bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of the Effects of a Sage (Salvia officinalis) Extract on Cognitive Performance in Adolescents and Young Adults
Authors: Edwards Kieron D. , Dubberke Anne , Meyer Nadin , Kugel Simone , Hellhammer Juliane
Published: May 2021

Background

Cognitive health is a major concern for many people, and with potential benefits to academic and professional life, maximising cognitive performance is of interest far beyond the older demographics. Several natural products have been suggested as nootropics, including the herb sage. Previous assessments of various Salvia species have reported a range of effects on cognitive performance and mood in both older adult and younger adult populations. This study was conducted with Sibelius™: Sage, an aqueous-ethanol extract of S. officinalis, to assess for the beneficial effects on cognitive performance in adolescents (12-14 year olds) and young adults (18-25 year olds).

Methods and Findings

An acute, double-blind, placebo-controlled study was conducted with two single doses of Sibelius™: Sage (150 mg and 300 mg). Cognitive performance was evaluated using CogTrack™, which probes aspects of cognitive performance covering attention, working memory and episodic/declarative memory through a series of computer-based tasks. Consistent with previous study of Sibelius™: Sage a significant effect was seen on the Immediate Word Recall task in young adults; suggesting acute treatment benefits to verbal episodic/declarative memory performance. Physiological effects of the treatment on salivary cortisol and oxytocin levels, as well as blood pressure and heart rate were also assessed, with limited evidence of an effect on these factors. No adverse events or side-effects linked to the study product intake was observed. The study was registered at the German Clinical Trials Register (DRKS-ID: DRKS00015716).

Conclusions

A significant improvement due to the Sage extract was shown for a task assessing short-term episodic memory (Immediate Word Recall), supporting beneficial effects on cognitive performance in young adults that are consistent with previous reports in healthy older adults. These findings suggest that further investigation of the effects observed in this study in larger, long-term human volunteer studies could be beneficial to pursue.
Effect of evidence updates on key determinants of measles vaccination impact: a DynaMICE modelling study in ten high-burden countries
Authors: Fu Han , Abbas Kaja , Klepac Petra , van Zandvoort Kevin , Tanvir Hira , Portnoy Allison , Jit Mark
Published: May 2021

Background

Model-based estimates of measles burden and the impact of measles-containing vaccine (MCV) are crucial for global health priority setting. Recently, evidence from systematic reviews and database analyses have improved our understanding of key determinants of measles vaccine impact. We explore how updated representations of these determinants affect model-based estimation of MCV impact in ten countries with highest measles burden.

Methods

Using Dynamic Measles Immunisation Calculation Engine (DynaMICE), an age-structured compartmental model of measles transmission and vaccination, we evaluated the effect of evidence updates for five determinants of MCV impact: case fatality risk, contact patterns, age-dependent vaccine efficacy, the potential of supplementary immunisation activities (SIAs) to reach zero-dose children, and the basic reproduction number. We also evaluated the incremental impact of the first dose (MCV1), second dose (MCV2), and SIA dose of measles vaccines, based on country-specific coverage estimates from the World Health Organization. The MCV impact was assessed by cumulative vaccine-averted cases, deaths, and disability-adjusted life years over 2000–2050.

Results

Incorporated with the updated data sources, DynaMICE projected 252 million measles cases, 3.7 million deaths and 230 million disability-adjusted life years incurred over 2000–2050 in the ten high-burden countries when MCV1, MCV2, and SIA doses were implemented. Compared to no vaccination, the administration of MCV1 contributed to 66% reduction in cumulative measles burden, while MCV2 and SIAs reduced this further to 89%. With routine and supplementary vaccination, India and countries with high vaccination coverage could maintain measles incidence below 1 per million. Among the updated determinants, shifting from fixed to linearly-varying vaccine efficacy by age and from static to time-varying case fatality risks had the biggest effect on the model projections of MCV impact. While varying the basic reproduction number showed a limited effect on vaccine-averted burden, updates on the other four determinants together led to an overall reduction of MCV impact by 0.87–26.7%.

Conclusions

High coverage of measles vaccine through both routine and SIA delivery platforms are essential for achieving and maintaining low incidence in high-measles burden settings. Incorporating updated evidence particularly on vaccine efficacy and case fatality risk reduces estimates of the impact of vaccination slightly, but its overall impact remains considerable.
CoMix: Changes in social contacts as measured by the contact survey during the COVID-19 pandemic in England between March 2020 and March 2021
Authors: Gimma Amy , Munday James D , Wong Kerry LM , Coletti Pietro , van Zandvoort Kevin , Prem Kiesha ,   CMMID COVID-19 working group, Klepac Petra , Rubin G. James , Funk Sebastian , Edmunds W John , Jarvis Christopher I
Published: May 2021

Background

During the COVID-19 pandemic, the UK government imposed public health policies in England to reduce social contacts in hopes of curbing virus transmission. We measured contact patterns weekly from March 2020 to March 2021 to estimate the impact of these policies, covering three national lockdowns interspersed by periods of lower restrictions.

Methods

Data were collected using online surveys of representative samples of the UK population by age and gender. We calculated the mean daily contacts reported using a (clustered) bootstrap and fitted a censored negative binomial model to estimate age-stratified contact matrices and estimate proportional changes to the basic reproduction number under controlled conditions using the change in contacts as a scaling factor.

