bluuebunny/crossref_metadata_2025 huggingface dataset:
Approach to FNA of Pancreatic Cysts
Authors: Jhala Nirag , Jhala Darshana
Published: October 2022

Pancreatic cysts are increasingly detected on imaging studies. Accurate determination of the type of cyst is important to provide appropriate care for patients. It is also very clear that not one single modality can provide adequate diagnostic information for pancreatic cysts. A multimodal approach to the diagnosis of pancreatic cyst is the key. This review will highlight how to approach to fine-needle aspiration of pancreatic cysts. The review will also highlight salient features of common neoplastic pancreatic cysts along with the use of ancillary testing which includes biochemical testing, commonly utilized molecular tests, and/or immunohistochemical tests to provide an accurate diagnosis.
Interaction of Depot Medroxyprogesterone Acetate and Tenofovir Disoproxil Fumarate/Emtricitabine on Peripheral Blood Mononuclear Cells and Cervical Tissue Susceptibility to HIV Infection and Pharmacokinetics
Authors: Coleman Jenell S. , Diniz Clarissa P. , Fuchs Edward J. , Marzinke Mark A. , Aung Wutyi , Bakshi Rahul P. , Farzadegan Homayoon , Bream Jay H. , Nilles Tricia L. , Hudson Sherry , Bumpus Namandjé N. , Schwartz George J. , Rosenblum Michael A. , Rooney James F. , Hendrix Craig W.
Published: October 2022

Background:

Depot medroxyprogesterone acetate (DMPA) is a widely used contraceptive method. HIV pre-exposure prophylaxis with emtricitabine and tenofovir disoproxil fumarate (F/TDF) is highly effective in reducing HIV acquisition in women. We sought to determine the impact of DMPA on F/TDF pharmacokinetics and pharmacodynamics.

Methods:

Twelve healthy premenopausal cisgender women were enrolled and each completed 4 sequential conditions: (1) baseline, (2) steady-state F/TDF alone, (3) steady-state F/TDF + DMPA, and (4) DMPA alone. Assessments included clinical, pharmacokinetic, viral infectivity (ex vivo challenge of peripheral blood mononuclear cells by X4- and R5-tropic green fluorescent protein pseudoviruses and cervical tissue by HIVBaL), endocrine, immune cell phenotyping, and renal function.

Results:

Compared with baseline, F/TDF (± DMPA) significantly decreased both %R5- and X4-infected CD4 T cells and F/TDF + DMPA decreased cervical explant p24 (all P < 0.05). The %R5- and X4-infected CD4 T cells were higher during DMPA alone than during F/TDF periods and lower than baseline (not statistically significant). Cervical explant p24 fell between baseline and F/TDF values (not statistically significant). There were neither statistically significant differences in F/TDF pharmacokinetics, including total or renal clearance of either antiviral drug, nor changes in glomerular filtration rate with the addition of DMPA. There were few immune cell phenotypic differences across conditions.

Conclusions:

F/TDF decreased HIV infection in both challenge assays, whereas DMPA alone did not enhance HIV infection in either challenge assay. DMPA did not alter F/TDF pharmacokinetics or renal function.
Syphilis With Multiple Pulmonary Nodules and Bone Lesions Detected on Computed Tomography and 18F Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography
Authors: Tahara Aoi , Hattori Hidekazu , Matsuyama Takahiro , Akamatsu Hokuto , Shigeyasu Yoshiko , Ina Takuma , Horiguchi Tomoya , Imaizumi Kazuyoshi , Saito Kenta , Iwata Yohei , Sugiura Kazumitsu , Tsukamoto Tetsuya , Toyama Hiroshi , Ohno Yoshiharu
Published: October 2022

Syphilis can cause a wide range of systemic manifestations, such as papular rash, malaise, weight loss, muscle aches, generalized lymphadenopathy, and meningitis. However, pulmonary involvement in patients with secondary syphilis is thought to be relatively rare. Moreover, bone involvement in patients with secondary syphilis is also considered rare, and only a few cases of involvement of lung and bone in such patients have been reported. In this paper, we report a case of secondary syphilis with pulmonary involvement in the form of multiple nodules with low attenuation areas, lymphadenopathy and multiple bone lesions detected on computed tomography and 18F fluorodeoxyglucose-positron emission tomography/computed tomography.
Human brucellosis: An observational study from a tertiary care centre in northern India
Authors: Kumari Renu , Kalyan Raj Kumar , Jain Amita , Kumar Puneet , Gupta Kamlesh Kumar , Jahan Asmat , Manoj Anunaya
Published: October 2022

Brucellosis is a neglected zoonotic disease that affects both humans and animals. In humans, brucellosis begins with chronic illness leading to great financial losses from not being able to work well and continued treatment costs. Joint pain is the common presentation of brucellosis and there are several risk factors associated with brucellosis. But few such researches have come from northern India. We studied to detect and characterize the Brucella species from patients having complaints of joint pain and also to know the potential causes of human brucellosis. A total of 200 blood samples were collected from the participants having joints pain, from September 2019 to September 2021 at Gandhi memorial and associated hospital of King George’s Medical University, Lucknow, Uttar Pradesh, and tested by serology for anti brucella IgM and IgG, molecular tests by RTPCR, conventional PCR and automated blood culture system. The study showed positive results by anti-brucella IgM ELISA 19 (9.5%), anti brucella IgG 23 (11.5%), and of those, 1 (0.5%) was positive for both anti-brucella IgM and anti-brucella IgG ELISA. Out of 19 anti-brucella IgM ELISA positive, 8 (4%) samples were positive for PCR/ RT-PCR and that was negative for anti-brucella IgG ELISA. All blood culture reports of all patients were negative.  Our study concluded that anti-brucella IgM ELISA was more accurate than anti-brucella IgG ELISA in detecting human brucellosis. Consumption of animal products (i.e. milk, a dairy product of cow, buffalo, goat, and meat of goat) and contact with animals were the main risk factors that were identified for brucella disease.
Viral aetiology of acute central nervous system infections in children, Iran
Authors: Khalili Maryam , Rahimi Hajiabadi Hamid , Akbari Mojtaba , Nasr Esfahani Bahram , Saleh Rana , Moghim Sharareh
Published: October 2022

