bluuebunny/crossref_metadata_2025 huggingface dataset:
VIII. Account of the repetition of Mr. Christie's experiments on the magnetic properties imported to an iron plate by rotation, at Port Bowen, in May and June,1825. By Lieutenant Henry Foster, R. N. F. R. S.; together with Mr. Christie's remarks thereon.
Authors: Foster Henry , Christie
Published: March 2022

Previous to our leaving England in 1824, Mr. Christie stated to me that he had some time ago discovered singular magnetic properties to be imparted to iron by simply making it revolve about an axis, and that these properties were exhibited in the different deviations which a plate of that metal would cause in a horizontal needle, according as it was made to revolve gently by the hand in one direction or the opposite: wishing me also to pursue these experiments as opportunities, offered, in the high magnetic latitudes we were likely' to visit in H. M. S. Hecla.
Mr. Christie's remarks on the repetition of his experiments by Lieut. Foster, at Port Bowen, in 1825.
Authors: Christie Samuel Hunter , Foster Henry
Published: March 2022

Having a considerable time previous to the sailing of the late North-Western Expedition, in 1824, discovered that peculiar magnetic effects were produced in iron by rotation, I was desirous of having some of the experiments which I had made, repeated under the very interesting circumstances, as connected with magnetic phenomena, in which that expedition was likely to be placed. Mr. Foster readily offered to do this; and I feel happy in having this opportunity of acknowledging my obligations to him for the zealous and careful manner in which he performed the task which he had so kindly undertaken.
IX. Observations to determine the amount of atmospherical refraction at Port Bowen in the Years 1824-25.
Authors: Parry William Edward , Foster Henry , Ross James Clark
Published: March 2022

To ascertain correctly by actual observation the amount of atmospherical refraction at low altitudes and at various states of the barometer and thermometer, is a problem which has long occupied the attention of practical astronomers; and many elaborate theories have also been given to explain the anomalies which have hitherto attended the most careful observations.
Importance of transmembrane helix 4 of l-alanine exporter AlaE in oligomer formation and substrate export activity in Escherichia coli
Authors: Ihara Kohei , Kim Seryoung , Ando Tasuke , Yoneyama Hiroshi
Published: March 2022

AlaE is the smallest amino acid exporter identified in

Escherichia coli

. It exports l-alanine using the proton motive force and plays a pivotal role in maintaining intracellular l-alanine homeostasis by acting as a safety valve. However, our understanding of the molecular mechanisms of substrate export by AlaE is still limited because structural information is lacking. Due to its small size (149 amino acid residues), it has been speculated that AlaE functions by forming an oligomer. In this study, we performed chemical cross-linking and pull-down assays and showed that AlaE indeed generates homo-oligomers as a functional unit. Previous random mutagenesis experiments identified three loss-of-function AlaE point mutations in the predicted transmembrane helix 4 (TM4) region, two of which are present in the GxxxG motif. When alanine-scanning mutagenesis was applied to the TM4 region, the AlaE derivatives that had amino acid substitutions around the GxxxG motif showed low l-alanine export activities, indicating that the GxxxG motif in TM4 plays an important role in substrate export. However, these AlaE variants with low activity could still form oligomers. We therefore concluded that AlaE forms homo-oligomers and that the GxxxG motif in the TM4 region plays an essential role in AlaE activity but is not involved in AlaE oligomer formation.
High frequency and persistence of Anti-DSG2 antibodies in post COVID-19 serum samples
Authors: Lee Edward , Tyler Ryan E. , Johnson Derrick , Koh Natalie , Chi Ong Biauw , Foo Shi Yin , Tan Jack
Published: March 2022

Background

There is growing recognition that COVID-19 does cause cardiac sequelae. The underlying mechanisms involved are still poorly understood to date. Viral infections, including COVID-19, have been hypothesized to contribute to autoimmunity, by exposing previously hidden cryptic epitopes on damaged cells to an activated immune system Given the high incidence of cardiac involvement seen in COVID-19, our aim was to determine the frequency of anti-DSG2 antibodies in a population of post COVID-19 patients.

Methods and Results

300 convalescent serum samples were obtained from a group of post COVID-19 infected patients from October 2020 to February 2021. 154 samples were drawn 6 months post-COVID-19 infection and 146 samples were drawn 9 months post COVID infection. 17 samples were obtained from the same patient at the 6- and 9-month mark. An electrochemiluminescent-based immunoassay utilizing the extracellular domain of DSG2 for antibody capture was used. The mean signal intensity of anti-DSG2 antibodies in the post COVID-19 samples was significantly higher than that of a healthy control population (19+/−83.2 vs. 2.1+/−6.8, P value <0.001). Of note, 29.3% of the post COVID-19 infection samples demonstrated a signal higher than the 90th percentile of the control population and 8.7% were higher than the median found in ARVC patients. The signal intensity between the 6-month and 9-month samples did not differ significantly.

Conclusions

We report for the first time that recovered COVID-19 patients demonstrate significantly higher and sustained levels of anti-DSG2 autoantibodies as compared to a healthy control population, comparable to that of a diagnosed ARVC group.
Conceptualization, operationalization, and utilization of race and ethnicity in major medical journals 1995-2018: a systematic review
Authors: Martinez Rae Anne M. , Wilbur Rachel E. , Andrabi Nafeesa , Goodwin Andrea N. , Smith Natalie R. , Zivich Paul N.
Published: March 2022

Background

Systemic racial and ethnic inequities continue to be perpetuated through scientific methodology and communication norms despite efforts by medical institutions.