Results

The survey recorded 101,350 observations from 19,914 participants who reported 466,710 contacts over 53 weeks. Contact patterns changed over time and by participants’ age, personal risk factors, and perception of risk. The mean of reported contacts among adults have reduced compared to previous surveys with adults aged 18 to 59 reporting a mean of 2.39 (95% CI 2.20 - 2.60) contacts to 4.93 (95% CI 4.65 - 5.19) contacts, and the mean contacts for school-age children was 3.07 (95% CI 2.89 - 3.27) to 15.11 (95% CI 13.87 - 16.41). The use of face coverings outside the home has remained high since the government mandated use in some settings in July 2020.

Conclusions

The CoMix survey provides a unique longitudinal data set for a full year since the first lockdown for use in statistical analyses and mathematical modelling of COVID-19 and other diseases. Recorded contacts reduced dramatically compared to pre-pandemic levels, with changes correlated to government interventions throughout the pandemic. Despite easing of restrictions in the summer of 2020, mean reported contacts only returned to about half of that observed pre-pandemic.
A potent myeloid response is rapidly activated in the lungs of premature Rhesus macaques exposed to intra-uterine inflammation
Authors: Jackson Courtney M. , Demmert Martin , Mukherjee Shibabrata , Isaacs Travis , Gray Jerilyn , Senthamaraikannan Paranthaman , Presicce Pietro , Chetal Kashish , Salomonis Nathan , Miller Lisa A. , Jobe Alan H. , Kallapur Suhas G. , Zacharias William J. , Lewkowich Ian P. , Deshmukh Hitesh , Chougnet Claire A.
Published: May 2021

Intrauterine inflammation/infection (IUI), which is present in up to 40% of premature births, leads to elevated levels of pro-inflammatory mediators and microbial products within the amniotic fluid, which come in close contact to fetal mucosae. Yet, knowledge on the fetal mucosal responses to IUI exposure remains limited. To address these questions, we used a non-human primate model of IUI, in which pregnant Rhesus macaques received intra-amniotic (IA) LPS, compared with IA saline.

We found that IA LPS exposure induced a robust and rapid inflammation of the fetal lung, but not the intestine. This inflammatory response was characterized by high levels of pro-inflammatory cytokines in the lung and the alveolar wash, and a potent myeloid cell response, dominated by neutrophils and monocytes/macrophages. scRNAseq analyses of fetal lungs showed that the infiltrating (neutrophils and inflammatory monocytes) and the resident (alveolar and interstitial macrophages) myeloid cells exhibited transcriptional profiles consistent with exposure to TLR ligands, as well as to cytokines, notably IL-1 and TNFα. However, blocking IL-1 signaling or TNFα, alone or simultaneously by administering inhibitors intra-amniotically and subcutaneously to the dam only partially blunted fetal lung inflammation.

Together, our novel data indicate that the fetal innate immune system can mount a rapid multi-factorial mucosal innate response to IUI, responding both to direct signaling by bacterial products and to indirect cytokine-mediated pathways of activation. These data thus provide more mechanistic insights into the association between IUI exposure and the post-natal lung morbidities of the premature infant.
Mating Strategies of Invasive Versus Indigenous Crayfish: Multiple Paternity as Driver for Invasion Success?
Authors: Francesconi Caterina , Pîrvu Mălina , Schrimpf Anne , Schulz Ralf , Pârvulescu Lucian , Theissinger Kathrin
Published: May 2021

The invasive spiny-cheek crayfish (Faxonius limosus) has been able to colonize many European waterbodies since its first introduction into Europe, threatening the indigenous crayfish fauna.Faxonius limosus’ remarkable reproductive plasticity has been suggested as an important factor contributing to this species’ alarming invasiveness. This is the first study comparing the reproductive strategies of an invasive (F. limosus) and a sympatric indigenous crayfish (Pontastacus leptodactylus). We investigated if and how parthenogenesis and multiple paternity contribute to the invasion process in the River Danube. Using microsatellites, we genotyped the offspring and their mothers of 11 clutches ofF. limosusand 18 clutches ofP. leptodactylus. While no parthenogenesis has been found inF. limosus’ populations, multiple paternity has been detected for the first time in both species, with comparable incidence. The results of the study indicate that multiple paternity does not play a dominant role inF. limosus’ successful colonization of the Danube. However, the presented results have to be regarded as pilot study, with a limited number of samples and loci investigated. Given the relevance of mating system knowledge for management measures, future studies with larger sample number could provide precious contributions to the conservation actions.
Differences in microglia morphological profiles reflect divergent emotional temperaments: Insights from a selective breeding model
Authors: Maras Pamela M. , Blandino Peter , Hebda-Bauer Elaine K. , Watson Stanley J. , Akil Huda
Published: May 2021

