bluuebunny/crossref_metadata_2025 huggingface dataset:
Clustering of colon, lung, and other cancer susceptibility genes with protein tyrosine phosphatases and protein kinases in multiple short genomic regions
Authors: Quan Lei , Demant Peter
Published: November 2023

Interactions of large gene families are poorly understood. We found that human, mouse, and rat colon and lung cancer susceptibility genes, presently considered as separate gene families, were frequently pairwise linked. The orthologous mouse map positions of 142 of 159 early discovered colon and lung cancer susceptibility genes formed 41 genomic clusters conserved >70 million years. These linked gene pairs concordantly affected both tumors and their majority was linked with two other gene families - protein tyrosine phosphatases and cancer driver protein kinases. 25% of both protein tyrosine phosphatases and protein kinases mapped <1 cM from a colon or lung cancer susceptibility gene, and 50% in <3 cM. Similar linkage was detected with most other human susceptibility genes that controlled 29 different cancer types. This concentration of tumor susceptibility genes with protein tyrosine phosphatases and driver protein kinases in multiple relatively short genomic regions suggests their possible functional diversity.
Molecular identification of a peroxidase gene controlling body size in the entomopathogenic nematodeSteinernema hermaphroditum
Authors: Schwartz Hillel T. , Tan Chieh-Hsiang , Peraza Jackeline , Raymundo Krystal Louise T. , Sternberg Paul W.
Published: November 2023

The entomopathogenic nematodeSteinernema hermaphroditumwas recently rediscovered and is being developed as a genetically tractable experimental system for the study of previously unexplored biology, including parasitism of its insect hosts and mutualism with its bacterial endosymbiontXenorhabdus griffiniae. Through whole-genome re-sequencing and genetic mapping we have for the first time molecularly identified the gene responsible for a mutationally defined phenotypic locus in an entomopathogenic nematode. In the process we observed an unexpected mutational spectrum following EMS mutagenesis in this species. We find that the ortholog of the essentialC. elegansperoxidase geneskpo-2controls body size and shape inS. hermaphroditum. We confirmed this identification by inactivating the gene using CRISPR-Cas9. We propose that the identification ofskpo-2will accelerate gene targeting in otherSteinernemaentomopathogenic nematodes used commercially in pest control, asskpo-2is X-linked and males hemizygous for loss of its function can mate, makingskpo-2an easily recognized and maintained marker for use in co-CRISPR.
High clonal diversity and spatial genetic admixture in early prostate cancer and surrounding normal tissue
Authors: Zhang Ning , Harbers Luuk , Simonetti Michele , Diekmann Constantin , Verron Quentin , Berrino Enrico , Bellomo Sara E. , Longo Gabriel M.C. , Ratz Michael , Schultz Niklas , Tarish Firas , Su Peng , Han Bo , Wang Wanzhong , Onorato Sofia , Giordano Silvia , Yang Qifeng , Sapino Anna , Frisén Jonas , Alkass Kanar , Druid Henrik , Roukos Vassilis , Helleday Thomas , Marchiò Caterina , Bienko Magda , Crosetto Nicola
Published: November 2023

Somatic copy number alterations (SCNAs) are pervasive in advanced human cancers, but their prevalence and spatial distribution in early-stage, localized tumors and their surrounding normal tissues are poorly characterized. Here, we performed multi-region, single-cell DNA sequencing to characterize the SCNA landscape across multiple tumor-rich and normal tissue regions (∼125 mm3tissue cubes) obtained from prostatectomy performed in two patients with localized prostate cancer. We identified two distinct populations of cells with abnormal karyotypes, one marked by sparse deletions or amplifications (‘pseudo-diploid’ cells) and the second characterized by genome-wide copy number changes reminiscent of ‘monster’ cells previously described in colorectal cancer. Pseudo-diploid cells formed numerous small-sized subclones ranging from highly spatially localized to broadly spread subclones mainly featuring (sub-)chromosomal arm deletions. In contrast, monster cells harbored whole-chromosome gains and losses and were mostly singular events detected throughout the prostate, including normal tissue regions. Targeted deep sequencing of cancer-associated genes revealed a more confined pattern of mutations overlapping with tumor-rich regions, although we also detected mutations in regions deemed normal based on morphological assessment and bulk RNA-seq. Highly localized pseudo-diploid subclones were confined within tumor-rich regions and typically carried deletions involving chromosome (chr) 6 and 13, resulting in simultaneous loss of multiple tumor-suppressor genes, includingFOXO1andFOXO3encoding two transcription factors belonging to the Forkhead family previously implicated in prostate carcinogenesis. Tumor-rich regions also contained mutations in genes frequently mutated in prostate cancer, includingFOXA1,LRP1B,SPOP, andSPTA1.Our study reveals that SCNAs are widespread in both normal and tumor regions across the prostate gland of patients with localized prostate cancer and suggests that a subset of pseudo-diploid cells harboring chromosomal deletions that result in the loss of specific tumor-suppressor genes drive tumorigenesis in the aging prostate.
FFCM-MRF: An accurate and generalizable cerebrovascular segmentation pipeline for humans and rhesus monkeys based on TOF-MRA
Authors: Cui Yue , Huang Haibin , Liu Jialu , Zhao Mingyang , Li Chengyi , Han Xinyong , Luo Na , Gao Jinquan , Yan Dongming , Zhang Chen , Jiang Tianzi , Yu Shan
Published: November 2023

Purpose

Cerebrovascular segmentation and quantification of vascular morphological features on humans and rhesus monkeys are essential for prevention, diagnosis, and treatment of brain diseases. However, current automated whole-brain vessel segmentation methods are often not generalizable to independent datasets, limiting their usefulness in real-world environments with their heterogeneity in participants, scanners, and species.