Purpose

To characterize methodological practices regarding race and ethnicity in U.S. research published in leading medical journals.

Data source

Articles published in Annals of Internal Medicine, BMJ, JAMA, The Lancet, and NEJM from 1995-2018 were sampled via PubMed.

Study Selection

All original, human subjects research conducted in the U.S.

Data Extraction

Information on definition, measurement, coding, use in analyses, and justifications was collected.

Data Synthesis

The proportion of U.S. medical research studies including race and/or ethnicity data increased between 1995 and 2018. No studies defined race or ethnicity. and most did not state how race and/or ethnicity was measured. Common coding schemes included: “Black, other, White,” “Hispanic, Non-Hispanic,” and “Black, Hispanic, other, White.” Race and/or ethnicity was most often used as a control variable, descriptive covariate, or matching criteria. Under 30% of studies included justification for their methodological choices regarding race and/or ethnicity.

Conclusions

Despite regular efforts by medical journals to implement new policies around race and ethnicity in medical research, pertinent methodological information was systematically absent from the majority of reviewed literature. This stymies critical disciplinary reflection and progress towards equitable practice.
Functional Determination of Calcium Binding Sites Required for the Activation of Inositol 1,4,5-trisphosphate receptors
Authors: Arige Vikas , Terry Lara E. , Wagner Larry E. , Baker Mariah R. , Fan Guizhen , Serysheva Irina I. , Yule David I.
Published: March 2022

Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) initiate a diverse array of physiological responses by carefully orchestrating intracellular calcium (Ca2+) signals in response to various external cues. Notably, IP3R channel activity is determined by several obligatory factors including IP3, Ca2+ and ATP. The critical basic amino acid residues in the N-terminal IP3-binding core (IBC) region that facilitate IP3 binding are well characterized. In contrast, the residues conferring the biphasic regulation by Ca2+ are yet to be ascertained. Using comparative structural analysis of Ca2+ binding sites identified in two main families of intracellular Ca2+-release channels, ryanodine receptors (RyRs) and IP3Rs, we identified putative acidic residues coordinating Ca2+ in the cytosolic calcium sensor region in IP3Rs. We determined the consequences of substituting putative Ca2+ binding, acidic residues in IP3R family members. We show that the agonist-induced Ca2+ release, single channel open probability (P0) and Ca2+ sensitivities are markedly altered when the negative charge on the conserved acidic side chain residues are neutralized. Remarkably, neutralizing the negatively charged side chain on two of the residues individually in the putative Ca2+ binding pocket shifted the Ca2+ required to activate IP3R to higher concentrations, indicating that these residues likely are a component of the Ca2+ activation site in IP3R. Taken together, our findings indicate that Ca2+ binding to a well conserved activation site is a common underlying mechanism resulted in increased channel activity shared by IP3Rs and RyRs.
Small molecule-mediated insulin hypersecretion induces transient unfolded protein response and loss of beta cell function
Authors: Rodrigues-dos-Santos Karina , Roy Gitanjali , Binns Derk D. , Grzemska Magdalena G. , Barella Luiz F. , Armoo Fiona , McCoy Melissa K. , Huynh Andrew V. , Yang Jonathan Z. , Posner Bruce A. , Cobb Melanie H. , Kalwat Michael A.
Published: March 2022

Pancreatic islet beta cells require a fine-tuned ER stress response for normal function; abnormal ER stress contributes to diabetes pathogenesis. Here, we identified a small molecule, SW016789, with time-dependent effects on beta cell ER stress and function. Acute treatment with SW016789 potentiated nutrient-induced calcium influx and insulin secretion, while chronic exposure to SW016789 transiently induced ER stress and shut down secretory function in a reversible manner. Distinct from the effects of thapsigargin, SW016789 did not affect beta cell viability or apoptosis, potentially due to a rapid induction of adaptive genes, weak signaling through the eIF2α kinase PERK, and lack of oxidative stress gene Txnip induction. We determined that SW016789 acted upstream of voltage-dependent calcium channels (VDCCs) and potentiated nutrient- but not KCl-stimulated calcium influx. Measurements of metabolomics, oxygen consumption rate, and G protein-coupled receptor signaling did not explain the potentiating effects of SW016789. In chemical co-treatment experiments we discovered synergy between SW016789 and activators of protein kinase C (PKC) and VDCCs, suggesting involvement of these pathways in the mechanism of action. Finally, chronically elevated calcium influx was required for the inhibitory impact of SW016789, as blockade of VDCCs protected human islets and MIN6 beta cells from hypersecretion-induced dysfunction. We conclude that beta cells undergoing this type of pharmacological hypersecretion have the capacity to suppress their function to mitigate ER stress and avoid apoptosis. These results have the potential to uncover beta cell ER stress mitigation factors and add support to beta cell rest strategies to preserve function.
Phenotypic Variation from Waterlogging in Multiple Perennial Ryegrass Varieties under Climate Change Conditions
Authors: Frisk Carl A. , Xistris-Songpanya Georgianna , Osborne Matthieu , Biswas Yastika , Melzer Rainer , Yearsley Jon M.
Published: March 2022