Microglia are known to play critical roles in healthy brain development and function, as well as the neuropathology underlying a range of brain diseases. Despite the growing evidence for a role for microglia in affective regulation and mood disorders, relatively little is known regarding how variation in microglia status relates to individual differences in emotionality. Using a selective breeding model based on locomotor response to novelty, we have generated rat lines with unique temperamental phenotypes that reflect broad emotional traits: low responder rats (bLRs) are novelty-averse and model a passive coping style, whereas high responder rats (bHRs) are highly exploratory and model an active coping style. To identify a possible functional role of microglia in these phenotypes, we administered minocycline, an antibiotic with potent microglia inhibiting properties. We found changes in emotional and social behaviors in bLRs, with no discernable effects in bHRs. Using detailed anatomical analyses, we went on to explore the nature of baseline differences in hippocampal microglia populations associated with the divergent temperaments. Interestingly, we found that although bHRs and bLRs had comparable total numbers of hippocampal microglia, selective breeding was associated with a shift in the morphological features of these cells. Specifically, microglia from bLRs were characterized by a hyper-ramified morphology, with longer processes and more complicated branching patterns than microglia from bHRs. This morphology is thought to reflect an early stage of microglia activation and suggests that microglia from bLRs may be in a reactive state even when animals are not overtly stressed or challenged. Taken together, our results provide novel evidence linking variation in inborn temperament with differences in the baseline morphological status of microglia cells and highlight the importance of considering the role of microglia not only in acute responses to stress but also in shaping enduring characteristics of emotionality.
Aberrant induction of p19Arf-mediated cellular senescence contributes to neurodevelopmental defects
Authors: Rhinn Muriel , Zapata-Bodalo Irene , Klein Annabelle , Plassat Jean-Luc , Knauer-Meyer Tania , Keyes William M.
Published: May 2021

Timely induction of cellular senescence is important during embryonic development and tissue repair, while aberrant activation contributes to many age-related diseases. However, whether abnormal induction of senescence in the embryo contributes to developmental defects remains unclear. To explore this, we investigated the clinically significant model of Valproic acid- (VPA) induced developmental defects. VPA is a widely prescribed drug to treat epilepsy, bipolar disorder and migraine. If taken during pregnancy however, exposure to the developing embryo can cause birth defects, cognitive impairment and Autism-Spectrum Disorder. How VPA causes these developmental defects remains unknown. We used embryonic mice and human organoids to model key features of drug exposure, including exencephaly, microcephaly and spinal defects. In the malformed tissues, in which neurogenesis is defective, we find pronounced induction of cellular senescence in the neuroepithelial cells. Critically, through genetic and functional studies, we identified p19Arf as the instrumental mediator of senescence and microcephaly, but surprisingly, not exencephaly and spinal defects. Together, these findings uncover how misregulated senescence in neuroepithelial cells can contribute to developmental defects.
Dissecting Functional, Structural, and Molecular Requirements for Serotonin Release from Mouse Enterochromaffin Cells
Authors: Shaaban Ahmed , Maaß Frederike , Schwarze Valentin , Lund Mari L. , Beuermann Sabine , Chan Michelle , Harenberg Christiane , Bewick Gavin A. , Keating Damien J. , Benseler Fritz , Cooper Benjamin H. , Imig Cordelia
Published: May 2021

Serotonergic enterochromaffin (EC) cells of the gut epithelium are secretory sensory cells that communicate with vagal neurons. EC cells exhibit many features of neurons in the brain, raising the hypothesis that synapse-like contacts may mediate fast and directed signalling. To dissect functional, structural, and molecular properties underlying serotonin release from genetically identified EC cells, we employed a multidisciplinary in vitro approach combining intestinal epithelial cell and organoid cultures, electrochemistry, correlated light- and electron microscopy, and gene expression and biochemical analyses. Despite the presence of key molecules of the synaptic neurotransmitter release machinery, we found that the majority of serotonin is released with slow kinetics from large dense-core rather than small synaptic-like vesicles. While we cannot exclude synapse-like transmission between EC cells and neurons in vivo, our data support the notion that the predominant mode of serotonin secretion is similar to that of other endocrine cell types.
Phenological segregation suggests speciation by time in the planktonic diatom Pseudo-nitzschia allochrona sp. nov.
Authors: Percopo Isabella , Ruggiero Maria Valeria , Sarno Diana , Longobardi Lorenzo , Rossi Rachele , Piredda Roberta , Zingone Adriana
Published: May 2021

The emergence of new species is poorly understood in marine plankton, where the lack of physical barriers and homogeneous environmental conditions limit spatial and ecological segregation. Here we combine molecular and ecological information from a long term time series and propose Pseudo-nitzschia allochrona, a new cryptic diatom, as a possible case of speciation by temporal segregation. The new species differs in several genetic markers (18S, LSU and ITS rDNA fragments and rbcL) and is reproductively isolated from its closest relative, which is morphologically identical. Data from a long term plankton time series show Pseudo-nitzschia allochrona invariably occurring in summer-autumn in the Gulf of Naples, where its sister species are instead found in winter-spring. Temperature and nutrients are the main factors associated with the occurrence of P. allochrona, which could have evolved in sympatry by switching its phenology and occupying a new ecological niche. This case of possible speciation by time shows the relevance of combining ecological time series with molecular information to shed light on the eco-evolutionary dynamics of marine microorganisms.
A robust approach to estimate relative phytoplankton cell abundance from metagenomes
Authors: Karlusich Juan José Pierella , Pelletier Eric , Zinger Lucie , Lombard Fabien , Zingone Adriana , Colin Sébastien , Gasol Josep M. , Dorrell Richard G. , Scalco Eleonora , Acinas Silvia G. , Wincker Patrick , de Vargas Colomban , Bowler Chris
Published: May 2021

