Published: September 2023

Background

Recent evidence suggests that transcranial direct current stimulation (tDCS) indirectly influences brain activity through cranial nerve pathways, particularly the trigeminal nerve. However, the electrophysiological effects of direct current (DC) stimulation on the trigeminal nerve (DC-TNS) and its impact on trigeminal nuclei remain unknown. These nuclei exert control over brainstem centers regulating neurotransmitter release, such as serotonin and norepinephrine, potentially affecting global brain activity.

Objectives

To investigate how DC-TNS impacts neuronal activity in the principal sensory nucleus (NVsnpr) and the mesencephalic nucleus of the trigeminal nerve (MeV).

Methods

Twenty male Sprague Dawley rats (n=10 each nucleus) were anesthetized with urethane. DC stimulation, ranging from 0.5 to 3 mA, targeted the trigeminal nerve’s marginal branch. Simultaneously, single-unit electrophysiological recordings were obtained using a 32-channel silicon probe, comprising three one-minute intervals: pre-stimulation, DC stimulation, and post-stimulation. Xylocaine was administered to block the trigeminal nerve as a control.

Results

DC-TNS significantly increased neuronal spiking activity in both NVsnpr and MeV, returning to baseline during the post-stimulation phase. When the trigeminal nerve was blocked with xylocaine, the robust 3 mA trigeminal nerve DC stimulation failed to induce increased spiking activity in the trigeminal nuclei.

Conclusion

Our results offer initial empirical support for trigeminal nuclei activity modulation via DC-TNS. This discovery supports the hypothesis that cranial nerve pathways may play a pivotal role in mediating tDCS effects, setting the stage for further exploration into the complex interplay between peripheral nerves and neural modulation techniques.

Highlights

Direct current stimulation of the trigeminal nerve (DC-TNS) modulates neural activity in rat NVsnpr and MeV.

Xylocaine administration reversibly blocks the DC-TNS effect on neural responses.

Trigeminal nerve stimulation should be considered a possible mechanism of action of tDCS.
Zinc is Essential for the Copper Reductase Activity of Yeast Nucleosomes
Authors: Vogelauer Maria , Cheng Chen , Karimian Ansar , Iranpour Hooman Golshan , Kurdistani Siavash K.
Published: September 2023

The histone H3-H4 tetramer is a copper reductase enzyme, facilitating the production of cuprous (Cu1+) ions for distribution to copper-dependent enzymes. It was, however, unknown if this enzymatic activity occurred within nucleosomes. To investigate this, we obtained native nucleosomes fromSaccharomyces cerevisiaeusing micrococcal nuclease digestion of chromatin in isolated nuclei and ion-exchange chromatographic purification. The purified nucleosomal fragments robustly reduced Cu2+to Cu1+ions, with the optimal activity dependent on the presence of zinc ions. Mutation of the histone H3 histidine 113 (H3H113) residue at the active site substantially reduced the enzymatic activity of nucleosomes, underscoring the catalytic role of histone H3. Consistently, limiting zinc ions reduced intracellular Cu1+levels and compromised growth, phenotypes that were mitigated by genetically enhancing the copper reductase activity of histone H3. These results indicate that yeast nucleosomes possess copper reductase activity, suggesting that the fundamental unit of eukaryotic chromatin is an enzyme complex.
GABA Release From Central Amygdala Neurotensin Neurons Differentially Modulates Reward and Consummatory Behavior in Male and Female Mice
Authors: Gereau Graydon B. , Torruella-Suárez María L. , Sizer Sarah E. , Xia Mengfan , Zhou Diana , Wykoff Luke A. , Teklezghi Adonay T. , Alvarez-Pamir Ali , Boyt Kristen M. , Kash Thomas L. , McElligott Zoé A.
Published: September 2023

The central nucleus of the amygdala is known to play key roles in alcohol use and affect. Neurotensin neurons in the central nucleus of the amygdala have been shown to regulate alcohol drinking in male mice. However, little is known about which neurotransmitters released by these cells drive alcohol consumption or whether these cells drive alcohol consumption in female mice. Here we show that knockdown of GABA release from central amygdala neurotensin neurons using aNts-cre-dependent vGAT-shRNA-based AAV strategy reduces alcohol drinking in male, but not female, mice. This manipulation did not impact avoidance behavior, except in a fasted novelty-suppressed feeding test, in which vGAT shRNA mice demonstrated increased latency to feed on a familiar high-value food reward, an effect driven by male mice. In contrast, vGAT shRNA female mice showed heightened sensitivity to thermal stimulation. These data show a role for GABA release from central amygdala neurotensin neurons in modulating consumption of rewarding substances in different motivational states.
Determinants of DDX3X sensitivity uncovered using a helicase activity in translation reporter
Authors: Wilkins Kevin C. , Schroeder Till , Gu Sohyun , Revalde Jezrael L. , Floor Stephen N.
Published: September 2023