Identifying how various components of climate change will influence ecosystems and vegetation subsistence will be fundamental to mitigate negative effects. Climate change-induced waterlogging is understudied in comparison to temperature and CO2. Grasslands are especially vulnerable through the connection with global food security, with perennial ryegrass dominating many flood-prone pasturelands in North-western Europe. We investigated the effect of long-term waterlogging on phenotypic responses of perennial ryegrass using four varieties grown in atmospherically controlled growth chambers (ambient vs 2050, +2°C and eCO2) during two months of peak growth. Using image analysis and PCA methodologies, we assess how multiple predictors (phenotypic, environmental, genetic and temporal) influence overall plant performance and productivity. Long-term waterlogging was found to reduce leaf-colour intensity, with younger plants having purple hues indicative of anthocyanins. Plant performance and yield was lower in waterlogged plants, with tetraploid varieties coping better than diploid ones. The climate change treatment was found to reduce colour intensities further. Flooding was found to reduce plant productivity via reductions in colour pigments and root proliferation. These effects will have negative consequences for global food security from facing extreme weather events and flooding. Our approach can be adapted as plant health diagnostics tools via remote sensing and drone-technology.
Impacts of recreational angling on fish population recovery after a commercial fishing ban
Authors: Dainys Justas , Jakubavičiūtė Eglė , Gorfine Harry , Kirka Mindaugas , Raklevičiūtė Alina , Morkvėnas Augustas , Pūtys Žilvinas , Ložys Linas , Audzijonyte Asta
Published: March 2022

It is often assumed that recreational fishing has negligible impact on fish stocks compared to commercial fishing. Yet, for inland water bodies in densely populated areas, this is unlikely to be true. In this study we demonstrate remarkably variable stock recovery rates among different fish species with similar life histories in a large productive inland freshwater ecosystem (Kaunas Reservoir, Lithuania), where all commercial fishing has been banned since 2013. We conducted over 900 surveys of recreational anglers during a period of four years (2016 to 2021) to assess recreational fishing catches. These surveys are combined with drone and fishfinder device-based assessment of recreational fishing effort. Fish population recovery rates were assessed using standardised catch per unit effort time series. We show that recreational fishing is having a major impact in retarding the recovery of predatory species, such as pikeperch and perch. In contrast, recovery of roach, rarely caught by anglers, has been remarkably rapid and the species is now dominating the ecosystem. Our study demonstrates that recreational fishing can have strong impacts on some fish species, alter relative species composition and potentially change ecosystem state and dynamics.
Ependymal cell maturation is heterogeneous and ongoing in the mouse spinal cord and dynamically regulated in response to injury
Authors: Rodrigo Albors Aida , Singer Gail A. , May Andrew P. , Ponting Chris P. , Storey Kate G.
Published: March 2022

The spinal cord neural stem cell potential resides within the ependymal cells lining the central canal. These cells are, however, heterogeneous, and we know little about the biological diversity this represents. Here we use single-cell RNA-sequencing to profile adult mouse spinal cord ependymal cells. We uncover transcriptomes of known subtypes and a new mature ependymal cell state, that becomes more prominent with age. Comparison of ependymal cell transcriptomes from the brain and spinal cord revealed that ongoing cell maturation distinguishes spinal cord ependymal cells from their postmitotic brain counterparts. Using an ex vivo model of spinal cord injury, we show that ependymal cell maturation is reversible but also highly regulated. We revisit ependymal cell identities in adult human spinal cord and uncover evidence for their maturation and surprising ventralisation with age. This first in-depth characterisation of spinal cord ependymal cells paves the way to manipulation of distinct ependymal subtypes, provides insights into ependymal cell maturation dynamics and informs strategies for coaxing ependymal cell-driven spinal cord repair.
Gliotransmission of D-serine promotes thirst-directed behaviors inDrosophila
Authors: Park Annie , Croset Vincent , Otto Nils , Agarwal Devika , Treiber Christoph D. , Meschi Eleanora , Sims David , Waddell Scott
Published: March 2022

Thirst emerges from a range of cellular changes that ultimately motivate an animal to consume water. Although thirst-responsive neuronal signals have been reported, the full complement of brain responses is unclear. Here we identify molecular and cellular adaptations in the brain using single-cell sequencing of water deprivedDrosophila. Water deficiency primarily altered the glial transcriptome. Screening the regulated genes revealed astrocytic expression of theastray-encoded phosphoserine phosphatase to bi-directionally regulate water consumption. Astray synthesizes the gliotransmitter D-serine and vesicular release from astrocytes is required for drinking. Moreover, dietary D-serine rescuesaay-dependent drinking deficits while facilitating water consumption and expression of water-seeking memory. D-serine action requires binding to neuronal NMDA-type glutamate receptors. Fly astrocytes contribute processes to tripartite synapses and the proportion of astrocytes that are themselves activated by glutamate increases with water deprivation. We propose that thirst elevates astrocytic D-serine release, which awakens quiescent glutamatergic circuits to enhance water procurement.
TOR coordinates Cytokinin and Gibberellin signals mediating development and defense
Authors: Marash Iftah , Gupta Rupali , Anand Gautam , Leibman-Markus Meirav , Lindner Naomi , Israeli Alon , Nir Dov , Avni Adi , Bar Maya
Published: March 2022