Materials and Methods

In this study, we proposed an automated, accurate and generalizable segmentation method for magnetic resonance angiography images called FFCM-MRF. This method integrates fast fuzzy c-means clustering and Markov random field optimization using blood vessel shape priors and spatial constraints. We used a total of 123 human and 44 macaque MRA images scanned at 1.5 T, 3 T, and 7 T MRI from 9 datasets to develop and validate the method.

Results

The average Dice score coefficients for multiple independent datasets were 69.16-89.63%, with the improvements in FFCM-MRF ranged from 0.16-16.14% compared with state-of-the-art machine learning methods. Quantitative analysis showed that FFCM-MRF can accurately segment major arteries in the Circle of Willis at the base of the brain and smaller distal pial arteries while effectively suppressing noise. Test-retest analysis showed that the model yielded high vascular volume and diameter reliability.

Conclusions

Our results demonstrate that the proposed method is highly accurate and reliable and largely independent of variations in field strength, scanner platforms, acquisition parameters, and species. The macaque MRA data and user-friendly open-source toolbox are freely available at OpenNeuro and GitHub to facilitate studies of imaging biomarkers for cerebrovascular and neurodegenerative diseases.
Comprehensive analysis of computational approaches in plant transcription factors binding regions discovery
Authors: Jyoti  , Ritu  , Gupta Sagar , Shankar Ravi
Published: November 2023

Transcription factors (TFs) are regulatory proteins which bind to a specific DNA region known as the transcription factor binding regions (TFBRs) to regulate the rate of transcription process. The identification of TFBRs has been made possible by a number of experimental and computational techniques established during the past few years. The process of TFBR identification involves peak identification in the binding data, followed by the identification of motif characteristics. Using the same binding data attempts have been made to raise computational models to identify such binding regions which could save time and resources spent for binding experiments. These computational approaches depend a lot on what way they learn and how. These existing computational approaches are skewed heavily around human TFBRs discovery, while plants have drastically different genomic setup for regulation which these approaches have grossly ignored. Here, we provide a comprehensive study of the current state of the matters in plant specific TF discovery algorithms. While doing so, we encountered several software tools’ issues rendering the tools not usable to researches. We fixed them and have also provided the corrected scripts for such tools. We expect this study to serve as a guide for better understanding of software tools’ approaches for plant specific TFBRs discovery and the care to be taken while applying them, especially during cross-species applications. The corrected scripts of these software tools are made available athttps://github.com/SCBB-LAB/Comparative-analysis-of-plant-TFBS-software.
Identification and Pharmacological Targeting of Treatment-Resistant, Stem-like Breast Cancer Cells for Combination Therapy
Authors: Worley Jeremy , Noh Heeju , You Daoqi , Turunen Mikko M. , Ding Hongxu , Paull Evan , Griffin Aaron T. , Grunn Adina , Zhang Mingxuan , Guillan Kristina , Bush Erin C. , Brosius Samantha J. , Hibshoosh Hanina , Mundi Prabhjot S. , Sims Peter , Dalerba Piero , Dela Cruz Filemon S. , Kung Andrew L. , Califano Andrea
Published: November 2023

Tumors frequently harbor isogenic yet epigenetically distinct subpopulations of multi-potent cells with high tumor-initiating potential—often called Cancer Stem-Like Cells (CSLCs). These can display preferential resistance to standard-of-care chemotherapy. Single-cell analyses can help elucidate Master Regulator (MR) proteins responsible for governing the transcriptional state of these cells, thus revealing complementary dependencies that may be leveraged via combination therapy. Interrogation of single-cell RNA sequencing profiles from seven metastatic breast cancer patients, using perturbational profiles of clinically relevant drugs, identified drugs predicted to invert the activity of MR proteins governing the transcriptional state of chemoresistant CSLCs, which were then validated by CROP-seq assays. The top drug, the anthelmintic albendazole, depleted this subpopulationin vivowithout noticeable cytotoxicity. Moreover, sequential cycles of albendazole and paclitaxel—a commonly used chemotherapeutic —displayed significant synergy in a patient-derived xenograft (PDX) from a TNBC patient, suggesting that network-based approaches can help develop mechanism-based combinatorial therapies targeting complementary subpopulations.

