bluuebunny/crossref_metadata_2025 huggingface dataset:
Aging-related cerebral microvascular changes visualized using Ultrasound Localization Microscopy in the living mouse
Authors: Lowerison Matthew R. , Sekaran Nathiya Chandra , Zhang Wei , Dong Zhijie , Chen Xi , Llano Daniel A. , Song Pengfei
Published: June 2021

Aging-related cognitive decline is an emerging health crisis; however, no established unifying mechanism has been identified for the cognitive impairments seen in an aging population. A vascular hypothesis of cognitive decline has been proposed but is difficult to test given the contradictory radiologic needs of high-fidelity microvascular imaging resolution and a broad and deep brain imaging field of view. Super-resolution ultrasound localization microscopy (ULM) offers a potential solution by exploiting circulating microbubbles to achieve a vascular resolution approaching the capillary scale without sacrificing imaging depth. In this report, we apply ULM imaging to a mouse model of aging and quantify differences in cerebral vascularity, blood velocity, and vessel tortuosity across several brain regions. We found significant decreases in blood velocity, and significant increases in vascular tortuosity, across all brain regions in the aged cohort, and significant decreases in blood volume in the cortex. These data provide the first-ever measurements of subcortical microvascular dynamics in vivo and reveal that aging has a major impact on these measurements.
Utilizing proteomics and phosphoproteomics to predict ex vivo drug sensitivity across genetically diverse AML patients
Authors: Gosline Sara JC , Tognon Cristina , Nestor Michael , Joshi Sunil , Modak Rucha , Damnernsawad Alisa , Moon Jamie , Hansen Joshua R. , Hutchinson-Bunch Chelsea , Gritsenko Marina A. , Weitz Karl K. , Traer Elie , Drucker Brian , Agarwal Anupriya , Piehowski Paul , McDermott Jason E. , Rodland Karin
Published: June 2021

Acute Myeloid Leukemia (AML) affects 20,000 patients in the US annually with a five-year survival rate of approximately 25%. One reason for the low survival rate is the high prevalence of clonal evolution that gives rise to heterogeneous sub-populations of leukemia. This genetic heterogeneity is difficult to treat using conventional therapies that are generally based on the detection of a single driving mutation. Thus, the use of molecular signatures, consisting of multiple functionally related transcripts or proteins, in making treatment decisions may overcome this hurdle and provide a more effective way to inform drug treatment protocols. Toward this end, the Beat AML research program prospectively collected genomic and transcriptomic data from over 1000 AML patients and carried out ex vivo drug sensitivity assays to identify signatures that could predict patient-specific drug responses. The Clinical Proteomic Tumor Analysis Consortium is in the process of extending this cohort to collect proteomic and phosphoproteomic measurements from a subset of these patient samples to evaluate the hypothesis that proteomic signatures can robustly predict drug response in AML patients. We sought to examine this hypothesis on a sub-cohort of 38 patient samples from Beat AML with proteomic and drug response data and evaluate our ability to identify proteomic signatures that predict drug response with high accuracy. For this initial analysis we built predictive models of patient drug responses across 26 drugs of interest using the proteomics and phosphproteomics data. We found that proteomics-derived signatures provide an accurate and robust signature of drug response in the AML ex vivo samples, as well as related cell lines, with better performance than those signatures derived from mutations or mRNA expression. Furthermore, we found that in specific drug-resistant cell lines, the proteins in our prognostic signatures represented dysregulated signaling pathways compared to parental cell lines, confirming the role of the proteins in the signatures in drug resistance. In conclusion, this pilot study demonstrates strong promise for proteomics-based patient stratification to predict drug sensitivity in AML.
The Effect of Pandemic Prevalence on the Reported Efficacy of SARS-CoV-2 Vaccine Candidates: A Systematic Review and Meta-analysis
Authors: Sharma Rajeev , Anand Abhijith
Published: June 2021

Importance

The efficacy of SARS-CoV-2 vaccine candidates reported in Phase 3 trials varies from ∼45% to ∼95%. It is important to explain the reasons for this heterogeneity.