Plants constantly perceive and process environmental signals and balance between the energetic demands of growth and defense. Growth arrest upon pathogen attack was previously suggested to result from a redirection of the plants’ metabolic resources towards the activation of plant defense. The energy sensor Target of Rapamycin (TOR) kinase is a conserved master coordinator of growth and development in all eukaryotes. Although TOR is positioned at the interface between development and defense, little is known about the mechanisms in which TOR may potentially regulate the relationship between these two modalities. The plant hormones cytokinin (CK) and gibberellin (GA) execute various aspects of plant development and defense. The ratio between CK and GA was reported to determine the outcome of developmental programs. Here, investigating the interplay between TOR-mediated development and TOR-mediated defense in tomato, we found thatTORsilencing resulted in rescue of several different aberrant developmental phenotypes, demonstrating that TOR is required for the execution of developmental cues. In parallel,TORinhibition enhanced immunity in genotypes with a low CK/GA ratio but not in genotypes with a high CK/GA ratio. TOR-inhibition mediated disease resistance was found to depend on developmental status, and was abolished in strongly morphogenetic leaves, while being strongest in mature, differentiated leaves. CK repressed TOR activity, suggesting that CK-mediated immunity may rely on TOR downregulation. At the same time, TOR activity was promoted by GA, andTORsilencing reduced GA sensitivity, indicating that GA signaling requires normal TOR activity. Our results demonstrate that TOR likely acts in concert with CK and GA signaling, executing signaling cues in both defense and development. Thus, differential regulation of TOR or TOR-mediated processes could regulate the required outcome of development-defense prioritization.
Plastid-specific RsmD methyltransferase and ribosome maturation factor RimM are crucial for 16S rRNA maturation and proteostasis
Authors: Liu Kaiwei , Lee Keun Pyo , Duan Jianli , Kim Eun Yu , Singh Rahul Mohan , Di Minghui , Meng Zhuoling , Kim Chanhong
Published: March 2022

Chloroplast pre-ribosomal RNA (rRNA) undergoes maturation, which is critical for ribosome assembly. While the central and auxiliary factors in rRNA maturation have been elucidated in bacteria, their mode of action remains largely unexplored in chloroplasts. We now reveal chloroplast-specific factors involved in 16S rRNA maturation, RsmD methyltransferase (AtRsmD) and ribosome maturation factor RimM-like protein (AtRimM) in Arabidopsis thaliana. A forward genetic screen aimed to find suppressors of the Arabidopsis yellow variegated 2 (var2) mutant defective in photosystem II (PSII) quality control found a causal nonsense mutation in AtRsmD. The substantially impaired 16S rRNA maturation and translation due to the mutation rescued the leaf variegation phenotype by lowering the levels of PSII core proteins in var2. The subsequent co-immunoprecipitation coupled with mass spectrometry analyses and bimolecular fluorescence complementation assay found that AtRsmD interacts with AtRimM. Consistent with their interaction, loss of AtRimM also considerably impairs 16S rRNA maturation, with less methylation in m2G915 in 16S rRNA catalyzed by AtRsmD. The atrimM mutation also rescued var2 mutant phenotypes, corroborating the functional interplay between AtRsmD and AtRimM towards 16S rRNA maturation and chloroplast proteostasis.
Protease Activity Analysis: A Toolkit for Analyzing Enzyme Activity Data
Authors: Soleimany Ava P. , Alonso Carmen Martin , Anahtar Melodi , Wang Cathy S. , Bhatia Sangeeta N.
Published: March 2022

Analyzing the activity of proteases and their substrates is critical to defining the biological functions of these enzymes and to designing new diagnostics and therapeutics that target protease dysregulation in disease. While a wide range of databases and algorithms have been created to better predict protease cleavage sites, there is a dearth of computational tools to automate analysis of in vitro and in vivo protease assays. This necessitates individual researchers to develop their own analytical pipelines, resulting in a lack of standardization across the field. To facilitate protease research, here we present Protease Activity Analysis (PAA), a toolkit for the preprocessing, visualization, machine learning analysis, and querying of protease activity datasets. PAA leverages a Python-based object-oriented implementation that provides a modular framework for streamlined analysis across three major components. First, PAA provides a facile framework to query datasets of synthetic peptide substrates and their cleavage susceptibilities across a diverse set of proteases. To complement the database functionality, PAA also includes tools for the automated analysis and visualization of user-input enzyme-substrate activity measurements generated through in vitro screens against synthetic peptide substrates. Finally, PAA can supports a set of modular machine learning functions to analyze in vivo protease activity signatures that are generated by activity-based sensors. Overall, PAA offers the protease community a breadth of computational tools to streamline research, taking a step towards standardizing data analysis across the field and in chemical biology and biochemistry at large.
Thyroid hormone induces B cells abnormal differentiation via overexpression of B cell-activating factor
Authors: Liu Shu , Li Guo-Qing , Gu Qing-Wei , Wang Jie , Cao Xin , Zhong Yi , Miao Jing-Jing , Sun Qi , Gu Wen-Sha , Mao Xiao-Ming
Published: March 2022