Statement of significance

Network-based approaches, as shown in a study on metastatic breast cancer, can develop effective combinatorial therapies targeting complementary subpopulations. By analyzing scRNA-seq data and using clinically relevant drugs, researchers identified and depleted chemoresistant Cancer Stem-Like Cells, enhancing the efficacy of standard chemotherapies.
Whole genome assembly and annotation of the King Angelfish (Holacanthus passer) gives insight into the evolution of marine fishes of the Tropical Eastern Pacific
Authors: Gatins Remy , Arias Carlos F. , Sánchez Carlos , Bernardi Giacomo , León Luis F. De
Published: November 2023

Holacanthusangelfishes are some of the most iconic marine fishes of the Tropical Eastern Pacific (TEP). However, very limited genomic resources currently exist for the genus. In this study we: i) assembled and annotated the nuclear genome of the King Angelfish (Holacanthus passer),and ii) examined the demographic history ofH. passerin the TEP. We generated 43.8 Gb of ONT and 97.3 Gb Illumina reads representing 75X and 167X coverage, respectively. The final genome assembly size was 583 Mb with a contig N50 of 5.7 Mb, which captured 97.5% complete Actinoterygii Benchmarking Universal Single-Copy Orthologs (BUSCOs). Repetitive elements account for 5.09% of the genome, and 33,889 protein-coding genes were predicted, of which 22,984 have been functionally annotated. Our demographic model suggests that population expansions ofH. passeroccurred prior to the last glacial maximum (LGM) and were more likely shaped by events associated with the closure of the Isthmus of Panama. This result is surprising, given that most rapid population expansions in both freshwater and marine organisms have been reported to occur globally after the LGM. Overall, this annotated genome assembly will serve as a resource to improve our understanding of the evolution ofHolacanthusangelfishes while facilitating novel research into local adaptation, speciation, and introgression in marine fishes.
Entorhinal cortex glutamatergic and GABAergic projections bidirectionally control discrimination and generalization of hippocampal representations
Authors: Robert Vincent , O’Neil Keelin , Rashid Shannon K. , Johnson Cara D. , De La Torre Rodrigo G. , Zemelman Boris V. , Clopath Claudia , Basu Jayeeta
Published: November 2023

Discrimination and generalization are crucial brain-wide functions for memory and object recognition that utilize pattern separation and completion computations. Circuit mechanisms supporting these operations remain enigmatic. We show lateral entorhinal cortex glutamatergic (LECGLU) and GABAergic (LECGABA) projections are essential for object recognition memory. Silencing LECGLUduringin vivotwo-photon imaging increased the population of active CA3 pyramidal cells but decreased activity rates, suggesting a sparse coding function through local inhibition. Silencing LECGLUalso decreased place cell remapping between different environments validating this circuit drives pattern separation and context discrimination. Optogenetic circuit mapping confirmed that LECGLUdrives dominant feedforward inhibition to prevent CA3 somatic and dendritic spikes. However, conjunctively active LECGABAsuppresses this local inhibition to disinhibit CA3 pyramidal neuron soma and selectively boost integrative output of LEC and CA3 recurrent network. LECGABAthus promotes pattern completion and context generalization. Indeed, without this disinhibitory input, CA3 place maps show decreased similarity between contexts. Our findings provide circuit mechanisms whereby long-range glutamatergic and GABAergic cortico-hippocampal inputs bidirectionally modulate pattern separation and completion, providing neuronal representations with a dynamic range for context discrimination and generalization.
Nicotinamide Riboside Supplementation Ameliorates Mitochondrial Dysfunction and Neuronal Loss in POLG Mutant Midbrain Organoids
Authors: Yangzom Tsering , Chen Anbin , Sullivan Gareth John , Liang Kristina Xiao
Published: November 2023

Mitochondrial dysfunction is associated with many neurodegenerative disorders and is particularly prominent in conditions tied toPOLGmutations.POLGencodes DNA polymerase gamma vital for mitochondrial DNA replication. Employing 3D human pluripotent stem cell-derived midbrain organoids (hMOs), harbouringPOLGmutations, this study explores their differentiation, transcriptional alterations, and underlying pathways of neurodegeneration associated withPOLGmutations. The generated hMOs displayed midbrain specificity and, at three months, a reduced diameter, suggesting growth challenges fromPOLGmutations. A reduced presence of dopaminergic neurons, particularly in DA2 and ventral midbrain classes, was evident. Intriguingly, post-treatment with 1 mM Nicotinamide Riboside (NR), an NAD+precursor, the organoids demonstrated an increased count of DA and VMN neurons and an elevated gene expression, especially in processes crucial to mitochondrial and synaptic functions. Our findings spotlight NAD+supplementation has potential therapeutic value in addressing POLG-associated neuronal and mitochondrial deficits. Moreover, the unique insights garnered from single-cell RNA sequencing, and enrichment analyses further emphasize the significance of mitochondrial disturbances and potential interventions for POLG-related neurodegenerative conditions. In summary, we underscore the transformative potential of NAD+in managing neurodegenerative diseases associated withPOLGmutations. It also establishes the utility ofPOLGmutant hMOs as a potent research model.
Clock driven waves of Tbx6 expression prefigure somite boundaries
Authors: Venzin Olivier F. , Jollivet Chloé , Chiaruttini Nicolas , Rosspopoff Olga , Helsens Clément , Morelli Luis G. , Uriu Koichiro , Oates Andrew C.
Published: November 2023