Phytoplankton account for >45% of global primary production, and have an enormous impact on aquatic food webs and on the entire Earth System. Their members are found among prokaryotes (cyanobacteria) and multiple eukaryotic lineages containing chloroplasts. Phytoplankton communities are generally studied by PCR amplification of bacterial (16S), nuclear (18S) or chloroplastic (16S) rRNA marker genes from DNA extracted from environmental samples. However, our appreciation of phytoplankton abundance or biomass is limited by PCR-amplification biases, rRNA gene copy number variations across taxa, and the fact that rRNA genes do not provide insights into metabolic traits such as photosynthesis. In addition, rRNA marker genes fail to capture both cyanobacteria and photosynthetic eukaryotes simultaneously. Here, we targeted the photosynthetic genepsbOfrom metagenomes to circumvent these limitations: the method is PCR-free, and the gene is universally and exclusively present in photosynthetic prokaryotes and eukaryotes, mainly in one copy per genome. We applied and validated this new strategy with theTaraOceans datasets, and showed improved correlations with flow cytometry and microscopy than when based on rRNA genes. Furthermore, we revealed unexpected features of the ecology of these organisms, such as the high abundance of picocyanobacterial aggregates and symbionts in the ocean, and the decrease in relative abundance of phototrophs towards the larger size classes of marine dinoflagellates. To facilitate the incorporation ofpsbOin molecular-based surveys, we compiled a curated database of >18,000 unique sequences. Overall,psbOappears to be a promising new gene marker for molecular-based evaluations of entire phytoplankton communities.
A suitable murine model for studying respiratory coronavirus infection and therapeutic countermeasures in BSL-2 laboratories
Authors: dos Santos Pereira Andrade Ana Cláudia , Campolina-Silva Gabriel Henrique , Queiroz-Junior Celso Martins , de Oliveira Leonardo Camilo , de Souza Barbosa Lacerda Larisse , Pimenta Jordane Clarisse , de Souza Filipe Resende Oliveira , de Meira Chaves Ian , Passos Ingredy Beatriz , Teixeira Danielle Cunha , Bittencourt-Silva Paloma Graziele , Costa Valadão Priscila Aparecida , Rossi-Oliveira Leonardo , Antunes Maisa Mota , Almeida Figueiredo André Felipe , Wnuk Natália Teixeira , Temerozo Jairo R. , Ferreira André Costa , Cramer Allysson , Oliveira Cleida Aparecida , Durães-Carvalho Ricardo , Arns Clarice Weis , Guimarães Pedro Pires Goulart , Costa Guilherme Mattos Jardim , de Menezes Gustavo Batista , Guatimosim Cristina , da Silva Glauber Santos Ferreira , Souza Thiago Moreno L. , Barrioni Breno Rocha , de Magalhães Pereira Marivalda , de Sousa Lirlândia Pires , Teixeira Mauro Martins , Costa Vivian Vasconcelos
Published: May 2021

Several animal models are being used to explore important features of COVID-19, nevertheless none of them recapitulates all aspects of the disease in humans. The continuous refinement and development of other options ofin vivomodels are opportune, especially ones that are carried out at BSL-2 (Biosafety Level 2) laboratories. In this study, we investigated the suitability of the intranasal infection with the murine betacoronavirus MHV-3 to recapitulate multiple aspects of the pathogenesis of COVID-19 in C57BL/6J mice. We demonstrate that MHV-3 replicated in lungs 1 day after inoculation and triggered respiratory inflammation and dysfunction. This MHV-model of infection was further applied to highlight the critical role of TNF in cytokine-mediated coronavirus pathogenesis. Blocking TNF signaling by pharmacological and genetic strategies greatly increased the survival time and reduces lung injury of MHV-3-infected mice.In vitrostudies showed that TNF blockage decreased SARS-CoV-2 replication in human epithelial lung cells and resulted in the lower release of IL-6 and IL-8 cytokines beyond TNF itself. Taken together, our results demonstrate that this model of MHV infection in mice is a useful BSL-2 screening platform for evaluating pathogenesis for human coronaviruses infections, such as COVID-19.
Using a recently approved tumor mutational burden biomarker to stratify patients for immunotherapy may introduce a sex bias
Authors: Sinha Neelam , Sinha Sanju , Cheng Kuoyuan , Madan Sanna , Erez Ayelet , Ryan Bríd M. , Schäffer Alejandro A. , Aldape Kenneth , Ruppin Eytan
Published: May 2021

The U.S. Food and Drug Administration (FDA) recently approved the treatment with pembrolizumab, an immune checkpoint inhibitor (ICI) targeting PD1 (anti-PD1), for patients with advanced solid tumors with a high tumor mutational burden (TMB) (defined as TMB ≥10 mutations/Mb). However, following recent studies suggest that TMB levels and response to ICI treatment may differ between male and female melanoma patients, we investigated whether using this high-TMB threshold for selecting patients for anti-PD1 treatment may induce a sex-dependent bias. We analyzed a large ICI cohort of 1,286 patients across nine cancer types treated with anti-PD1/PDL1. We find that using this threshold would indeed result in an unwarranted sex bias in melanoma, successfully stratifying female but not male patients. While this threshold is currently not a regulatory prerequisite for ICI treatment in melanoma, it is important to raise awareness to this bias. Notably, no sex-dependent significant differences were observed in the response of melanoma patients to anti-CTLA4 therapies, different chemotherapies or combination therapies. Beyond melanoma, the high-TMB threshold additionally introduces a sex bias of considerable magnitude in glioblastoma and in patients with cancers of unknown origin, however, these results are not statistically significant. A power analysis shows that these biases may become significant with larger sample size, warranting further careful testing in larger cohorts.
Transcriptional analysis of peripheral memory T cells reveals Parkinson’s disease-specific gene signatures
Authors: Dhanwani Rekha , Lima-Junior João Rodrigues , Sethi Ashu , Pham John , Williams Gregory , Frazier April , Xu Yaqian , Amara Amy W. , Standaert David G. , Goldman Jennifer G. , Litvan Irene , Alcalay Roy N. , Peters Bjoern , Sulzer David , Arlehamn Cecilia S. Lindestam , Sette Alessandro
Published: May 2021