Objective

To test the hypothesis that the efficacy of SARS-CoV-2 vaccine candidates falls with increasing prevalence of the COVID-19 pandemic.

Data Sources

ClinicalTrials.gov, WHO, McGill and LSHTM trackers of COVID-19 candidate vaccines, peer reviewed publications, and press releases were searched until March 31st, 2021.

Study Selection

All RCTs reporting efficacy outcomes from Phase 3 trials till March 31st, 2021 were included. Of the 11 vaccine candidates that had started their Phase 3 trials by November 1, 2020. Phase 3 efficacy outcomes were available for 8 vaccine candidates. (PROSPERO CRD42021243121).

Data Extraction and Synthesis

Both authors independently extracted the data required from identified sources, using PRISMA guidelines. The analysis included all RCTs reported in peer reviewed publications and publicly available sources. A random effects model with restricted maximum likelihood estimator was used to summarize the treatment effects. Cochrane Risk of Bias Assessment Tool was used to assess risk of bias. Certainty of evidence was assessed using the GRADE tool.

Main Outcomes and Measures

SARS-CoV-2 infections per protocol in vaccine and placebo groups, risk ratio, prevalence of the COVID-19 infection rate in the populations where the Phase 3 trials were conducted.

Results

8 vaccine candidates had reported efficacy data from a total of 20 independent Phase 3 trials, representing a total of 221,968 subjects, 453 infections across the vaccinated groups and 1,554 infections across the placebo groups. The overall estimate of the risk-ratio is 0.24 (95% CI, 0.17-0.34, p < 0.01), with an I2 statistic of 88.73%. The meta-regression analysis with pandemic prevalence as the moderator explains almost half the variance in risk ratios across trials (R2=49.06%, p<0.01).

Conclusion and Relevance

Pandemic prevalence explains almost half of the between-trial variance in reported efficacies. Efficacy of SARS-CoV-2 vaccine candidates declines as the pandemic prevalence increases.

Key Points

Question

Does the prevalence of the COVID-19 pandemic explain the heterogeneity in efficacies reported across Phase 3 trials of SARS-CoV-2 vaccine candidates?

Findings

Almost 50% of the variance in efficacies reported across Phase 3 trials can be explained by differences in COVID-19 infection rate prevailing across trials. Efficacy of evaluated SARS-CoV-2 vaccine candidates falls significantly with increasing prevalence of the COVID-19 pandemic across trial sites.

Meaning

Efficacy of SARS-CoV-2 vaccine candidates needs to be interpreted in conjunction with the prevalence of the COVID-19 pandemic. Adjustment for location-level prevalence analysis would provide better insights into the efficacy results of Phase 3 trials.
“Time does not heal all wounds”: Sexual victimisation is associated with depression, anxiety and PTSD in old age
Authors: Nobels Anne , Lemmens Gilbert M.D. , Thibau Lisa , Beaulieu Marie , Vandeviver Christophe , Keygnaert Ines
Published: June 2021

Background

Sexual violence (SV) has an important impact on mental health. Childhood sexual abuse is linked to internalising disorders in later life. In older adults, SV occurs more often than previously believed. Moreover, health care workers lack the skills to address SV in later life. Studies researching the mental health impact of lifetime SV, i.e. SV during childhood, adulthood and old age, are lacking.

Methods

Between July 2019 and March 2020, 513 older adults living in Belgium participated in structured face-to-face-interviews. Selection occurred via a cluster random probability sampling with a random walk finding approach. Depression, anxiety and posttraumatic stress syndrome (PTSD) were measured using validated scales. Participants were asked about suicide attempts and self-harm during their lifetime and in the past 12-months. SV was measured using behaviourally specific questions based on a broad SV definition.