The segmented body plan of vertebrates is established during embryogenesis by periodic and sequential formation of multi-cellular structures called somites. Somitogenesis is an example of patterning by a biological oscillator, the segmentation clock, which manifests as traveling waves of oscillating Hes/Her gene expression, reiterating during the formation of each1–3. How these waves are converted into the striped Mesp gene expression pattern that prefigures morphological somite boundaries4–8remains unclear. Here, we image this conversion in real-time at single-cell resolution in zebrafish, using light-sheet microscopy of a novel reporter of Tbx6, a key activator of Mesp expression. We observe cellular oscillations and kinematic waves of Tbx6 expression that are driven by Hes/Her genes. Tbx6 waves arrest precisely in boundary cells that eventually express Mesp, thereby prefiguring the Mesp pattern, whereas Hes/Her waves do not. Although Hes/Her oscillations began before somitogenesis9–11, the first Tbx6 wave defines the boundary cells of the anterior-most somite, forming the head-trunk interface. Our findings imply that Tbx6 acts as a genetic clutch, converting Her/Hes pacemaker waves into Mesp stripes. We propose that this clock design shields the pacemaker from external perturbations, allowing flexible and robust patterning, making it of interest for organoids and tissue-engineering.
Computationally Driven Discovery and Characterization of SIRT3 Activating Compounds that Fully Recover Catalytic Activity under NAD+Depletion
Authors: Guan Xiangying , Upadhyay Alok , Dumpati Rama Krishna , Munshi Sudipto , Roy Samir , Chall Santu , Rahnamoun Ali , Reverdy Celina , Errasti Gauthier , Delacroix Thomas , Ghosh Anisha , Chakrabarti Raj
Published: November 2023

Mammalian sirtuins (SIRT1-SIRT7) are a family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacylases that play critical roles in lifespan and age-related diseases. The physiological importance of sirtuins has stimulated intense interest in designing sirtuin activating compounds. However, except for allosteric activators of SIRT1-catalyzed reactions that are limited to specific substrates, methodologies for the rational design of sirtuin activating compounds -- including compounds that activate mitochondrial sirtuins implicated in the age-related decline of cellular metabolism -- have been lacking. Here, we use computational high-throughput screening methodologies and a biophysical model for activation of the major mitochondrial sirtuin SIRT3 to identify novel small molecule activators of the human SIRT3 enzyme from a 1.2 million compound library. Unlike previously reported SIRT3 activators like Honokiol, which only transiently upregulate SIRT3 under non-steady state conditions and reduce the steady state catalytic efficiency of the enzyme, several of the novel compounds identified here are potent SIRT3 activators in both the steady and non-steady states. Two such compounds can almost double the catalytic efficiency of the enzyme with respect to NAD+, which would be sufficient to almost entirely compensate for the loss in SIRT3 activity that occurs due to the reduction in mitochondrial coenzyme concentration associated with aging, and display AC50s (concentrations of half-maximal activation) as low as 100 nM. The current work thus reports first-in-class, non-allosteric steady state activators that activate SIRT3 through a novel, mechanism-based mode of activation and that may be developed further for therapeutic applications.
Importations of SARS-CoV-2 lineages decline after nonpharmaceutical interventions in phylogeographic analyses
Authors: Goliaei S. , Foroughmand-Araabi M.H. , Roddy A. , Weber A. , Översti S. , Kühnert D. , McHardy A.C.
Published: November 2023

The onset of the SARS-CoV-2 pandemic marked a period of substantial challenges as the virus and its variants rapidly spread, placing enormous strain on both society and healthcare systems. Prior to the widespread availability of vaccines, non-pharmaceutical interventions such as reducing contacts, antigenic testing, or travel restrictions were the primary means of reducing viral transmission and case numbers, and quantifying the success of these measures is therefore key for future pandemic preparedness. Using SARS-CoV-2 genomes collected in systematic surveillance, we studied lineage importations for the third, pandemic wave in Germany, employing a large-scale Bayesian phylogenetic and phylogeographic analysis coupled to a longitudinal assessment of lineage importation dynamics over multiple sampling strategies. We evaluated the effect of twelve major nationwide nonpharmaceutical interventions (NPIs) on lineage importations and dissemination within the country. All NPIs were followed by reduced lineage importations, with the most substantial decreases seen for the provision of free rapid tests, the strengthening of regulations on mask-wearing in public transport and stores, as well as on internal movements and gatherings. Most SARS-CoV-2 lineages first appeared in the three states with the largest populations and most cases, and from there spread within the country. Importations began to rise before and peaked shortly after the Christmas holidays. Analysis of SARS-CoV-2 data revealed the substantial effects of free rapid tests and obligatory medical/surgical mask-wearing, suggesting these as key for pandemic preparedness, given their relatively few, negative socioeconomic effects. The approach quantifies the relationships between environmental factors at the host population level to viral lineage dissemination from genomic surveillance data, facilitating similar analyses of rapidly evolving pathogens in the future.
Temporal relationships between food insecurity, water insecurity, and generalized anxiety among rural Kenyans: seeking to clarify a climate-related syndemic
Authors: Goodman Michael L. , Sharma Shreela , Woldu Dawit , McPherson Heidi , Ramphul Ryan , Gitari Stanley , Gatwiri Christine
Published: November 2023

Background

Increased water and food insecurity are one mechanism through which climate change can undermine global mental health. Understanding correlations between mental health and resource insecurity is imperative to support local adaptive responses to climate change.

Objective

We investigate temporal relationships between food insecurity, water insecurity, and generalized anxiety within rural Kenyans (n=152 adults) during a period of erratic rainfall.

Method

Using refined existing scales of food and water insecurity and generalized anxiety, we assess temporal relationships between these factors using cross-lagged panel analysis of survey data collected in October 2021 and October 2022 among participants in a community empowerment program.