Breakdown of tolerance and abnormal activation in B cells is an important mechanism in Graves’ disease (GD) pathogenesis. However, the mechanism by which B cells are abnormal differentiated and activated in GD remains elusive. Here, we show that elevated BAFF expression is positively correlated with serum thyroid hormone (TH) levels in GD patients and high TH levels can induce BAFF overexpression and lead to the abnormal differentiation of B cells in mice. This BAFF overexpression can be seen in many tissues. In the spleens of mice, high TH levels induce M1 macrophages polarization, which generates BAFF overexpression. Our findings open a new perspective on the interactions between endocrine and immune system and provide insight into the involvement of thyroid hormones in the development and progression of GD.
Helix 8 in chemotactic receptors of the complement system
Authors: Wisniewski Szymon , Dragan Paulina , Makal Anna , Latek Dorota
Published: March 2022

Host response to infection involves activation of the complement system leading to producing of anaphylotoxins C3a and C5a. A complement factor C5a exerts its effect through activation of C5aR1, chemotactic receptor 1, and triggers the G protein-coupled signaling cascade. Orthosteric and allosteric antagonists of C5aR1 are a novel strategy for anti-inflammatory therapies. Here, we discuss recent crystal structures of inactive C5aR1 in terms of an inverted orientation of helix H8, unobserved in other GPCR structures. Analysis of mutual interactions of subunits in the C5aR1 - G protein complex has provided new insights into the activation mechanism of this distinct receptor. By comparison of C5aR1 and its homolog C5aR2 we explained differences between their signaling pathways on the molecular level. A comparison of microsecond MD trajectories started from active and inactive receptor conformations also enabled to elucidate details of local and global changes in the transmembrane domain induced by interactions with the Gα subunit and to explain the impact of inverted H8 on the receptor activation.
Sequential epiretinal stimulation improves discrimination in simple shape discrimination tasks only
Authors: Christie Breanne , Sadeghi Roksana , Kartha Arathy , Caspi Avi , Tenore Francesco V. , Klatzky Roberta L. , Dagnelie Gislin , Billings Seth
Published: March 2022

Objective

Electrical stimulation of the retina can elicit flashes of light called phosphenes, which can be used to restore rudimentary vision for people with blindness. Functional sight requires stimulation of multiple electrodes to create patterned vision, but phosphenes tend to merge together in an uninterpretable way. Sequentially stimulating electrodes in human visual cortex has recently demonstrated that shapes could be “drawn” with better perceptual resolution relative to simultaneous stimulation. The goal of this study was to evaluate if sequential stimulation would also form clearer shapes when the retina is the neural target.

Approach

Two human participants with retinitis pigmentosa who had Argus® II retinal prostheses participated in this study. We evaluated different temporal parameters for sequential stimulation in phosphene shape mapping and forced-choice discrimination tasks. For the discrimination tasks, performance was compared between stimulating electrodes simultaneously versus sequentially.

Main results

Phosphenes elicited by different electrodes were reported as vastly different shapes. Sequential electrode stimulation outperformed simultaneous stimulation in simple discrimination tasks, in which shapes were created by stimulating 3-4 electrodes, but not in more complex discrimination tasks involving 5+ electrodes. For sequential stimulation, the optimal pulse train duration was 200 ms when stimulating at 20 Hz and the optimal gap interval was tied between 0 and 50 ms. Efficacy of sequential stimulation also depended strongly on selecting electrodes that elicited phosphenes with similar shapes and sizes.

Significance

An epiretinal prosthesis can produce coherent simple shapes with a sequential stimulation paradigm, which can be used as rudimentary visual feedback. However, success in creating more complex shapes, such as letters of the alphabet, is still limited. Sequential stimulation may be most beneficial for epiretinal prostheses in simple tasks, such as basic navigation, rather than complex tasks such as object identification.
Metabolic changes induced by pharmacological castration of young, healthy men: a study of the plasma metabolome
Authors: Guedes Jéssica de Siqueira , Pla Indira , Sahlin K. Barbara , Monnerat Gustavo , Appelqvist Roger , Marko-Varga György , Giwercman Aleksander , Domont Gilberto Barbosa , Sanchez Aniel , Nogueira Fábio César Sousa , Malm Johan
Published: March 2022

Testosterone is a hormone that plays a key role in carbohydrate, fat, and protein metabolism. Testosterone deficiency is associated with multiple comorbidities, e.g., metabolic syndrome and type 2 diabetes. Despite its importance in many metabolic pathways, the mechanisms by which it controls metabolism are not fully understood. The present study investigated the short-term metabolic changes of pharmacologically induced castration and testosterone supplementation in healthy young males. Thirty subjects were submitted to testosterone depletion (TD) followed by testosterone supplementation (TS). Plasma samples were collected three times corresponding to basal, low, and restored testosterone levels. An untargeted metabolomics study was performed by liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) to monitor the metabolic changes induced by the altered hormone levels. Our results demonstrated that TD is associated with major metabolic changes partially restored by TS. Carnitine and amino acid metabolism were the metabolic pathways most impacted by variations in testosterone. Furthermore, our results also indicate that LH and FSH might strongly alter the plasma levels of indoles and lipids, especially glycerophospholipids and sphingolipids. Our results demonstrate major metabolic changes induced by low testosterone that may be important for understanding the mechanisms behind the association of testosterone deficiency and its comorbidities.
Selection of optimum formulation of RBD-based protein sub-unit covid19 vaccine (Corbevax) based on safety and immunogenicity in an open-label, randomized Phase-1 and 2 clinical studies
Authors: Thuluva Subhash , Paradkar Vikram , Turaga Kishore , Gunneri SubbaReddy , Yerroju Vijay , Mogulla Rammohan , Kyasani Mahesh , Manoharan Senthil Kumar , Medigeshi Guruprasad , Singh Janmejay , Shaman Heena , Singh Chandramani , Venkateshwar Rao A
Published: March 2022

Background

We present the data from an open-label study involved in the selection of optimum formulation of RBD-based protein sub-unit COVID-19 vaccine.