Introduction. Viral infections are increasingly an important cause of central nervous system (CNS) complications.

Hypothesis/Gap Statement. There is no comprehensive insight about CNS infections due to viral agents among Iranian children.

Aim. This study aimed to investigate the viral aetiology, clinical and epidemiological profile of children with acute infections of the CNS.

Methodology. A prospective study was conducted on children at the referral hospital in Isfahan, Iran, from June 2019 to June 2020. A multiplex PCR assay was used to detect the viral causative agent in cerebrospinal fluid and throat/rectal swab samples.

Results. Among 103 patients with eligible criteria, a confirmed or probable viral aetiology was detected in 41 (39.8 %) patients, including enteroviruses – 56.1 %, herpes simplex virus 1/2 (HSV-1/2) – 31.7 %, Epstein-Barr virus – 17.1 %, varicella-zoster virus (VZV) – 9.7 %, influenza A virus (H1N1) –4.9 % and mumps – 2.4 %. There was a higher proportion of PCR-positive samples in infants than in other age groups. Encephalitis and meningoencephalitis were diagnosed in 68.3 % (28/41) and 22 % (9/41) PCR-positive cases, respectively.

Conclusion. The findings of this research provide insights into the clinical and viral aetiological patterns of acute CNS infections in Iran, and the importance of molecular methods to identify CNS viruses. HSV and VZV were identified as important causes of encephalitis in young children.
CRISPR-cas heterogeneity and plasmid incompatibility types in relation to virulence determinants of Shigella
Authors: Das Ankita , Doss Kamali , Mandal Jharna
Published: October 2022

Introduction. Virulence factors (VFs) are the most potent weapon in the molecular armoury of

Shigella

. In bacteria, the mobile genetic elements (MGEs) are contributors to the evolution of different types of clustered regularly interspaced short palindromic repeats-CRISPR associated genes (CRISPR-cas) variants and plasmid incompatibility types. The present study explored the virulence potential of

Shigella

in relation to the CRISPR-cas pattern and incompatibility types among the isolates.

Hypothesis/Gap Statement. The profile of the CRISPR-cas systems among clinical isolates of

Shigella

in India has not been reported earlier. Limited knowledge is available on the pattern of plasmid incompatibility groups among clinical isolates

Shigella

. The bias is always towards studying the genetic elements associated with AMR, but the present study highlights CRISPR-cas and incompatibility types among

Shigella

in association with virulence.

Aim. We aimed to investigate the distribution of virulence factors, CRISPR-cas pattern followed by plasmid incompatibility types among

Shigella

isolates.

Methodology. Between 2012–2017, a total of 187 isolates of

Shigella

were included in the study. The virulence genes' distribution was carried out. CRISPR-cas profiling followed by analysis of the repeats and spacers was carried out. PCR-based replicon typing was used to determine the incompatibility types. The interplay was statistically determined using STATA.

Results. The distribution of virulence genes showed varied pattern with ipaH present in all the isolates followed by ompA (93.6 %), virF (66.8 %), ial and sen (60.4 %), set1A (39.6 %) and set1B (39 %). CRISPR 1, CRISPR 3 and Cas6-Cas5 region were dominantly conserved. Twenty-two types of spacers were identified. The CRISPR3 repeat appeared to have a highly conserved sequence. CRISPR2 being the least common CRISPR type showed a strong association with an array of virulence genes (ial-set1A-set1B-virF) while CRISPR1 being the most dominant showed the least association with virulence genes (sen-virF). The dominant plasmids were found to be belonging to the inc FII group. The incompatibility groups FII, IncIγ, U, FIIS, FIIK, K, A/C, I1alpha was found to be associated with a greater number of virulence genes.

Conclusion. The isolates showed increasing diversity in their gene content that contributes to increasing heterogeneity among the isolates, which is a known virulence strategy among pathogens.
Angular reproduction numbers improve estimates of transmissibility when disease generation times are misspecified or time-varying
Authors: Parag Kris V , Cowling Benjamin J , Lambert Ben C
Published: October 2022