Results

Food and water insecurity demonstrated significant, positive, reciprocal cross-lagged correlations. Generalized anxiety demonstrated significant, positive, reciprocal cross-lagged correlations with water insecurity. Food insecurity was not correlated with generalized anxiety within or between panels.

Conclusions

Supporting climate adaptation requires understanding temporal relationships between mental health and water and food security. Anxiety may reduce capacities to adapt to water insecurity, as well as be reduced by water insecurity. Food security may increase the capacity of households to adapt to water insecurity, though further research is required to establish causation and mechanisms for all observed temporal correlations in this study.
‘Admissions to paediatric medical wards with a primary mental health diagnosis: a systematic review of the literature’
Authors: Vázquez-Vázquez Adriana , Smith Abigail , Gibson Faith , Roberts Helen , Mathews Gabrielle , Ward Joseph , Viner Russell , Nicholls Dasha , Cornaglia Francesca , Roland Damian , Phillips Kirsty , Hudson Lee
Published: November 2023

Objective

To systematically review the literature describing children and young people (CYP) admissions to paediatric general wards because of primary mental health reasons, particularly in MH crisis.

Design

PubMed, Embase, PsychINFO, Web of Science and Google Scholar were searched. We addressed five search questions to inform: trends and/or the number of admissions, the risk factors for adverse care, the experiences of CYP, families/carers and health care professionals (HCPs) and the evidence of interventions aimed at improving the care during admissions.

Two reviewers independently assessed the relevance of abstracts identified, extracted data and undertook quality assessment. This review was registered with Prospero (CRD42022350655).

Results

Thirty-two studies met the inclusion criteria. Eighteen addressed trends and or numbers/proportions of admissions, 12 provided data about the views/experiences of HCPs, two provided data about CYPs’ experiences and four explored improving care. We were unable to identify studies examining risk factors for harm during admissions, but studies did report the length of stay in general paediatric/adult settings while waiting for specialised care, which could be considered a risk factor while caring for this group.

Conclusions

MH admissions to children’s wards are a long-standing issue and are increasing. CYP will continue to need to be admitted in crisis, with paediatric wards a common allocation whilst waiting for assessment. For services to be delivered effectively and for CYPs and their families/carers to feel supported and HCPs to feel confident, we need to facilitate more integrated physical and MH pathways of care.

What is already known on this topic?

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There is evidence that both the number of paediatric admissions and the severity of MH crisis in CYP have increased. Children’s wards are not designed to treat CYP with MH problems and HCPs haven’t had enough training.

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There is no published systematic review on this topic.

What this study adds?

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This is the first systematic review on CYP admissions to paediatric wards with a primary MH indication.

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Evidence suggested increased numbers of admissions to paediatric wards over time. HCPs reported concerns about skill sets to manage CYP with MH presentations and questioned the appropriateness of the acute ward for this care.

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There is limited evidence on CYP experiences during admissions and on studies to improve care. We found no evidence of specific risk factors for adverse care for CYP and families/carers during admissions and no studies on families/carers’ experiences.
A mechanical model of ocular bulb vibrations and implications for acoustic tonometry
Authors: Tambroni Nicoletta , Tomassetti Giuseppe , Lombardi Silvia , Repetto Rodolfo
Published: November 2023

In this study, we propose a comprehensive mechanical model of ocular bulb vibrations and discuss its implications for acoustic tonometry. The model describes the eye wall as a spherical, pre-stressed elastic shell containing a viscoelastic material and accounts for the interaction between the elastic corneoscleral shell and the viscoelastic vitreous humor. We investigate the natural frequencies of the system and the corresponding vibration modes, expanding the solution in terms of scalar and vector spherical harmonics. Our findings reveal the significant role of intraocular pressure (IOP) and ocular rigidity in influencing vibration frequencies, while the vitreous rheological properties primarily affect damping. This study contributes to the understanding of the mechanical behavior of the eye under dynamic conditions, with potential implications for non-contact intraocular pressure measurement techniques such as acoustic tonometry. The model can also be relevant for other ocular pathological conditions, such as traumatic retinal detachment, which are believed to be influenced by the dynamic behavior of the eye.
Topic: Effect of Lockdown Of COVID-19 And The Impact On People Living In Enugu State, Nigeria
Authors: Ojielo Nwadiuto C , Onwuliri Daniel C , Onuh Augustine , Ilo Ada , Njeze Ngozi R
Published: November 2023

Introduction

When the coronavirus (COVID-19) pandemic struck, countries employed diverse strategies in the control of the virus aimed at preventing, detecting, controlling and mitigating the impact of the pandemic. Initially, there was no known cure for this viral infection so this ‘stay-at-home’ necessitated the preventive measures to break the chain of transmission. This study aims to examine the different challenges people passed through as a result of this pandemic and the effect of the lockdown on people. This study will serve as the basis for future reference to know if this lockdown could be repeated in the face of another pandemic.

Methodology

The study was carried out in Enugu Metropolis, South East, Nigeria. This is a cross-sectional study among people living in Enugu State. Google forms were dispatched to adults from 18-65 years on social media or the internet. Data entry was to Excel, then to SPSS version 26 and analyzed with student’s t-test and Chi-square.