Methods

The randomized Phase-1/2 trial followed by a Phase-2 trial was carried out to assess safety and immunogenicity of different formulation of COVID-19 vaccine (Corbevax) and select an optimum formulation for a phase 3 study. Healthy adults without a history of Covid-19 vaccination or SARS-CoV-2 infection, were enrolled.

Findings

Low incidence of adverse events were reported post-vaccination of different Corbevax formulations and majority were mild in nature and no Grade-3 or serious adverse events were observed. All formulations in Phase-1/2 study showed similar profile of humoral and cellular immune-response with higher response associated with increasing CpG1018 adjuvant content at same RBD protein content. Hence, high concentration of CpG1018 was tested in phase-2 study, which showed significant improvement in immune-responses in terms of anti-RBD-IgG concentrations, anti-RBD-IgG1 titers, nAb-titers and cellular immune-responses while maintaining the safety profile. Interestingly, binding and neutralizing antibody titers were persisted consistently till 6 months post second vaccine dose.

Interpretations

Corbevax was well tolerated with no observed safety concerns. Neutralizing antibody titers were suggestive of high vaccine effectiveness compared with human convalescent plasma or protective thresholds observed during vaccine efficacy trials of other COVID-19 vaccines. The study was prospectively registered with clinical trial registry of India-CTRI/2021/06/034014 and CTRI/2020/11/029032.

Funding

Bill & Melinda Gates Foundation, BIRAC-division of Department of Biotechnology, Govt of India, and the Coalition for Epidemic Preparedness Innovations funded the study.
Booster vaccination protection against SARS-CoV-2 infections in young adults during an Omicron BA.1-predominant period: a retrospective cohort study
Authors: Wan Jiayue , Cazer Casey L. , Clarkberg Marin E. , Henderson Shane G. , Lee Scarlett E. , Meredith Genevive , Osman Marwan , Shmoys David B. , Frazier Peter I.
Published: March 2022

Background

While booster vaccinations clearly reduce the risk of severe COVID-19 and death, the impact of boosters on SARS-CoV-2 infection has not been fully characterized: doing so requires understanding their impact on asymptomatic and mildly symptomatic infections that often go unreported but nevertheless play an important role in spreading SARS-CoV-2. We sought to estimate the impact of COVID-19 booster doses on SARS-CoV-2 infection in a vaccinated population of young adults during an Omicron BA.1-predominant period.

Methods and Findings

We implemented a cohort study of young adults in a college environment (Cornell University’s Ithaca campus) from a period when Omicron BA.1 was the predominant SARS-CoV-2 variant on campus (December 5 to December 31, 2021). Participants included 15,800 university students who completed an initial vaccination series with a vaccine approved by the World Health Organization for emergency use, were enrolled in mandatory at-least-weekly surveillance PCR testing, and had no positive SARS-CoV-2 PCR test within 90 days before the start of the study period. Robust multivariable Poisson regression with the main outcome of a positive SARS-CoV-2 PCR test was performed to compare those who completed their initial vaccination series and a booster dose to those without a booster dose.

1,926 unique SARS-CoV-2 infections were identified in the study population. Controlling for sex, student group membership, date of completion of initial vaccination series, initial vaccine type, and temporal effect during the study period, our analysis estimates that receiving a booster dose further reduces the rate of having a PCR-detected SARS-CoV-2 infection relative to an initial vaccination series by 56% (95% confidence interval [42%, 67%], P <0.001). While most individuals had recent booster administration before or during the study period (a limitation of our study), this result is robust to the assumed delay over which a booster dose becomes effective (varied from 1 day to 14 days). The mandatory active surveillance approach used in this study, under which 86% of the person-days in the study occurred, reduces the likelihood of outcome mis-classification. Key limitations of our methodology are that we did not have ana prioriprotocol or statistical analysis plan because the analysis was initially done for institutional research purposes, and some analysis choices were made after observing the data.