Parkinson’s disease (PD) is a multi-stage neurodegenerative disorder with largely unknown etiology. Recent findings have identified PD-associated autoimmune features including roles for T cells. To further characterize the role of T cells in PD, we performed RNA sequencing on PBMC and peripheral CD4 and CD8 memory T cell subsets derived from PD patients and age-matched healthy controls. When the groups were stratified by their T cell responsiveness to alpha-synuclein (α-syn) as a proxy for ongoing inflammatory autoimmune response, the study revealed a broad differential gene expression profile in memory T cell subsets and a specific PD associated gene signature. We identified a significant enrichment of transcriptomic signatures previously associated with PD, including for oxidative stress, phosphorylation, autophagy of mitochondria, cholesterol metabolism and inflammation, and the chemokine signaling proteins CX3CR1, CCR5 and CCR1. In addition, we identified genes in these peripheral cells that have previously been shown to be involved in PD pathogenesis and expressed in neurons, such as LRRK2, LAMP3, and aquaporin. Together, these findings suggest that features of circulating T cells with α-syn-specific responses in PD patients provide insights into the interactive processes that occur during PD pathogenesis and suggest potential intervention targets.
Multi-Omics Analysis of Fibroblasts from the Invasive Tumor Edge Reveals that Tumor-Stroma Crosstalk Induces O-glycosylation of the CDK4-pRB Axis
Authors: Bouchard Gina , Marques Fernando Jose Garcia , Karacosta Loukia Georgiou , Zhang Weiruo , Bermudez Abel , Riley Nicholas McIlvain , Mehl Lindsey Catherine , Benson Jalen Anthony , Shrager Joseph B , Bertozzi Carolyn Ruth , Pitteri Sharon , Giaccia Amato J , Plevritis Sylvia Katina
Published: May 2021

The invasive leading edge represents a potential gateway for tumor invasion. We hypothesize that crosstalk between tumor and stromal cells within the tumor microenvironment (TME) results in the activation of key biological pathways depending on their location in the tumor (edge vs core). Here, we highlight phenotypic differences between Tumor-Adjacent-Fibroblasts (TAFs) from the invasive edge and Cancer-Associated Fibroblasts (CAFs) from the tumor core, established from human lung adenocarcinomas. We use an innovative multi-omics approach that includes genomics, proteomics and, O-glycoproteomics to characterize crosstalk between TAFs and cancer cells. Our analysis shows that O-glycosylation, an essential post-translational modification resulting from sugar metabolism, alters key biological pathways including the CDK4-pRB axis in the stroma, and indirectly modulates pro-invasive features of cancer cells. In summary, aside from improving the efficacy of CDK4 inhibitors anti-cancer agents, the O-glycoproteome poses a new consideration for important biological processes involved in tumor-stroma crosstalk.
Boundary cells in the representation of episodes in the human hippocampus
Authors: Yoo Hye Bin , Umbach Gray , Lega Bradley C.
Published: May 2021

The representation of episodes is a fundamental requirement for forming episodic memories, but the specific electrophysiological mechanisms supporting episode construction in the human hippocampus remain unknown. Experiments in rodent models indicate that a population of neurons sensitive to edges of an environment, termed border or boundary neurons in spatial navigation, fulfills a role analogous to episode demarcation. We hypothesized that such boundary neurons could be identified in the human mesial temporal lobe, with firing rates sensitive specifically to the beginning and end of mnemonically-relevant episodes in the free recall task. Using a generalized linear model to control for factors such as encoding success and item onset times along with other variables, we found 44 Boundary neurons out of a total 736 single neurons recorded across 27 subjects. We distinguish boundary neurons from a separate population of ramping neurons, which are time-sensitive neurons whose activity provides complementary but distinct information during episodic representation. We also describe evidence that the firing of boundary neurons within the preferred windows (at the beginning and end of episodes) is organized by hippocampal theta oscillations, using spike-field coherence metrics.
Aldosterone and Dexamethasone Activate African Lungfish Mineralocorticoid Receptor: Increased Activation After Removal of the Amino-Terminal Domain
Authors: Katsu Yoshinao , Oana Shin , Lin Xiaozhi , Hyodo Susumu , Baker Michael E.
Published: May 2021

Aldosterone, the main physiological mineralocorticoid in humans and other terrestrial vertebrates, first appears in lungfish, which are lobe-finned fish that are forerunners of terrestrial vertebrates. Aldosterone activation of the MR regulates internal homeostasis of water, sodium and potassium, which was critical in the conquest of land by vertebrates. We studied transcriptional activation of the slender African lungfish MR by aldosterone, other corticosteroids and progesterone and find that aldosterone, 11-deoxycorticosterone, 11-deoxycortisol and progesterone have half-maximal responses (EC50s) below 1 nM and are potential physiological mineralocorticoids. In contrast, EC50s for corticosterone and cortisol were 23 nM and 66 nM, respectively. Unexpectedly, truncated lungfish MR, consisting of the DNA-binding, hinge and steroid-binding domains, had a stronger response to corticosteroids and progesterone than full-length lungfish MR, indicating that the N-terminal domain represses steroid activation of lungfish MR, unlike human MR in which the N-terminal domain contains an activation function. BLAST searches of GenBank did not retrieve a GR ortholog, leading us to test dexamethasone and triamcinolone for activation of lungfish MR. At 10 nM, both synthetic glucocorticoids are about 4-fold stronger than 10 nM aldosterone in activating full-length lungfish MR, leading us to propose that lungfish MR also functions as a GR.
Somatic mutations of activated signaling genes, transcription factors, or tumor suppressors are a precondition for leukemic transformation from myelodysplastic syndromes: a sequencing analysis of 64 paired samples
Authors: Li Xiao , Chang Chun-Kang , Xu Feng , Wu Lin-Yun , Guo Juan , Song Lu-Xi , Tao Yin , He Qi , Zhang Zheng , Wu Dong , Zhou Li-Yu , Xiao Chao , Su Ji-Ying
Published: May 2021