Results

Rates for depression, anxiety and PTSD were 27%, 26% and 6% respectively, 2% had attempted suicide, 1% reported self-harm in the past 12-months. Over 44% experienced lifetime SV, 8% in the past 12-months. Lifetime SV was linked to depression (p =.001), anxiety (p =.001), and PTSD in participants with a chronic illness/disability (p = .002) or no/lower education (p <.001). We found no link between lifetime SV and suicide attempts or self-harm in the past 12-months.

Conclusions

Lifetime SV is linked to mental health problems in late life. Tailored mental health care for older SV victims is necessary. Therefore, capacity building of professionals, and development of clinical guidelines and care procedures are important.
Identifying Charismatic Bird Species and Traits with Community Science Observations
Authors: Stoudt Sara , Goldstein Benjamin R. , De Valpine Perry
Published: June 2021

Abstract

Identifying which species are perceived as charismatic can improve the impact and efficiency of conservation outreach, as charismatic species receive more conservation funding and have their conservation needs prioritized (9; 17; 13). Sociological experiments studying animal charisma have relied on stated preferences to find correlations between hypothetical “willingness to pay” or “empathy” for a species’ conservation and species’ size, color, and aesthetic appeal (51; 13; 16). Recognizing the increasing availability of digital records of public engagement with animals that reveal preferences, an emerging field of “culturomics” uses Google search results, Wikipedia article activities, and other digital modes of engagement to identify charismatic species and traits (46; 31; 10; 41). In this study, we take advantage of community science efforts as another form of digital data that can reveal observer preferences. We apply a multi-stage analysis to ask whether opportunistic birders contributing to iNaturalist engage more with larger, more colorful, and rarer birds relative to a baseline, from eBird contributors, approximating unbiased detection. We find that body mass, color contrast, and range size all predict over-representation in the opportunistic dataset. We also find evidence that, across 473 modeled species, 52 species are significantly overreported and 158 are significantly underreported, indicating a wide variety of species-specific effects. Understanding which birds are charismatic can aid conservationists in creating impactful outreach materials and engaging new naturalists. The quantified differences between two prominent community science efforts may also be of use for researchers leveraging the data from one or both of them to answer scientific questions of interest.
DeepCME: A deep learning framework for solving the Chemical Master Equation
Authors: Gupta Ankit , Schwab Christoph , Khammash Mustafa
Published: June 2021

Stochastic models of biomolecular reaction networks are commonly employed in systems and synthetic biology to study the effects of stochastic fluctuations emanating from reactions involving species with low copy-numbers. For such models, the Kolmogorov’s forward equation is called the chemical master equation (CME), and it is a fundamental system of linear ordinary differential equations (ODEs) that describes the evolution of the probability distribution of the random state-vector representing the copy-numbers of all the reacting species. The size of this system is given by the number of states that are accessible by the chemical system, and for most examples of interest this number is either very large or infinite. Moreover, approximations that reduce the size of the system by retaining only a finite number of important chemical states (e.g. those with non-negligible probability) result in high-dimensional ODE systems, even when the number of reacting species is small. Consequently, accurate numerical solution of the CME is very challenging, despite the linear nature of the underlying ODEs. One often resorts to estimating the solutions via computationally intensive stochastic simulations.

The goal of the present paper is to develop a novel deep-learning approach for solving high-dimensional CMEs by reformulating the stochastic dynamics using Kolmogorov’s backward equation. The proposed method leverages superior approximation properties of Deep Neural Networks (DNNs) and is algorithmically based on reinforcement learning. It only requires a moderate number of stochastic simulations (in comparison to typical simulation-based approaches) to train the “policy function”. This allows not just the numerical approximation of the CME solution but also of its sensitivities to all the reaction network parameters (e.g. rate constants). We provide four examples to illustrate our methodology and provide several directions for future research.
SC-MEB: spatial clustering with hidden Markov random field using empirical Bayes
Authors: Yang Yi , Shi Xingjie , Liu Wei , Zhou Qiuzhong , Lau Mai Chan , Lim Jeffrey Chun Tatt , Sun Lei , Yeong Joe , Liu Jin
Published: June 2021