Results

From the study, 35% said there were financial losses, some complained of poor recreation, 52% of people said there was loss of learning opportunities for their children due to school shutdown 23% had a reduction in their income with 35% losing their job, 57.9% of people said the crime rate increased, 26.6% had a mental breakdown, 45.1% of people had relationship/spousal problems and 64.1% of people lost someone during the COVID-19 lockdown and There were also some benefits of the lockdown like 70% said there was reduction in RTA, air pollution, introduction to remote working popularly known as “working from home” and 32% of people claimed it caused family bonding. In all, 73% of people said they would not want or support a repeat lockdown.

Conclusion

The impact of the lockdown on the residents of Enugu State was generally not a palatable experience. From this study, though some good things were achieved, it led to a number of irreversible crises. It also caused serious implications like a decline to access to healthcare, economic effects, political, social and cultural effects, educational impacts, an increase in crime rate, domestic violence, religious impact, and environmental effects. In future, a better method of approach is recommended.
A 4-year review of amniocentesis at a tertiary hospital in Ethiopia: an experience from a LMIC
Authors: Mekuria Haile G. , Suga Hilkiah K. , Bekele Gadise
Published: November 2023

Background

Amniocentesis is a technique for withdrawing amniotic fluid from the uterine cavity using a needle via a trans-abdominal approach. It has multiple diagnostic and therapeutic uses such as prenatal genetic studies and amnioreduction for polyhydramnios. The commonest indications are advanced maternal age and increased risk on maternal serum screening. The objective of this study is to review the common indications, outcomes and complications of amniocentesis at a tertiary hospital in Ethiopia.

Methods

A retrospective cross-sectional study was conducted at a tertiary hospital in Ethiopia. Data was collected from the Fetomaternal division’s log records and follow-up charts during the time period of 2019 to 2022. All records of patients who had amniocentesis done were included in the study. Socio-demographic information and obstetric history and variables related to the procedures were retrieved. Descriptive statistics was done using the software IBM Statistical Package for Social Sciences (SPSS) version 25.

Results

A total of 35 patients’ records were reviewed. The mean maternal age was 32 years (range, 19 – 43 years). The mean gestational age was 20.9 weeks (SD ± 2.2). The commonest indications for amniocentesis were previous history of Down syndrome (11%), advanced maternal age (9%) and QUAD 1:200 for Down syndrome (6%). Karyotype test was done in 29 of the 35 amniocentesis cases which was normal in 72% of the cases, 17% had Trisomy-21 and 11% had Trisomy-18. Fifty-two percent of the pregnancy had a live full term delivery and 25% of the cases terminated the pregnancy.

Conclusion

The most common indications for amniocentesis in Ethiopia were abnormal ultrasound finding, advanced maternal age and abnormal QUAD test results. Around a quarter of the genetic tests which were done after the procedure had chromosomal abnormalities, from which, the majority were terminated. There was no complication related to the procedure.
Anemia during pregnancy and adverse maternal outcomes in Georgia – a birth registry-based cohort study
Authors: Skhvitaridze Natia , Gamkrelidze Amiran , Manjavidze Tinatin , Brenn Tormod , Anda Erik , Rylander Charlotta
Published: November 2023

Background

Anemia in pregnancy is an important public health challenge; however, it has not been thoroughly studied in Georgia. We assessed the prevalence of anemia during pregnancy across Georgia and the association between anemia in the third trimester of pregnancy and adverse maternal outcomes.

Methods

We used data from the Georgian Birth Registry and included pregnant women who delivered between January 1, 2019, and August 31, 2022 (n=158,668). The prevalence of anemia (hemoglobin (Hb) < 110 g/L) at any time during pregnancy was calculated per region. Women in the third trimester were classified into three groups, based on their lowest measured Hb value: no (Hb ≥110 g/L, reference group); mild (Hb 100-109 g/L); and moderate to severe anemia (Hb <99 g/L). Adjusted odds ratios (aOR) with 95% confidence intervals (CIs) were calculated for the associations between anemia status and post-delivery intensive care unit (ICU) admission and preterm delivery.

Results

The prevalence of anemia occurring at least once during pregnancy was 40.6%, with large regional differences in anemia prevalence (25.1%–47.0%). Of 105,811 pregnant women with Hb measurements in the third trimester, 71.0% had no anemia; 20.9%, mild anemia; and 8.1%, moderate or severe anemia. The odds of post-delivery ICU admission did not increase linearly with decreasing Hb value (Pfor trend .13), and the relationship was inverse for preterm delivery (Pfor trend .01).

Conclusions

A considerable proportion of pregnant women in Georgia have anemia during pregnancy, and the prevalence and quality of reporting differ across regions. Anemia occurring in the third trimester did not substantially increase the odds of maternal ICU admission or preterm delivery. To accelerate national progress toward the Sustainable Development Goals and mitigate the consequences of anemia, equal countrywide access to high-quality antenatal care programs and complete registration of Hb values should be ensured.
c-Jun Signaling During Initial HSV-1 Infection Modulates Latency to Enhance Later Reactivation in addition to Directly Promoting the Progression to Full Reactivation
Authors: Dochnal Sara A. , Whitford Abigail L. , Francois Alison K. , Krakowiak Patryk A. , Cuddy Sean , Cliffe Anna R.
Published: November 2023