Conclusions

We observed that boosters are effective, relative to completion of initial vaccination series, in further reducing the rate of SARS-CoV-2 infections in a college student population during a period when Omicron BA.1 was predominant; booster vaccinations for this age group may play an important role in reducing incidence of COVID-19.
Epidemiology and genomic analysis of Klebsiella oxytoca from a single hospital network in Australia
Authors: Stewart James , Judd Louise M. , Jenney Adam , Holt Kathryn E. , Wyres Kelly L. , Hawkey Jane
Published: March 2022

Infections caused by Klebsiella oxytoca are the second most common cause of Klebsiella infections in humans. Most studies to date have focused on K. oxytoca outbreaks and few have examined the broader clinical context of K. oxytoca. Here, we collected all clinical isolates identified as K. oxytoca in a hospital microbiological diagnostic lab across a 15-month period (n=239). The majority of isolates were sensitive to antimicrobials, however 22 isolates were resistant to third-generation cephalosporins (3GCR), of which five were also carbapenem resistant. Whole genome sequencing of a subset of 92 isolates (all invasive, 3GCR and non-urinary isolates collected >48h after admission) showed those identified as K. oxytoca by the clinical laboratory actually encompassed four distinct species (K. oxytoca, Klebsiella michiganensis, Klebsiella grimontii and Klebsiella pasteurii), referred to as the K. oxytoca species complex (KoSC). There was significant diversity within the population, with only 10/67 multi-locus sequence types (STs) represented by more than one isolate. Strain transmission was rare, with only a single likely event identified. Six isolates had either extended spectrum beta-lactamase (blaSHV-12 and/or blaCTX-M-9) or carbapenemase (blaIMP-4) genes. One pair of K. michiganensis and K. pasteurii genomes carried an identical blaIMP-4 IncL/M plasmid, indicative of plasmid transmission. Whilst antimicrobial resistance was rare, the resistance plasmids were similar to those found in other Enterobacterales, demonstrating that KoSC has access to the same plasmid reservoir and thus there is potential for multi-drug resistance. Further genomic studies are required to improve our understanding of the KoSC population and facilitate investigation into the attributes of successful nosocomial isolates.
Cell Surface-Bound La Protein Regulates The Cell Fusion Stage Of Osteoclastogenesis
Authors: Whitlock Jarred M. , Leikina Evgenia , Melikov Kamran , De Castro Luis Fernandez , Mattijssen Sandy , Maraia Richard J. , Collins Michael T. , Chernomordik Leonid V.
Published: March 2022

Multinucleated osteoclasts, essential for skeletal remodeling in health and diseases, are formed by fusion of osteoclast precursors with each fusion event raising their bone-resorbing activity. Here we report that nuclear RNA chaperone, La protein moonlights as an osteoclast fusion regulator. Monocyte-to-osteoclast differentiation starts with a drastic decrease in La levels. Then La reappears as a proteasecleaved species at the cell surface where it promotes fusion by mechanisms independent of La-RNA interactions. Appearance-and-disappearance of cell-surface La act as an on-and-off switch of the fusion activity with fusion slowing down when surface La is replaced in mature osteoclasts by full-length nuclear La. Inhibiting surface La in a novel explant model of fibrous dysplasia inhibits excessive osteoclast formation characteristic of this disease, highlighting La’s potential as a therapeutic target.

One-Sentence Summary

A nuclear RNA chaperon moves to the surface of osteoclasts to control their formation and function in bone metabolism.
Multi-omics profiling, in vitro and in vivo enhancer assays dissect the cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy
Authors: Van de Sompele Stijn , Small Kent W. , Cicekdal Munevver Burcu , Soriano Víctor López , D’haene Eva , Shaya Fadi S. , Agemy Steven , Van der Snickt Thijs , Rey Alfredo Dueñas , Rosseel Toon , Van Heetvelde Mattias , Vergult Sarah , Balikova Irina , Bergen Arthur A. , Boon Camiel J. F. , De Zaeytijd Julie , Inglehearn Chris F. , Kousal Bohdan , Leroy Bart P. , Rivolta Carlo , Vaclavik Veronika , van den Ende Jenneke , van Schooneveld Mary J. , Gómez-Skarmeta José Luis , Tena Juan J. , Martinez-Morales Juan R. , Liskova Petra , Vleminckx Kris , De Baere Elfride
Published: March 2022

North Carolina macular dystrophy (NCMD) is a rare autosomal dominant disease affecting macular development. The disease is caused by non-coding single nucleotide variants (SNVs) in two hotspot regions near PRDM13 and by duplications in two distinct chromosomal loci, overlapping DNase I hypersensitive sites near either PRDM13 or IRX1.

To unravel the mechanisms by which these variants cause disease, we first established a genome-wide multi-omics retinal database, RegRet. Integration of UMI-4C profiles we generated on adult human retina then allowed fine-mapping of the interactions of the PRDM13 and IRX1 gene promoters, and the identification of eighteen candidate cis-regulatory elements (cCREs), the activity of which was investigated by luciferase and Xenopus enhancer assays.

Next, luciferase assays showed that the non-coding SNVs located in the two hotspot regions of PRDM13 affect cCRE activity, including two novel NCMD-associated non-coding SNVs that we identified. Interestingly, the cCRE containing one of these SNVs was shown to interact with the PRDM13 promoter, demonstrated in vivo activity in Xenopus, and is active at the developmental stage when progenitor cells of the central retina exit mitosis, putting forward this region as a PRDM13 enhancer.

Finally, mining of single-cell transcriptional data of embryonic and adult retina revealed the highest expression of PRDM13 and IRX1 when amacrine cells start to synapse with retinal ganglion cells, supporting the hypothesis that altered PRDM13 or IRX1 expression impairs interactions between these cells during retinogenesis.

Overall, this study gained insight into the cis-regulatory mechanisms of NCMD and supports that this condition is a retinal enhanceropathy.