DDX3X regulates the translation of a subset of human transcripts containing complex 5′ untranslated regions (5′ UTRs). In this study we developed the helicase activity reporter for translation (HART) which uses DDX3X-sensitive 5′ UTRs to measure DDX3X mediated translational activity in cells. To dissect the structural underpinnings of DDX3X dependent translation, we first used SHAPE-MaP to determine the secondary structures present in DDX3X-sensitive 5′ UTRs and then employed HART to investigate how their perturbation impacts DDX3X-sensitivity. Additionally, we identified residues 38-44 as potential mediators of DDX3X’s interaction with the translational machinery. HART revealed that both DDX3X’s association with the ribosome complex as well as its helicase activity are required for its function in promoting the translation of DDX3X-sensitive 5′ UTRs. These findings suggest DDX3X plays a crucial role regulating translation through its interaction with the translational machinery during ribosome scanning, and establish the HART reporter as a robust, lentivirally encoded measurement of DDX3X-dependent translation in cells.
Wnt signaling and contact-mediated repulsion shape sensory dendritic fields
Authors: Tzeng Christopher P. , Shen Kang
Published: September 2023

The complete and non-redundant coverage of sensory tissues by neighboring neurons enables effective detection of stimuli in the environment. How the neurites of adjacent neurons establish their boundaries to achieve this completeness in coverage remains incompletely understood. Here, we use distinct fluorescent reporters to study two neighboring sensory neurons with complex dendritic arbors, FLP and PVD, inC. elegans. We quantify the sizes of their dendritic fields, and identify CWN-2/Wnt and LIN-17/Frizzled as a ligand and receptor that regulate the relative dendritic field sizes of these two neurons. Loss of eithercwn-2orlin-17results in complementary changes in the size of the dendritic fields of both neurons; the FLP arbor expands, while that of PVD shrinks. Using an endogenous knock-in mNeonGreen-CWN-2/Wnt, we find that CWN-2/Wnt is localized along the path of growing FLP dendrites. Dynamic imaging shows a significant braking of FLP dendrite growth upon CWN-2/Wnt contact. We find that LIN-17/Frizzled functions cell-autonomously in FLP to limit dendritic field size and propose that PVD fills the space left by FLP through contact-induced retraction. Our results reveal that interactions of dendrites with adjacent dendrites and with environmental cues both shape the boundaries of neighboring dendritic fields.

Highlights

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Secreted Wnt CWN-2 and cell-autonomous activity of neuronal LIN-17/Frizzled receptors restrict FLP dendritic field sizes

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Endogenously tagged CWN-2/Wnt is punctate and visible in the same plane of growing FLP dendrites

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Growth of developing FLP dendrites is inhibited upon contact with extracellular CWN-2/Wnt and with PVD dendrites
Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics
Authors: Ose Nicholas J. , Campitelli Paul , Modi Tushar , Kazan I. Can , Kumar Sudhir , Ozkan S. Banu
Published: September 2023

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into the molecular adaptations of the SARS-COV-2 Spike (S) protein. With this approach, we first identified Candidate Adaptive Polymorphisms (CAPs) of the SARS-CoV-2 Spike protein and assessed the impact of these CAPs through dynamics analysis. Not only have we found that CAPs frequently overlap with well-known functional sites, but also, using several different dynamics-based metrics, we reveal the critical allosteric interplay between SARS-CoV-2 CAPs and the S protein binding sites with the human ACE2 (hACE2) protein. CAPs interact far differently with the hACE2 binding site residues in the open conformation of the S protein compared to the closed form. In particular, the CAP sites control the dynamics of binding residues in the open state, suggesting an allosteric control of hACE2 binding. We also explored the characteristic mutations of different SARS-CoV-2 strains to find dynamic hallmarks and potential effects of future mutations. Our analyses reveal that Delta strain-specific variants have non-additive (i.e., epistatic) interactions with CAP sites, whereas the less pathogenic Omicron strains have mostly additive mutations. Finally, our dynamics-based analysis suggests that the novel mutations observed in the Omicron strain epistatically interact with the CAP sites to help escape antibody binding.