The transformation biology of secondary AML from MDS is still not fully understood. Here, we performed a large cohort of paired sequences including target, whole-exome and single cell sequencing to search AML transformation-related mutations (TRM). The results showed that fifty-five out of the 64 (85.9%) patients presented presumptive TRM involving activated signaling, transcription factors, or tumor suppressors. Most of TRM (63.6%, 35 cases) emerged at the leukemia transformation point. All five of the remaining nine patients analyzed by paired whole exome sequencing showed TRM which are not included in the reference targets. Single-cell sequencing indicated that the activated cell signaling route was related to TRM which take place prior to phenotypic development. Of note, defined TRM was limited to a small set of genes (less than ten, in the order: NRAS/KRAS, CEBPA, TP53, FLT3, RUNX1, CBL, PTPN11 and WT1, accounted for 91.0% of the mutations). In conclusion, somatic mutations involving in activated signaling, transcription factors, or tumor suppressors appeared to be a precondition for AML transformation from myelodysplastic syndromes. The TRM may be considered as new therapy targets.
A connectomic study of a petascale fragment of human cerebral cortex
Authors: Shapson-Coe Alexander , Januszewski Michał , Berger Daniel R. , Pope Art , Wu Yuelong , Blakely Tim , Schalek Richard L. , Li Peter H. , Wang Shuohong , Maitin-Shepard Jeremy , Karlupia Neha , Dorkenwald Sven , Sjostedt Evelina , Leavitt Laramie , Lee Dongil , Bailey Luke , Fitzmaurice Angerica , Kar Rohin , Field Benjamin , Wu Hank , Wagner-Carena Julian , Aley David , Lau Joanna , Lin Zudi , Wei Donglai , Pfister Hanspeter , Peleg Adi , Jain Viren , Lichtman Jeff W.
Published: May 2021

We acquired a rapidly preserved human surgical sample from the temporal lobe of the cerebral cortex. We stained a 1 mm3 volume with heavy metals, embedded it in resin, cut more than 5000 slices at ∼30 nm and imaged these sections using a high-speed multibeam scanning electron microscope. We used computational methods to render the three-dimensional structure containing 57,216 cells, hundreds of millions of neurites and 133.7 million synaptic connections. The 1.4 petabyte electron microscopy volume, the segmented cells, cell parts, blood vessels, myelin, inhibitory and excitatory synapses, and 104 manually proofread cells are available to peruse online. Many interesting and unusual features were evident in this dataset. Glia outnumbered neurons 2:1 and oligodendrocytes were the most common cell type in the volume. Excitatory spiny neurons comprised 69% of the neuronal population, and excitatory synapses also were in the majority (76%). The synaptic drive onto spiny neurons was biased more strongly toward excitation (70%) than was the case for inhibitory interneurons (48%). Despite incompleteness of the automated segmentation caused by split and merge errors, we could automatically generate (and then validate) connections between most of the excitatory and inhibitory neuron types both within and between layers. In studying these neurons we found that deep layer excitatory cell types can be classified into new subsets, based on structural and connectivity differences, and that chandelier interneurons not only innervate excitatory neuron initial segments as previously described, but also each other’s initial segments. Furthermore, among the thousands of weak connections established on each neuron, there exist rarer highly powerful axonal inputs that establish multi-synaptic contacts (up to ∼20 synapses) with target neurons. Our analysis indicates that these strong inputs are specific, and allow small numbers of axons to have an outsized role in the activity of some of their postsynaptic partners.
Strain-level variation influences Methanothermococcus fitness in marine hydrothermal systems
Authors: Hoffert Michael , Anderson Rika , Reveillaud Julie , Murphy Leslie , Stepanauskas Ramunas , Huber Julie A.
Published: May 2021

Hydrogenotrophic methanogens are ubiquitous chemoautotrophic archaea inhabiting globally distributed deep-sea hydrothermal vent ecosystems and associated subseafloor niches within the rocky subseafloor, yet little is known about how they adapt and diversify in these habitats. To determine genomic variation and selection pressure within methanogenic populations at vents, we examined five Methanothermococcus single cell amplified genomes (SAGs) in conjunction with 15 metagenomes and 10 metatranscriptomes from venting fluids at two geochemically distinct hydrothermal vent fields on the Mid-Cayman Rise in the Caribbean Sea. We observed that some Methanothermococcus strains and their transcripts were more abundant than others in individual vent sites, and among the genes differentiating the Methanothermococcus SAGs were those related to nitrogen fixation and the CRISPR/Cas immune system. SAGs possessing these genes were less abundant than those missing that genomic region. Overall, patterns in nucleotide variation indicated that the population dynamics of Methanothermococcus were not governed by clonal expansions or selective sweeps, at least in the habitats and sampling times included in this study. Together, our results show that although specific lineages of Methanothermococcus co-exist in these habitats, some outcompete others, and possession of accessory metabolic functions does not necessarily provide a fitness advantage in these habitats in all conditions. This work highlights the power of combining single-cell, metagenomic, and metatranscriptomic datasets to determine how evolution shapes microbial abundance and diversity in hydrothermal vent ecosystems.
Genome assemblies across the diverse evolutionary spectrum of Leishmania protozoan parasites
Authors: Warren Wesley C. , Akopyants Natalia S. , Dobson Deborah E. , Hertz-Fowler Christiane , Lye Lon-Fye , Myler Peter J. , Ramasamy Gowthaman , Shanmugasundram Achchuthan , Silva-Franco Fatima , Steinbiss Sascha , Tomlinson Chad , Wilson Richard K. , Beverley Stephen M.
Published: May 2021