Graphical abstract
Distinct denitrifying phenotypes of predominant bacteria mould nitrous oxide metabolism in upland agricultural soils
Authors: Wu Qiaoyu , Ji Mengmeng , Yu Siyu , Li Ji , Wu Xiaogang , Ju Xiaotang , Liu Binbin , Zhang Xiaojun
Published: March 2022

Denitrifying nitrous oxide (N2O) emissions in agroecosystems result from variations in microbial composition and soil properties. However, the microbial mechanisms of differential N2O emissions in agricultural soils are less understood. Microcosm experiments of two types of Chinese farmland soil were conducted with nitrate (250 mg/kg) and a combination of glucose (1000 mg/kg) and nitrate, and a case with no addition was used as the control. The results show that N2O accumulation in black soil (BF) was significantly higher than that in fluvo-aquic soil (FF) independent of carbon and nitrogen supply. The abundance of denitrifying genes was significantly higher in FF, but the ratios of genes responsible for N2O production (narG, nirS, and nirK) to the gene for N2O reduction (nosZ) did not significantly differ between the two soils. However, the soils showed obvious discrepancies in denitrifying bacterial communities. High accumulation of N2O was verified by the isolates of Rhodanobacter, which is predominant in BF due to its truncated denitrifying genes and lack of N2O reduction capacity. The dominance of complete denitrifiers such as Castellaniella in FF led to a rapid reduction in N2O and reduced N2O accumulation, as demonstrated when its corresponding isolate was inoculated into both studied soils. Therefore, the different phenotypes of N2O metabolism of the distinct denitrifiers maintained in the two soils caused their differing N2O accumulation. This knowledge could guide the regulation of the denitrifying bacterial community and the phenotypes of N2O metabolism in agricultural soils to reduce N2O emissions.
Single-cell atlas of human liver development reveals pathways directing hepatic cell fates
Authors: Wesley Brandon T. , Ross Alexander D. B. , Muraro Daniele , Miao Zhichao , Saxton Sarah , Tomaz Rute A. , Morell Carola M. , Ridley Katherine , Zacharis Ekaterini D. , Petrus-Reurer Sandra , Kraiczy Judith , Mahbubani Krishnaa T. , Brown Stephanie , Garcia-Bernardo Jose , Alsinet Clara , Gaffney Daniel , Tysoe Olivia C. , Botting Rachel A. , Stephenson Emily , Popescu Dorin-Mirel , MacParland Sonya , Bader Gary , McGilvray Ian D. , Ortmann Daniel , Sampaziotis Fotios , Saeb-Parsy Kourosh , Haniffa Muzlifah , Stevens Kelly R. , Zilbauer Matthias , Teichmann Sarah A. , Vallier Ludovic
Published: March 2022

The liver has been studied extensively due to the broad number of diseases affecting its vital functions. However, therapeutic advances, especially in regenerative medicine, are currently hampered by the lack of knowledge concerning human hepatic cell development. Here, we addressed this limitation by describing the developmental trajectories of different cell types comprising the human fetal liver at single-cell resolution. These transcriptomic analyses revealed that sequential cell-to-cell interactions direct functional maturation of hepatocytes, with non-parenchymal cells playing critical, supportive roles during organogenesis. We utilised this information to derive bipotential hepatoblast organoids and then exploited this novel model system to validate the importance of key signalling pathways and developmental cues. Furthermore, these insights into hepatic maturation enabled the identification of stage-specific transcription factors to improve the functionality of hepatocyte-like cells generated from human pluripotent stem cells. Thus, our study establishes a new platform to investigate the basic mechanisms of human liver development and to produce cell types for clinical applications.
miR-329 and miR-495-mediated Prr7 downregulation is required for homeostatic synaptic depression in rat hippocampal neurons
Authors: Inouye Michiko O. , Colameo David , Ammann Irina , Schratt Gerhard
Published: March 2022

Homeostatic synaptic depression (HSD) in excitatory neurons is a cell autonomous mechanism which protects excitatory neurons from over-excitation as a consequence of chronic increases in network activity. In this process, excitatory synapses are weakened and eventually eliminated, as evidenced by a reduction in synaptic AMPA receptor expression and dendritic spine loss. Originally considered a global, cell-wide mechanism, local forms of regulation, such as the local control of mRNA translation in dendrites, are being increasingly recognized in HSD. Yet, identification of excitatory proteins whose local regulation is required for HSD is still limited. Here, we show that Proline-rich protein 7/Transmembrane Adapter Protein 3 (Prr7) downregulation in dendrites of rat hippocampal neurons is necessary for HSD induced by chronic increase in network activity resulting from a blockade of inhibitory synaptic transmission by picrotoxin (PTX). We further identify two activity-regulated miRNAs, miR-329-3p and miR-495-3p, which inhibit Prr7 mRNA translation and are required for HSD. Moreover, we found that Prr7 knockdown reduces expression of the synaptic scaffolding protein SPAR, which is rescued by pharmacological inhibition of CDK5, indicating a role of Prr7 protein in the maintenance of excitatory synapses via protection of SPAR from degradation. Together, our findings highlight a novel HSD mechanism in which chronic activity leads to miR-329 and miR-495-mediated local Prr7 reduction upstream of the CDK5-SPAR pathway.