We introduce theangular reproduction numberΩ, which measures time-varying changes in epidemic transmissibility resulting from variations in both the effective reproduction numberR, and generation time distributionw. Predominant approaches for tracking pathogen spread either inferRor the epidemic growth rater. However,Ris biased by mismatches between the assumed and truew, whileris difficult to interpret in terms of the individual-level branching process underpinning transmission.Randrmay also disagree on the relative transmissibility of epidemics or variants (i.e.,rA>rBdoes not implyRA>RBfor variants A and B). We find that Ω responds meaningfully to mismatches and time-variations inwwhile mostly maintaining the interpretability ofR. We prove that Ω>1 impliesR>1 and that Ω agrees withron the relative transmissibility of pathogens. Estimating Ω is no more difficult than inferringR, uses existing software, and requires no generation time measurements. These advantages come at the expense of selecting one free parameter. We propose Ω as complementary statistic toRandrthat improves transmissibility estimates whenwis misspecified or time-varying and better reflects the impact of interventions, when those interventions concurrently changeRandwor alter the relative risk of co-circulating pathogens.
Changes in Treatment and Severity of Multisystem Inflammatory Syndrome in Children: An EHR-based cohort study from the RECOVER program
Authors: Schuchard Julia , Thacker Deepika , Webb Ryan , Bailey Charles , Bennett Tellen D. , Cogen Jonathan D. , Jhaveri Ravi , Jone Pei-Ni , Lee Grace M. , Maltenfort Mitchell , Mejias Asuncion , Rogerson Colin M. , Schulert Grant S. , Mendonca Eneida A.
Published: October 2022

Objectives

The purpose of this study was to examine how the treatment and severity of multisystem inflammatory syndrome in children (MIS-C) has changed over more than two years of the COVID-19 pandemic in the United States.

Methods

Electronic health record data were retrieved from the PEDSnet network as part of the NIH Researching COVID to Enhance Recovery (RECOVER) Initiative. The study included data for children ages 0 to 20 years hospitalized for MIS-C from March 1, 2020 through July 20, 2022. Descriptive statistics for MIS-C treatments and laboratory results were computed for three time periods of interest: March 1, 2020 – May 31, 2021 (pre-Delta); June 1 – December 31, 2021 (primarily Delta); January 1 – July 20, 2022 (primarily Omicron). Standardized differences measured the effect size of the difference between Omicron and pre-Omicron cohorts.

Results

The study included 946 children with a diagnosis of MIS-C. The largest differences in the Omicron period compared to prior years were decreases in the percentage of children with abnormal troponin (effect size = 0.40), abnormal lymphocytes (effect size = 0.33), and intensive care unit (ICU) visits (effect size = 0.34). There were small decreases in the Omicron period for the majority of treatments and abnormal laboratory measurements examined, including infliximab, anticoagulants, furosemide, aspirin, IVIG without steroids, echocardiograms, mechanical ventilation, platelets, ferritin, and sodium.

Conclusions

This study provides the first evidence that the severity of MIS-C declined in the first half of the year 2022 relative to prior years of the COVID-19 pandemic in the United States.

Article Summary

Using electronic health record data for 946 children, we found evidence that the severity of MIS-C declined during the first half of the year 2022.

What’s Known on This Subject

The clinical management of multisystem inflammatory syndrome in children (MIS-C) has commonly included intravenous immune globulin, steroids, and non-steroidal anti-inflammatory agents. Many children with MIS-C have required intravenous fluids, inotropes and vasopressors, and in some cases, mechanical ventilation.

What This Study Adds

Recent decreases in the percentage of children with MIS-C that have abnormal troponin, abnormal lymphocytes, or intensive care unit visits provide evidence that the severity of MIS-C has declined in the first half of the year 2022.
Distribution of gestational age by maternal and infant characteristics in US birth certificate data: informing gestational age assumptions when clinical estimates are not available
Authors: Margulis Andrea V , Calingaert Brian , Kawai Alison T , Rivero-Ferrer Elena , Anthony Mary S
Published: October 2022

We aimed to describe the distribution of gestational age at birth (GAB) to inform the estimation of GAB when clinical or obstetric estimates are not available for perinatal epidemiologic research. We estimated GAB (median, mode, mean, standard deviation) and percentage born at each gestational week in groups based on plurality and other variables for live births in CDC’s US birth data.

In 2020, 3,617,213 newborns had birth certificates with nonmissing GAB. Among singletons (3,501,693), median and mode GAB were both 39 weeks. Births with lower median GAB were from women with eclampsia (37 weeks) or receiving intensive care (37 weeks); newborns receiving intensive care (37 weeks); infants with birth weight < 2,500 grams (35 weeks), < 1,500 grams (28 weeks), or < 1,000 grams (25 weeks); and newborns not discharged alive (23 weeks). Among twins (112,633), median GAB was 36 weeks (mode, 37 weeks). Additional noteworthy groups were women with 7-8 (median, 35 weeks) or 0-6 prenatal visits (median, 34 weeks) or aged 15-19 years (median, 35 weeks).

Some maternal and infant groups had distinct GAB distributions in the US. This information can be useful in estimating GAB when individual-level clinical estimates are not available.
Long-Term Forecasting of a Motor Outcome Following Rehabilitation in Chronic Stroke via a Hierarchical Bayesian Model of Motor Learning
Authors: Schweighofer Nicolas , Ye Dongze , Luo Haipeng , D’Argenio David Z. , Winstein Carolee
Published: October 2022

Background

Given the heterogeneity of stroke, it is important to determine the best course of motor therapy for each patient, i.e., to personalize rehabilitation based on predictions of long-term outcomes. Here, we propose a Hierarchical Bayesian dynamical (i.e., state-space) model of motor learning to forecast long-term changes in a motor outcome due to rehabilitation in the chronic phase post-stroke.