We report high-quality draft assemblies and gene annotation for 13 species and/or strains of the protozoan parasite genera Leishmania, Endotrypanum and Crithidia, which span the phylogenetic diversity of the Leishmaniinae sub-family within the kinetoplastid order of the phylum Euglenazoa. These resources will support studies on the origins of parasitism.
Three-dimensional tracking of tethered particles for probing nanometer-scale single-molecule dynamics using plasmonic microscope
Authors: Ma Guangzhong , Wan Zijian , Yang Yunze , Jing Wenwen , Wang Shaopeng
Published: May 2021

Three-dimensional (3D) tracking of surface-tethered single-particle reveals the dynamics of the molecular tether. However, most 3D tracking techniques lack precision, especially in axial direction, for measuring the dynamics of biomolecules with spatial scale of several nanometers. Here we present a plasmonic imaging technique that can track the motion of ∼100 tethered particles in 3D simultaneously with sub-nanometer axial precision at millisecond time resolution. By tracking the 3D coordinates of tethered particle with high spatial resolution, we are able to determine the dynamics of single short DNA and study its interaction with enzyme. We further show that the particle motion pattern can be used to identify specific and non-specific interactions in immunoassays. We anticipate that our 3D tracking technique can contribute to the understanding of molecular dynamics and interactions at the single-molecule level.
Apical Actin-myosin Network Regulates the Tight Junction of Polarized Madin-Darby Canine Kidney Cells
Authors: Lu Chia-hsuan , Wen Fu-Lai , Hsueh Shawn Ching-Chung , Wu Wen-hsiu , Lin Yu-Fang , Prouveur Mathieu , Boudier Thomas , Lin Keng-hui
Published: May 2021

The tight junction outlines the apicolateral border of epithelial cells like a belt, sealing the paracellular space when cells form contacts with each other. The permeability and morphology of tight junction are regulated by actomyosin contractility, which has been conventionally thought from the purse-string-like circumferential actomyosin belt along tight junction. Spatially, the tight junction is close to the apical actin network, which exerts inward contractions orthogonal to the tight junction. To test the contributions from apical actin network, we laser-ablated spots on the apical surface of polarized Madin-Darby Canine Kidney (MDCK) epithelial cells. Laser ablation severed the apical cytoskeleton network, decreased in-plane tension, increased the apical surface area, and rendered the tight junction less tortuous in shape. Consistent with these observations, changes in MDCK cell sheet morphology due to cell proliferation, or perturbation with the ROCK inhibitor Y27632 increased the density of the apical actin network and decreased tight junction tortuosity. The morphological analysis revealed scutoids in flat MDCK cell sheets, contrary to predictions from a previous model that only considered cell-cell interactions as line tension. Additional cell-cell interactions from apical in-plane tension provides probable cause for the occurrence of scutoids on flat geometry. Taken together, our findings identify the importance of the apical actin network exerting in-plane apical tension to regulate tight-junction mechanobiology and epithelial cell shape.

Significance Statement

The tight junction is located at the apicolateral cell border and regulates paracellular diffusion. Adjacent to the tight junction, the actin cytoskeleton forms a dense network beneath the apical surface and an actomyosin belt that circumscribes the lateral surface of the cell. Tight junctions are connected to the actin cytoskeleton which regulates paracellular transport, but the role of tension-mediated regulation of the tight junction by various actin structures is poorly understood. Here, we provide evidence that tension on the tight junction is mediated by the apical actin network. Our results provide a reinterpretion of past reports and broaden our understanding the mechanobiology of tight junctions.
A fast and objective hidden Markov modeling for accurate analysis of biophysical data with numerous states
Authors: Liu Hanjin , Shima Tomohiro
Published: May 2021

The hidden Markov model (HMM) is widely used to analyze biophysical chronological data with discrete states, such as binding/detachment of biomolecules, protein/nucleotide conformational changes and step-like movement of single proteins. Despite its usefulness, classical HMM fitting has practical drawbacks that it requires the determination of the number of hidden states and fine initialization of many parameters before fitting. To overcome these drawbacks, several HMM pre-analyses have been reported, but do not provide enough accuracy when data have unknown kinetics and/or low signal-to-noise ratio. Therefore, in many cases, HMM fitting needs trial-and-error manual process that can impair the objectivity of the analysis. Moreover, for data composed of numerous hidden states, such as stepping data of cytoskeletal motors, there has been difficulty in HMM analysis because the large number of parameters were hardly properly initialized. Here, by combining a statistical step-finding method and the Gaussian mixture model clustering, we developed a new algorithm for more objective HMM analysis. Our algorithm can execute accurate state number estimation and parameter optimization with fully automated way. Simulation analysis demonstrated that our algorithm accurately fit both fast- and slow-transition trajectories. Compared with the previous method, the speed of our algorithm was 10–20 times faster for standard size data. Our algorithm also showed the accurate fit of the simulated motor-stepping data with more than 10 transition states, suggesting the applicability of the method to the data with numerous states. Furthermore, the algorithm is flexible enough to cope with cases where some kinetics are known in advance. Some available prior information, such as the dwell time of each state, can be integrated into the algorithm via two user-tunable parameters. In summary, our method enables fast, accurate and objective HMM analysis, and broadens the application range of HMM fitting that can provide more accurate interpretation of a wide variety of biophysical data.
Uterine artery embolisation or myomectomy for women with uterine fibroids wishing to avoid hysterectomy: a cost–utility analysis of the FEMME trial
Authors: Rana D , Wu O , Cheed V , Middleton LJ , Moss J , Lumsden M‐A , McKinnon W , Daniels J , Sirkeci F , Manyonda I , Belli A‐M , McPherson K ,   the FEMME Trial Collaborative Group
Published: May 2021