Spatial transcriptomics has been emerging as a powerful technique for resolving gene expression profiles while retaining tissue spatial information. These spatially resolved transcriptomics make it feasible to examine the complex multicellular systems of different microenvironments. To answer scientific questions with spatial transcriptomics and expand our understanding of how cell types and states are regulated by microenvironment, the first step is to identify cell clusters by integrating the available spatial information. Here, we introduce SC-MEB, an empirical Bayes approach for spatial clustering analysis using a hidden Markov random field. We have also derived an efficient expectation-maximization algorithm based on an iterative conditional mode for SC-MEB. In contrast to BayesSpace, a recently developed method, SC-MEB is not only computationally efficient and scalable to large sample sizes but is also capable of choosing the smoothness parameter and the number of clusters. We performed comprehensive simulation studies to demonstrate the superiority of SC-MEB over some existing methods. We applied SC-MEB to analyze the spatial transcriptome of human dorsolateral prefrontal cortex tissues and mouse hypothalamic preoptic region. Our analysis results showed that SC-MEB can achieve a similar or better clustering performance to BayesSpace, which uses the true number of clusters and a fixed smoothness parameter. Moreover, SC-MEB is scalable to large ‘sample sizes’. We then employed SC-MEB to analyze a colon dataset from a patient with colorectal cancer (CRC) and COVID-19, and further performed differential expression analysis to identify signature genes related to the clustering results. The heatmap of identified signature genes showed that the clusters identified using SC-MEB were more separable than those obtained with BayesSpace. Using pathway analysis, we identified three immune-related clusters, and in a further comparison, found the mean expression of COVID-19 signature genes was greater in immune than non-immune regions of colon tissue. SC-MEB provides a valuable computational tool for investigating the structural organizations of tissues from spatial transcriptomic data.
The influence of stimulus and behavioral histories on predictive control of smooth pursuit eye movements
Authors: Miyamoto Takeshi , Hirata Yutaka , Katoh Akira , Miura Kenichiro , Ono Seiji
Published: June 2021

The pursuit system has the ability to perform predictive control of eye movements. Even when the target motion is unpredictable due to velocity or direction changes, preceding changes in eye velocity are generated based on weighted averaging of past stimulus timing. However, it is still uncertain whether behavioral history influences the control of predictive pursuit. Thus, we attempted to clarify the influences of stimulus and behavioral histories on predictive pursuit to randomized target velocity. We used alternating-ramp stimuli, where the rightward velocity was fixed while the leftward velocity was either fixed (predictable) or randomized (unpredictable). Predictive eye deceleration was observed regardless of whether the target velocity was predictable or not. In particular, the predictable condition showed that the predictive pursuit responses corresponded to future target velocity. The linear mixed-effects model showed that both stimulus and behavioral histories of the previous two or three trials had influences on the predictive pursuit responses to the unpredictable target velocity. Our results suggest that the predictive pursuit system allows to track randomized target motion using the information from previous several trials, and the information of sensory input (stimulus) and motor output (behavior) in the past time sequences have partially different influences on predictive pursuit.
Cardiac sympathovagal activity initiates a functional brain-body response to emotional processing
Authors: Candia-Rivera Diego , Catrambone Vincenzo , Thayer Julian F. , Gentili Claudio , Valenza Gaetano
Published: June 2021

A century-long debate on bodily states and emotions persists. While the involvement of bodily activity in emotion physiology is widely recognized, the specificity and causal role of such activity related to brain dynamics has not yet been demonstrated. We hypothesize that the peripheral neural monitoring and control of cardiovascular activity prompts and sustains brain dynamics during an emotional experience, so these afferent inputs are processed by the brain by triggering a concurrent efferent information transfer to the body. To this end, we investigated the functional brain-heart interplay under emotion elicitation in publicly available data from 62 healthy participants using a computational model based on synthetic data generation of EEG and ECG signals. Our findings show that sympathovagal activity plays a leading and causal role in initiating the emotional response, in which ascending modulations from vagal activity precede neural dynamics and correlate to the reported level of arousal. The subsequent dynamic interplay observed between the central and autonomic nervous systems sustains emotional processing. These findings should be particularly revealing for the psychophysiology and neuroscience of emotions.