Methods

The model incorporates the effects of clinician-supervised training, self-training, and forgetting. In addition, to improve forecasting early in rehabilitation, when data are sparse or unavailable, we use a hierarchical Bayesian structure, which incorporates prior information from similar patients. We use this dynamical model to re-analyze Motor Activity Log (MAL) data of participants with chronic stroke included in two clinical trials: 1) the DOSE trial, in which participants were assigned to a 0, 15, 30, or 60-hour dose condition (data of 40 participants analyzed), and 2) the EXCITE trial, in which participants were assigned a 60-hour dose, in either an immediate or a delayed condition (95 participants analyzed).

Results

For both datasets, the dynamical model accounts well for individual trajectory in the MAL during and outside of training and better fits the data than other simpler models without the effects of either supervised training, self-training or forgetting or (static) regression models. We then show how the model can be used to forecast the MAL of new participants up to 8 months ahead and how the hierarchical structure improves the accuracy of the predictions early in training when data are sparse. Finally, we verify that this model, despite its simplicity, can reproduce previous findings of the DOSE trial on the efficiency, efficacy, and retention of motor therapy.

Conclusion

In future work, such forecasting models can be simulated for different stages of recovery, dosages, and training schedules to optimize rehabilitation for each person.
An integrated compositional approach to investigating the full effect of dietary intake on health
Authors: Corrêa Leite Maria Léa
Published: October 2022

Nutritional epidemiology studies aim to investigate the impact of diet on disease risk, and their findings inform subsequent dietary recommendations. The issue of whether foods or nutrients should be the unit of exposure in such studies is a topic of debate. However, although nutrient-based analyses can elucidate biological mechanisms, they are technically problematic; furthermore, although foods have been considered the most suitable unit of dietary exposure because “we eat food, not nutrients” and the findings of food-based analyses can be easily translated into dietary advice, there is a greater risk of confounding and/or reverse causation because food selection and consumption are closely related to socio-economic and behavioural factors. This note describes an integrated approach that combines the positive aspects of nutrient-and food-based analyses. Individual dietary exposure is characterised by its overall macro-and micronutrient compositions and, in line with the compositional nature of dietary data, methods based on log-ratio transformations of nutrient compositions are used in diet/outcome association analyses that provide fully adjusted isocaloric estimates of the impact of specific nutrient balances on health outcomes. These estimates can then be combined with the nutrient compositions of selected foods to produce outcome-related scores which, as they are defined regardless of a subject’s food selection/consumption, are not subject to confounding or reverse causation, and therefore have important implications for public health professionals. Data coming from an Italian population-based study were used to illustrate the approach in the context of diet/serum uric acid relationships, and some resulting new insights were briefly discussed.
Efficacy of Linear Regression Modelling of SARS-CoV-2 cases based on local wastewater surveillance
Authors: Lehmann Martin , Geissler Michael , Hahn Waldemar , Gebler Richard , Helm Björn , Dumke Roger , Dalpke Alexander , Wolfien Markus
Published: October 2022

In the ongoing SARS-CoV-2 pandemic, there is a need for new strategies for surveillance and identification of arising infection waves. Reported cases of new infections based on individual testing are soon deemed inaccurate due to ever changing regulations and limited testing capacity. Wastewater based epidemiology is one promising solution that can be broadly applied with low efforts in comparison to current large-scale testing of individuals. Here, we are combining local wastewater data from the city of Dresden (Germany) along with reported cases and vaccination data from a central database (Robert-Koch-Institute) with virus variant information to investigate the correlation of virus concentrations in the wastewater and reported SARS-CoV-2 cases. In particular, we compared Linear Regression and Machine Learning (ML) models, which are both revealing an existing correlation of virus particles in wastewater and reported cases. Our findings demonstrate that the different virus variants of concern (Alpha, Delta, BA.1, and BA.2) contribute differently over time and parameters vary between variants, as well. By comparing the Linear Regression and ML-based models, we observed that ML can achieve a good fit for training data, but Linear Regression is a more robust tool, especially for new virus variants. We hereby conclude that deriving the rate of new infections from local wastewater by applying Linear Regression may be a robust approximation of tracing the state of the pandemic for practitioners and policy makers alike.
Meeting the 2030 End TB goals in the wake of COVID-19: a modelling study of countries in the USAID TB portfolio
Authors: Arinaminpathy Nimalan , Mukadi Ya Diul , Bloom Amy , Vincent Cheri , Ahmedov Sevim
Published: October 2022

Progress towards the 2030 End TB goals has seen severe setbacks due to disruptions arising from the COVID-19 pandemic. For governments and international partner organizations supporting the global TB response, there is a need to assess what level of effort is now needed to reach these goals. Using mathematical modelling, we addressed this question for the countries being supported by the United States Agency for International Development (USAID). We aggregated the 24 countries in the USAID portfolio into three geographical country groups: South Asia; sub-Saharan Africa; and Central Asian Republics/Europe (CAR/EU). From 2023 onwards we modelled a combination of interventions acting at different stages of the care cascade, including improved diagnostics; reducing the patient care seeking delay; and the rollout of a disease-preventing vaccine from 2025 onwards. We found that in all three country groups, meeting the End TB goals by 2030 will require a combination of interventions acting at stages of the TB care cascade. Specific priorities may depend on country settings, for example with public-private mix playing an important role in countries in South Asia and elsewhere. When a vaccine becomes available, its required coverage to meet the 2030 goals will vary by setting, depending on the amount of preventive therapy that has already been implemented. Monitoring the number-needed-to-test to identify 1 person with TB in community settings can provide a useful measure of progress towards the End TB goals.
Association of indoor use of pesticides with CKD of unknown origin
Authors: Alvand Saba , Alatab Sudabeh , Dalvand Sahar , Shahraki-Sanavi Fariba , Kaykhaei Mahmoud Ali , Shahraki Elham , Barar Erfaneh , Sepanlou Sadaf G , Ansari-Moghaddam Alireza
Published: October 2022