Herpes simplex virus-1 (HSV-1) establishes a latent infection in peripheral neurons and can periodically reactivate to permit transmission and clinical manifestations. Viral transactivators required for lytic infection are largely absent during latent infection and therefore HSV-1 relies on the co-option of neuronal host signaling pathways to initiate its gene expression. Activation of the neuronal c-Jun N-terminal kinase (JNK) cell stress pathway is central to initiating biphasic reactivation in response to multiple stimuli. However, how host factors work with JNK to stimulate the initial wave of gene expression (known as Phase I) or the progression to full, Phase II reactivation remains unclear. Here, we found that c-Jun, the primary target downstream of neuronal JNK cell stress signaling, functions during reactivation but not during the JNK-mediated initiation of Phase I gene expression. Instead, c-Jun was required for the transition from Phase I to full HSV-1 reactivation and was detected in viral replication compartments of reactivating neurons. Interestingly, we also identified a role for both c-Jun and enhanced neuronal stress during initial neuronal infection in promoting a more reactivation-competent form of HSV-1 latency. Therefore, c-Jun functions at multiple stages during HSV latent infection of neurons to promote reactivation. Importantly, by demonstrating that initial infection conditions can contribute to later reactivation abilities, this study highlights the potential for latently infected neurons to maintain a molecular scar of previous exposure to neuronal stressors.

Importance

The molecular mechanisms that regulate the reactivation of HSV-1 from latent infection are unknown. In addition, studies on the mechanisms of reactivation can be complicated by factors that act during latency establishment to ultimately impact reactivation. Here we focused on the host transcription and pioneer factor c-Jun because it is the main target of the JNK cell stress pathway known to be important in exit of HSV from latency. Surprisingly, we found that c-Jun does not act with JNK during exit from latency but instead promotes the transition to full reactivation. Moreover, c-Jun and enhanced neuronal stress during initial neuronal infection promoted a more reactivation-competent form of HSV-1 latency. c-Jun therefore functions at multiple stages during HSV latent infection of neurons to promote reactivation and serves as a relevant therapeutic target for attenuating reactivation and related clinical consequences. Importantly, this study contributes to a growing body of evidence thatde novoHSV-1 infection conditions can modulate latent infection and impact future reactivation events, raising important questions on the clinical impact of stress during initial HSV-1 acquisition on future reactivation events and consequences.
A systematic screening assay identifies efficient small guide RNAs for CRISPR activation
Authors: Arvidsson Elin , Lobo Diana Duarte , Sabarese Ermelinda , Duarte Fabio , Nobre Rui Jorge , Lundberg Cecilia , Quintino Luis
Published: November 2023

CRISPR-mediated gene activation (CRISPRa) encompasses a growing field of biotechnological approaches with exciting implications for gene therapy. However, there is a lack of experimental validation tools for selecting efficient sgRNAs for downstream applications. Here, we present a screening assay capable of identifying efficient single- and double sgRNAs through fluorescence quantification in vitro. In addition, we provide a tailored Golden Gate cloning workflow for streamlined incorporation of selected sgRNA candidates into lentiviral (LVs) or adeno-associated vectors (AAVs). The overall workflow was validated using therapeutically relevant genes for neurodegenerative diseases, such asTfeb,Adam17, andSirt1. The most efficient sgRNAs also demonstrated activation of endogenous gene expression at mRNA and protein levels. Further proof- of-principle assays usingTfebindicated that gene activation was accompanied by increased levels of Lc3b. This data demonstrates the potential of the screening assay to identify functionally efficient sgRNA candidates across multiple genes along with streamlined cloning of viral vectors and may assist in accelerating future developments of CRISPRa-focused applications.
Thermal and pigment characterization of environmental fungi in the urban heat island of Baltimore City
Authors: Smith Daniel F. Q. , Bencomo Alexa , Faiez Tasnim Syakirah , Casadevall Arturo
Published: November 2023

One of the major barriers of fungal infections of mammals is the inability to grow and/or survive at mammalian body temperature, typically around 37°C. This has provided mammals an advantage over fungi. However, environmental fungi may soon adapt to persist at higher temperatures, consistent with mammalian body temperature, due to thermal selection pressures imposed by climate change, global warming, and increased frequency of extreme heat events. Consequently, there is a need for more updated information about the thermal tolerance range of fungi near humans, such as in urban areas. The heat island effect suggests that cities are up to 8°C warmer than their suburban counterparts because of increased heat production, asphalt coatings and reduced greenspace among other factors, and it is more common in lower income and marginalized urban communities. Thus, urban centers are at increased risk for the emergence of heat tolerant fungi. In this study, we developed a methodology to collect and archive fungal isolates from sidewalk and soil samples in both warmer and cooler neighborhoods in Baltimore, Maryland. We demonstrate a novel methodology for fungal sample collection from sidewalks, employing the use of standardized and commercially available taffy. Analysis of fungal isolates collected from warmer neighborhoods revealed greater thermal tolerance and lower pigmentation, suggesting local adaptation to heat. Lower pigmentation in hotter areas is consistent with the notion that fungi use pigmentation to help regulate their temperature. Further, we identified the robust presence of the polyextremotolerant fungusAureobasidium pullalansfrom the warmest neighborhood in Baltimore, further showing that the extreme conditions of cities can drive proliferation of extremotolerant fungi. This study develops new techniques for environmental fungal collection and provides insight on the fungal census in an urban setting that can inform future work to study how urban environments may drive stress/thermotolerance in fungi, which could alter fungal interactions with humans and impact human health.
Metabolic rewiring compensates for the loss of glutamate and aspartate biosynthesis inBacillus subtilis
Authors: Mardoukhi Mohammad Saba Yousef , Rapp Johanna , Irisarri Iker , Gunka Katrin , Link Hannes , Marienhagen Jan , de Vries Jan , Stülke Jörg , Commichau Fabian M.
Published: November 2023