Objectives

To assess the cost‐effectiveness of uterine artery embolisation (UAE) and myomectomy for women with symptomatic uterine fibroids wishing to avoid hysterectomy.

Design

Economic evaluation alongside the FEMME randomised controlled trial.

Setting

29 UK hospitals.

Population

Premenopausal women who had symptomatic uterine fibroids amenable to UAE or myomectomy wishing to avoid hysterectomy. 254 women were randomised to UAE (127) and myomectomy (127).

Methods

A within‐trial cost–utility analysis was conducted from the perspective of the UK NHS.

Main outcome measures

Quality‐adjusted life years (QALYs) measured using the EuroQoL EQ‐5D‐3L, combined with costs to estimate cost‐effectiveness over 2 and 4 years of follow‐up.

Results

Over a 2‐year time horizon, UAE was associated with higher mean costs (difference £645; 95% CI −1381 to 2580) and lower QALYs (difference −0.09; 95% CI −0.11 to −0.04) when compared with myomectomy. Similar results were observed over the 4‐year time horizon. Thus, UAE was dominated by myomectomy. Results of the sensitivity analyses were consistent with the base case results for both years. Over 2 years, UAE was associated with higher costs (difference £456; 95% CI −1823 to 3164) and lower QALYs (difference −0.06; 95% CI −0.11 to −0.02).

Conclusions

Myomectomy is a cost‐effective option for the treatment of uterine fibroids. The differences in costs and QALYs are small. Women should be fully informed and have the option to choose between the two procedures.

Tweetable abstract

Fully informed women with uterine fibroids should have a choice between uterine artery embolisation or myomectomy.
Fermentation and the microbial community of Japanese koji and miso: A review
Authors: Allwood Joanne G. , Wakeling Lara T. , Bean David C.
Published: May 2021

Miso is a well‐known traditional Japanese fermented food, with a characteristic savory flavor and aroma, known predominately as the seasoning in miso soup. Miso production involves a two‐stage fermentation, where first a mold, such as Aspergillus oryzae, is inoculated onto a substrate to make koji. A subsequent fermentation, this time by bacteria and yeast, occurs when the koji is added to a salt and soybean mash, with the miso left to ferment for up to 2 years. The microbial community of miso is considered essential to the development of the unique taste, texture, and nutritional profile of miso. Despite the importance of microorganisms in the production of miso, very little research has been undertaken to characterize and describe the microbial process. In this review, we provide an overview of the two‐stage fermentation process, describe what is currently known about the microbial communities involved and consider any potential health benefits associated with the consumption of miso, along with food safety concerns. As the popularity of miso continues to expand globally and is produced under new environmental conditions, understanding the microbiological processes involved will assist to ensure that global production of miso is safe as well as delicious.
Utility of positron emission tomography imaging in the diagnosis of chronic Q fever: A Systematic Review
Authors: Sivabalan Pirathaban , Visvalingam Rozanne , Grey Victoria , Blazak John , Henderson Andrew , Norton Robert
Published: May 2021

Chronic Q fever is a diagnostic challenge. Diagnosis relies on serology and/or the detection of DNA from blood or tissue samples. PET‐CT identifies tissues with increased glucose metabolism, thus identifying foci of inflammation. Our aim was to review the existing literature on the use of PET‐CT to help diagnose chronic Q fever. A literature search was conducted in PubMed and Google Scholar to ascertain publications that included the terms ‘Positron Emission Tomography’ and ‘PET CT’ in combination with subheadings ‘chronic Q fever’ and ‘Coxiella burnetii’ within the search. To broaden our search retrieval, we used the terms ‘chronic Q fever’ and ‘PET‐CT’. Published literature up to 16th April 2020 was included. 274 articles were initially identified. Post‐exclusion criteria, 46 articles were included. Amongst case reports and series, the most frequent focus of infection was vascular, followed by musculoskeletal then cardiac. 79.5% of patients had a focus detected with 55.3% of these having proven infected prosthetic devices. Amongst the retrospective and prospective studies, a total of 394 positive sites of foci were identified with 186 negative cases. Some had follow‐up scans (53), with 75.5% showing improvement or resolution. Average timeframe for documented radiological resolution post‐initiating treatment was 8.86 months. PET‐CT is a useful tool in the management of chronic Q fever. Knowledge of a precise focus enables for directed surgical management helping reduce microbial burden, preventing future complications. Radiological resolution of infection can give clinicians reassurance on whether antimicrobial therapy can be ceased earlier, potentially limiting side effects.