Diabetes mellitus and hypertension are the two main etiologies of chronic kidney disease (CKD). However, CKD subjects of unknown origin (CKDu) have been recognized recently. One of the proposed causes is pesticide use in farmers. On the other hand, house use of pesticides has never been investigated in developing countries. In this study, we aimed to investigate the association between house use of pesticide and their exposure time with CKDu. This study is part of the population-based cohort of Prospective Epidemiological Research Studies in Iran. We used the baseline data of the Zahedan Adult Cohort Study. We dropped all subjects with diabetes mellitus and/ or hypertension, egfr 60-89 ml/min/1.73 m2, and unavailable creatinine measurement. Subjects with egfr of less than 60 ml/min/1.73 m2through MDRD equations were defined as CKDu and compared with subjects with egfr of more than 90 ml/min/1.73 m2. The house use of pesticides and exposure time were asked through a questionnaire. In this study 10072 participants enrolled, and 1079 remained in the final sample after appliance the exclusion criteria. Female sex, single marital status, low physical activity, TG more than 150 mg/dl, BMI of more than 25, non-smokers, house use of pesticide, and more time exposed to pesticides were associated with CKDu. The effects of age, female sex, TG more than 150 mg/dl, pesticide use (1.36;95%CI 1.01-1.84), and the third tertile of exposure time compared to non-users (1.64;95%CI 1.07-2.51) remained significant in multivariable analysis. We found a positive association between the use and exposure time with kidney function in cases without diabetes mellitus and hypertension. Further longitudinal studies should be carried out to assess this effect.
Mechano-Cas12a Assisted Tension Sensor (MCATS) for Massively Amplified Cell Traction Force Measurements
Authors: Duan Yuxin , Szlam Fania , Hu Yuesong , Chen Wenchun , Li Renhao , Ke Yonggang , Sniecinski Roman , Salaita Khalid
Published: October 2022

Cells transmit piconewton forces to mediate essential biological processes such as coagulation. One challenge is that cell-generated forces are infrequent, transient, and difficult to detect. Here, we report the development of Mechano-Cas12a Assisted Tension Sensor (MCATS) that utilizes CRISPR-Cas12a to transduce and amplify the molecular forces generated by cells. We demonstrate the power of MCATS by detecting the forces generated by as few as ~103human platelets in a high-throughput manner. Platelet forces are significantly inhibited when blood samples are treated with FDA-approved drugs such as aspirin, eptifibatide(integrilin®), 7E3(Reopro®), and ticagrelor (Brelinta®). Because MCATS requires <5uL of blood/measurement, a single blood draw can generate a personalized dose-response curve and IC50for this panel of drugs. Platelet activity and force-generation are tightly associated, and hence MCATS was used to quantify platelet dysfunction following cardiopulmonary bypass (CPB) in a pilot study of 7 cardiac patients. We found that MCATS detected platelet dysfunction which strongly correlated with the need for platelet transfusion to limit bleeding. These results indicate MCATS may be a useful assay for clinical applications.
Hexanucleotide repeat expansions in C9orf72 alter microglial responses and prevent a coordinated glial reaction in ALS
Authors: Masrori Pegah , Bijnens Baukje , Davie Kristofer , Poovathingal Suresh Kumar , Storm Annet , Hersmus Nicole , Fumagalli Laura , Van Den Bosch Ludo , Fiers Mark , Thal Dietmar Rudolf , Mancuso Renzo , Van Damme Philip
Published: October 2022

Neuroinflammation is an important hallmark in amyotrophic lateral sclerosis (ALS). Experimental evidence has highlighted a role of microglia in the modulation of motor neuron degeneration. However, the exact contribution of microglia to both sporadic and genetic forms of ALS is still unclear. We generated single nuclei profiles of spinal cord and motor cortex from sporadic andC9orf72ALS patients, as well as controls. We particularly focused on the transcriptomic responses of both microglia and astrocytes. We confirmed thatC9orf72is highly expressed in microglia and shows a diminished expression in carriers of the hexanucleotide repeat expansion (HRE). This resulted in an impaired response to disease, with specific deficits in phagocytic and lysosomal transcriptional pathways. Astrocytes also displayed a dysregulated response inC9orf72ALS patients, remaining in a homeostatic state. This suggests that C9orf72 HRE alters a coordinated glial response, which ultimately would increase the risk for developing ALS. Our results indicate thatC9orf72HRE results in a selective microglial loss-of-function, likely impairing microglial-astrocyte communication and preventing a global glial response. This is relevant as it indicates that sporadic and familial forms of ALS may present a different cellular substrate, which is of great importance for patient stratification and treatment.
Species Richness and Speciation Rates for all Terrestrial Animals Emerge from a Synthesis of Ecological Theories
Authors: Fernandes Lucas D. , Hintzen Rogier E. , Thompson Samuel E. D. , Barychka Tatsiana , Tittensor Derek , Harfoot Mike , Newbold Tim , Rosindell James
Published: October 2022