Glutamate serves as the major cellular amino group donor. InBacillus subtilis, glutamate is synthesized by the combined action of the glutamine synthetase and the glutamate synthase (GOGAT). The glutamate dehydrogenases are devoted to glutamate degradationin vivo. To keep the cellular glutamate concentration high, the genes and the encoded enzymes involved in glutamate biosynthesis and degradation need to be tightly regulated depending on the available carbon and nitrogen sources. Serendipitously, we found that the inactivation of theansRandcitGgenes encoding the repressor of theansABgenes and the fumarase, respectively, enables the GOGAT-deficientB. subtilismutant to synthesize glutamate via a non-canonical fumarate-based ammonium assimilation pathway. We also show that the de-repression of theansABgenes is sufficient to restore aspartate prototrophy of anaspBaspartate transaminase mutant. Moreover, with excess nitrogen,B. subtilismutants lacking fumarase activity show a growth defect that can be relieved byaspBoverexpression, by reducing arginine uptake and by decreasing the metabolic flux through the TCA cycle. It will be interesting to investigate whether theB. subtilisstrain using the alternative glutamate biosynthesis route can evolve in such a way that it robustly grows during nitrogen limitation and excess.
The impact of knocking out theLeishmania majortelomerase RNA (LeishTER): from altered cell proliferation to decreased parasite infectivity
Authors: de Oliveira Beatriz Cristina Dias , Shiburah Mark Ewusi , Assis Luiz Henrique de Castro , Fontes Veronica Silva , Gallo-Francisco Pedro Henrique , Giorgio Selma , Batista Marcos Meuser , Correia Soeiro Maria Nazaré , Menna-Barreto Rubem Figueiredo Sadok , Aoki Juliana Ide , Coelho Adriano Cappellazzo , Cano Maria Isabel Nogueira
Published: November 2023

The telomerase RNA, TER, is an intrinsic component of the telomerase ribonucleoprotein complex. It contains the telomere template sequence copied by the enzyme during telomere elongation. This unique molecule shows divergent nucleotide sequences but a more conserved secondary structure containing domains involved with telomerase assembly and biogenesis. The present work aims to characterize the biological roles played by theLeishmaniaTER component (LeishTER) in parasite homeostasis. We generated double knockout (LmTER-/-) parasites, which showed a distinct growth pattern at early passages, characterized by lower density and an extended stationary phase compared to the control. Although this pattern normalized after multiple in vitro passages, ablation ofLeishTER affected cell division and proliferation, with cells arrested at the G0/G1 phase. Progressive telomere shortening was also observed during continuous passages, along with a reduction in the expression of TERRA29. Complementation with the episomal expression ofLeishTER did not restore telomere length to the control levels, corroborating preliminary results showing that the overexpression of TER has a dominant negative effect on parasite lifespan.LmTER-/-also presented a higher percentage of gamma-H2A phosphorylation, likely due to stalled replication forks since no DNA damage was observed. Also, no plasma membrane modifications were detected, but pro-survival autophagic signals were present. Intriguingly,LmTER-/-retained the ability to transform into metacyclic forms, although its in vitro infectivity and growth inside the host cell were compromised. Together, these results highlight the importance of TER in parasite lifespan and open a discussion about its potential as a drug target againstLeishmania.
Tick extracellular vesicles undermine epidermal wound healing during hematophagy
Authors: Marnin Liron , Valencia Luisa M. , Bogale Haikel N. , Laukaitis-Yousey Hanna J. , Rolandelli Agustin , Ferraz Camila Rodrigues , O’Neal Anya J. , Schmitter-Sánchez Axel D. , Cuevas Emily Bencosme , Nguyen Thu-Thuy , Leal-Galvan Brenda , Rickert David M. , Tays Mendes M. , Samaddar Sourabh , Rainer Butler L. , Singh Nisha , Paz Francy E. Cabrera , Oliver Jonathan D. , Jameson Julie M , Munderloh Ulrike G. , Chávez Adela S. Oliva , Mulenga Albert , Park Sangbum , Serre David , Pedra Joao H.F.
Published: November 2023

Wound healing has been extensively studied through the lens of inflammatory disorders and cancer, but limited attention has been given to hematophagy and arthropod-borne diseases. Hematophagous ectoparasites, including ticks, subvert the wound healing response to maintain prolonged attachment and facilitate blood-feeding. Here, we unveil a strategy by which extracellular vesicles (EVs) ensure blood-feeding and arthropod survival in three medically relevant tick species. We demonstrate through single cell RNA sequencing and murine genetics that wildtype animals infested with EV-deficientIxodes scapularisdisplay a unique population of keratinocytes with an overrepresentation of pathways connected to wound healing. Tick feeding affected keratinocyte proliferation in a density-dependent manner, which relied on EVs and dendritic epidermal T cells (DETCs). This occurrence was linked to phosphoinositide 3-kinase activity, keratinocyte growth factor (KGF) and transforming growth factor β (TGF-β) levels. Collectively, we uncovered a strategy employed by a blood-feeding arthropod that impairs the integrity of the epithelial barrier, contributing to ectoparasite fitness.