Abstract

The total number of species on earth and the rate at which new species are created are fundamental questions for ecology, evolution and conservation. These questions have typically been approached separately, despite their obvious interconnection. In this manuscript we approach both questions in conjunction, for all terrestrial animals, which enables a more holistic integration and generates novel emergent predictions. To do this, we combine two previously unconnected bodies of theory: general ecosystem modelling and individual based ecological neutral theory. General ecosystem models provide us with estimated numbers of individual organisms, separated by functional group and body size. Neutral theory, applied within a guild of functionally similar individuals, connects species richness, speciation rate and number of individual organisms. In combination, for terrestrial endotherms where species numbers are known, they provide us with estimates for speciation rates as a function of body size and diet class. Extrapolating the same rates to guilds of ectotherms enables us to estimate the species richness of those groups, including species yet to be described. We find that speciation rates per species per million years decrease with increasing body size. Rates are also higher for carnivores compared to omnivores or herbivores of the same body size. Our estimate for the total number of terrestrial species of animals is in the range 1.03 − 2.92 million species, a value consistent with estimates from previous studies, despite having used a fundamentally new approach. Perhaps what is most remarkable about these results is that they have been obtained using only limited data from larger endotherms and their speciation rates, with the rest of the predictive process being based on mechanistic theory. This work illustrates the potential of a new approach to classic eco-evolutionary questions, while also adding weight to existing predictions. As we now face an era of dramatic biological change, new methods will be needed to mechanistically model global biodiversity at the species and individual organism level. This will be a huge challenge but the combination of general ecosystem models and neutral theory that we introduce here could be the only way to tractably achieve it.
Intuitive interpretation of heterochromatin and euchromatin through rapid Hi-C analysis
Authors: Sumikama Takashi , Fukuma Takeshi
Published: October 2022

Hi-C is a technique that provides contact frequencies between pairs of loci on chromosomes. The conventional classification of heterochromatin and euchromatin based on Hi-C data is performed by principal component analysis; however, it requires long computational times and does not provide insight into the difference in contact frequencies between heterochromatin and euchromatin. Here, we propose a simple, intuitive and rapid method named the scaled contact number (SCN), which allows the contact frequencies to be visually interpreted and heterochromatin and euchromatin to be classified based on Hi-C results in a few minutes for long chromosomes at 1-kb resolution. The robustness of SCN was validated by confirming that SCN with reduced reads gives almost the same results as the original SCN. Overall, the approach described herein thus considerably decreases the time and computing power required to analyze Hi-C and further provides mechanistic insight indicating that euchromatin has more contacts than heterochromatin.
Detection of adaptation to light environment in myopia-associated loci Diversity of the myopia genetic background
Authors: Xia Tian , Nakayama Kazuhiro
Published: October 2022

The time spent outdoors and exposure to bright sunlight have been reported to play important roles in preventing myopia progression. Myopia prevalence is generally low in Europe, and we hypothesized that local adaptation of ancestors in insufficient sunlight regions might underlie this low prevalence in Europeans. To verify this conjecture and understand how ancestry adaptation influenced on the diversity of myopia genetic background, polygenic risk scores (PRS) was calculated and revealed that the genetic risk of myopia increased as latitude decreased in the 1000 genome projects (1KGP) EUR, and we further determined selection signatures near the rhodopsin (RHO) coding region in 1KGP Finnish. The derived allele frequencies of identified loci correlated with sunshine duration worldwide, and the allele age was estimated to be ∼20,000 years, coincidently after the divergence of Europeans and East Asians.TSPAN10(rs9747347) is significantly associated with both myopia and pigmentation in Europeans, and we found selection favored the myopia risk allele in EUR. Haplotype comparison highlighted the divergence between EAS and EUR inRHOand pigmentation-associated loci, and the frequency diversity in Admixed American (AMR) of these loci was found to originate from recent admixture and local adaptation. We concluded that local adaptation played a role in myopia prevalence deviation, and selective pressure in the myopia-associated loci may originate from adaptation to sunlight environments rather than myopia itself. These findings reveal traces of evolution history of myopia’s genetic background, providing a new aspect of understanding the patterns and diversity of myopia prevalence.

Author Summary

The explanation for the distinct bias of myopia prevalence among ethnicities remains controversial, we took an evolutionary approach to understanding the history and diversity of the genetic background of myopia. We detected selection signatures of myopia-associated loci near the rhodopsin gene (RHO) in the 1000 Genome Project Europeans. Ambient light exposure is crucial for myopia;RHOis mainly expressed in rod cells and is extremely sensitive to light, indicating that local adaptation might contribute to myopia prevalence bias. Parallel geographical disposition of allele frequencies of myopia-associated loci inRHOand pigmentation-associated markers was observed, implying that selective pressure in myopia-associated loci may originate from adaptation events involved in sunlight exposure rather than myopia itself.
Engineering the substrate specificity of toluene degrading enzyme XylM using biosensor XylS and machine learning
Authors: Ogawa Yuki , Saito Yutaka , Yamaguchi Hideki , Katsuyama Yohei , Ohnishi Yasuo
Published: October 2022

Enzyme engineering using machine learning has been developed in recent years. However, to obtain a large amount of data on enzyme activities for training data, it is necessary to develop a high-throughput and accurate method for evaluating enzyme activities. Here, we examined whether a biosensor-based enzyme engineering method can be applied to machine learning. As a model experiment, we aimed to modify the substrate specificity of XylM, a rate-determining enzyme in a multistep oxidation reaction catalyzed by XylMABC inPseudomonas putida. XylMABC naturally converts toluene and xylene to benzoic acid and toluic acid, respectively. We aimed to engineer XylM to improve its conversion efficiency to a non-native substrate, 2,6-xylenol. Wild-type XylMABC slightly converted 2,6-xylenol to 3-methylsalicylic acid, which is the ligand of the transcriptional regulator XylS inP. putida. By locating a fluorescent protein gene under the control of thePmpromoter to which XylS binds, a XylS-producingEscherichia colistrain showed higher fluorescence intensity in a 3-methylsalicylic acid concentration-dependent manner. We evaluated the 3-methylsalicylic acid productivity of XylM variants using the fluorescence intensity of the sensor strain as an indicator. The obtained data provided the training data for machine learning for the directed evolution of XylM. Two cycles of machine learning-assisted directed evolution resulted in the acquisition of XylM-D140E-V144K-F243L-N244S with 15 times higher productivity than wild-type XylM. These results demonstrate that an indirect enzyme activity evaluation method using biosensors is sufficiently quantitative and high-throughput to be used as training data for machine learning. The findings expand the versatility of machine learning in enzyme engineering.
Theta phase specific modulation of hippocampal memory neurons
Authors: Rahsepar Bahar , Noueihed Jad , Norman Jacob F. , Lahner Benjamin , Quick Melanie H. , Ghaemi Kevin , Pandya Aashna , Fernandez Fernando R. , Ramirez Steve , White John A.
Published: October 2022

I.

The theta rhythm, a quasi-periodic 4-10 Hz oscillation, is observed during memory processing in the hippocampus, with different phases of theta hypothesized to separate independent streams of information related to the encoding and recall of memories. At the cellular level, the discovery of hippocampal memory cells (engram neurons), as well as the modulation of memory recall through optogenetic activation of these cells, has provided evidence that certain memories are stored, in part, in a sparse ensemble of neurons in the hippocampus. In previous research, however, engram reactivation has been carried out using open loop stimulation at fixed frequencies; the relationship between engram neuron reactivation and ongoing network oscillations has not been taken into consideration. To address this concern, we implemented a closed-loop reactivation of engram neurons that enabled phase-specific stimulation relative to theta oscillations in the local field potential. Using this real-time approach, we tested the impact of activating engram neurons during the peak (encoding phase) and trough (recall phase) of theta oscillations. Consistent with previously hypothesized functions of theta oscillations in memory function, we show that stimulating engram neurons at the trough of theta is more effective in eliciting behavioral recall than either fixed frequency stimulation or stimulation at the peak of theta. Moreover, phase-specific trough stimulation is accompanied by an increase in the coupling between gamma and theta oscillations in CA1 hippocampus. Oure results provide a causal link between phase-specific activation of engram cells and the behavioral expression of memory.
Urine-based detection of biomarkers indicative of chronic kidney disease in a patient cohort from Ghana
Authors: Wruck Wasco , Boima Vincent , Erichsen Lars , Thimm Chantelle , Koranteng Theresa , Kwakyi Edward , Antwi Sampson , Adu Dwomoa , Adjaye James
Published: October 2022

Chronic kidney disease (CKD) is a global health burden with a continuously increasing prevalence associated with an increasing incidence of diabetes and hypertension in aging populations. The CKD definition of a more than three months lasting low glomerular filtration rate (GFR) or other renal impairments including proteinuria implies that multiple factors may contribute to the disease. While there are indications of ethnic differences it is hard to disentangle these from confounding social factors. Usually, CKD is detected in later stages of the disease when irreversible renal damage has already occurred, thus suggesting a need for early non-invasive diagnostic markers.

In this study, we explored the urine secretome of a CKD patient cohort from Ghana employing a kidney-injury and a more general cytokine assay.

We identified panels of kidney-specific cytokine markers which were also gender-specific and a panel of gender-independent cytokine markers. The gender-specific markers are IL10 and MME for male and CLU, RETN, AGER, EGFR and VEGFA for female. The gender-independent cytokine markers were APOA1, ANGPT2, C5, CFD, GH1, ICAM1, IGFBP2, IL8, KLK4, MMP9 and SPP1 (up-regulated) and FLT3LG, CSF1, PDGFA, RETN and VEGFA (down-regulated).

APOA1 – the major component of HDL particles – was up-regulated in Ghanaian CKD patients and its co-occurrence with APOL1 in a subpopulation of HDL particles may point to specific CKD-predisposing APOL1 haplotypes in patients of African descent – this however needs further investigation. The identified panels may lay down the foundation for CKD-biomarker assays to be confirmed in further studies with a larger cohort of patients.
The functional and structural characterization ofXanthomonas campestrispv.campestriscore effector XopP revealed a new kinase activity
Authors: Kotsaridis Konstantinos , Michalopoulou Vassiliki A. , Tsakiri Dimitra , Kotsifaki Dina , Kefala Aikaterini , Koundourakis Nikolaos , Celie Patrick H.N. , Kokkinidis Michael , Sarris Panagiotis F.
Published: October 2022

The exocyst complex subunit protein Exo70B1 plays a crucial role in a variety of cell mechanisms including immune responses against pathogens. The calcium dependent kinase 5 (CPK5) ofArapidopsis thaliana, phosphorylatesAtExo70B1 upon functional disruption. We previously reported that, theXanthomonas campestrispv.campestiseffector XopP, compromises Exo70B1 and bypasses the host’s hypersensitive response (HR), in a way that is still unclear.

Herein we designed an experimental approach based on biophysical, biochemical and molecular assays, based on structural and functional predictions, as well as, utilizing Aplhafold and DALI online servers respectively, in order to characterize thein vivo XccXopP function.

The interaction betweenAtExo70B1 andXccXopP is very stable in high temperatures, while theAtExo70B1 appeared to be phosphorylated atXccXopP expressing transgenicArabidopsis.XccXopP reveals similarities with known mammalian kinases, and phosphorylatesAtExo70B1 at Ser107, Ser111, Ser248, Thr309 and Thr364. Furthermore,XccXopP protectsAtExo70B1 from AtCPK5 phosphorylation.

Together these findings show that,XccXopP is an effector, which not only functions as a novel serine/threonine kinase upon its host’s protein targetAtExo70B1, but also protects the latter from the innate AtCPK5 phosphorylation, to bypass the host’s immune responses.
Induction of telomerase in p21-positive cells counteracts capillaries rarefaction in aging mice lung
Authors: Lipskaia Larissa , Breau Marielle , Cayrou Christelle , Churikov Dmitri , Braud Laura , Fouillade Charles , Curras-Alonso Sandra , Bauwens Serge , Jourquin Frederic , Fiore Frederic , Castellano Rémy , Josselin Emmanuelle , Sánchez-Ferrer Carlota , Giovinazzo Giovanna , Gilson Eric , Flores Ignacio , Londono-Vallejo Arturo , Adnot Serge , Géli Vincent
Published: October 2022

Telomerase is required for long-term cell proliferation and linked to stem cells. This is evident in the lung where short telomeres are associated with lung dysfunction. We constructed a mouse model in which the telomerase (Tert) is expressed from the p21Cdkn1apromoter. We found that this peculiar Tert expression curb age-related emphysema and pulmonary perivascular fibrosis in old mice. In old mice lungs, such Tert expression preferentially occurs in endothelial cells where it reduces the number of senescent endothelial cells. Remarkably, we report that Tert counteracts the age-related decline in capillary density. This was associated with an increased number of Cd34+ cells identified as a subclass of capillary cells with proliferative capacity. Expression of catalytically inactiveTertneither prevents the decline of capillary density in old mice nor protects against age-related emphysema and fibrosis. These findings reveal that telomerase decreases age-decline of pulmonary functions by sustaining microvasculature regeneration and outgrowth.
EEG mismatch responses in a multi-modal roving stimulus paradigm provide evidence for probabilistic inference across audition, somatosensation and vision
Authors: Grundei Miro , Schröder Pia , Gijsen Sam , Blankenburg Felix
Published: October 2022

The human brain is constantly subjected to a multi-modal stream of probabilistic sensory inputs. EEG signatures, such as the mismatch negativity (MMN) and the P3, can give valuable insight into neuronal probabilistic inference. Although reported for different modalities, mismatch responses have largely been studied in isolation, with a strong focus on the auditory MMN. To investigate the extent to which early and late mismatch responses across modalities represent comparable signatures of uni- and cross-modal probabilistic inference in the hierarchically structured cortex, we recorded EEG from 32 participants undergoing a novel tri-modal roving stimulus paradigm. The employed sequences consisted of high and low intensity stimuli in the auditory, somatosensory and visual modalities and were governed by uni-modal transition probabilities and cross-modal conditional dependencies. We found modality specific signatures of MMN (∼100-200ms) in all three modalities, which were source localized to the respective sensory cortices and shared right lateralized pre-frontal sources. Additionally, we identified a cross-modal signature of mismatch processing in the P3a time range (∼300-350ms), for which a common network with frontal dominance was found. Across modalities, the mismatch responses showed highly comparable parametric effects of stimulus train length, which were driven by standard and deviant response modulations in opposite directions. Strikingly, the P3a responses across modalities were increased for mispredicted compared to predicted and unpredictable stimuli, suggesting sensitivity to cross-modal predictive information. Finally, model comparisons indicated that the observed single trial dynamics were best captured by Bayesian learning models tracking uni-modal stimulus transitions as well as cross-modal conditional dependencies.
Cell-intrinsic and -extrinsic functions of the ESCRT-III component Shrub in cytokinetic abscission ofDrosophilaSensory Organ precursor
Authors: Bruelle Céline , Pinot Mathieu , Daniel Emeline , Daudé Marion , Mathieu Juliette , Borgne Roland Le
Published: October 2022

While the molecular mechanisms underlying the abscission of isolated cells are largely decrypted, those of fast-cycling, epithelial progenitors surrounded by epidermal cells (ECs) connected by junctions remain largely unexplored. Here, we investigated the remodeling of the permeability barrier ensured by septate junctions (SJs) during cytokinesis of Drosophila sensory organ precursor (SOP). We report that SOP cytokinesis involves the coordinated polarized assembly and remodeling of SJs in the dividing cell and its neighbors, which remained connected via membrane protrusions pointing toward the SOP midbody. SJs assembly and midbody basal displacement occur more rapidly in SOP than in ECs, leading to a faster disentanglement of the protrusions that precedes midbody release. As reported in isolated cells, the endosomal sorting complex required for transport-III component Shrub/CHMP4B is recruited at the midbody and cell-autonomously regulates abscission. In addition, we found that Shrub is recruited to membrane protrusions, is required for SJ integrity, and that alteration of SJ integrity leads to premature abscission. Our study uncovers cell-intrinsic and -extrinsic functions of Shrub in epithelial abscission to support the coordination of permeability barrier maintenance and abscission in SOPs.