Significance

We investigate the temporal dynamics of brain and cardiac activities in healthy subjects who underwent an emotional elicitation through videos. We demonstrate that, within the first few seconds, emotional stimuli modulate the heart activity, which in turn stimulate an emotion-specific cortical response in the brain. Then, the conscious emotional experience is sustained by a bidirectional brain-heart interplay and information exchange. Moreover, the perceived intensity of an emotional stimulus is predicted by the intensity of neural control regulating the heart activity. These findings may constitute the fundamental knowledge linking neurophysiology and psychiatric disorders, including the link between depressive symptoms and cardiovascular disorders.
Effects of immunosuppressive therapy reduction and early post-infection graft function in kidney transplant recipients with COVID-19
Authors: Alfano Gaetano , Damiano Francesca , Fontana Francesco , Ferri Camilla , Giaroni Francesco , Melluso Andrea , Montani Martina , Morisi Niccolò , Tei Lorenzo , Plessi Jessica , Giovanella Silvia , Ligabue Giulia , Mori Giacomo , Guaraldi Giovanni , Magistroni Riccardo , Cappelli Gianni
Published: June 2021

Background

Kidney transplant recipients with COVID-19 are at high risk of poor outcome because of comorbidities and immunosuppression. The effects of immunosuppressive therapy reduction are unclear in patients with COVID-19.

Methods

We conducted a retrospective study on 45 consecutive kidney transplant recipients followed at the University Hospital of Modena who tested positive for COVID-19 by RT-PCR analysis.

Results

The median age of patients was 56.1 (interquartile range, [IQR] 47.3-61.1) years with a predominance of male (64.4%). Kidney transplantation vintage was 10.1 (2.7-16) years, and more than half of patients (55.6%) was on triple immunosuppressive therapy. Early reduction of immunosuppression occurred in 62.8% of patients and included antimetabolite (88.8%) and calcineurin inhibitor withdrawal (22.2%).

Of the 45 patients, 88.9% became symptomatic and 40% required hospitalization. Overall mortality was 17.8%. There were no differences in outcomes between full- and reduced-dose immunosuppressive therapy at the end of follow-up. One hospitalized patient experienced irreversible graft failure. There were no differences in serum creatinine level and proteinuria in non-hospitalized patients with COVID-19. Admitted patients had better kidney function after dismission (P=0.019). Risk factors for death were age (odds ratio [OR]: 1.19; 95%CI: 1.01-1.39), and duration of kidney transplant (OR: 1.17; 95%CI: 1.01-1.35). One kidney transplant recipient experienced symptomatic COVID-19 reinfection after primary infection and anti-SARS-CoV-2 mRNA vaccine.

Conclusions

Despite the reduction of immunosuppression, COVID-19 affected survival of kidney transplant recipients with COVID-19. Age and duration of kidney transplant were independent predictors of death in COVID-19. Early kidney function was favorable in most survivors after COVID-19.
Structural insights into the modes of relaxin-binding and tethered-agonist activation of RXFP1 and RXFP2
Authors: Sethi Ashish , Bruell Shoni , Ryan Tim , Yan Fei , Tanipour Mohammad , Mok Yee-Foong , Draper-Joyce Chris , Khandokar Yogesh , Metcalfe Riley D. , Griffin Michael D. W. , Scott Daniel J. , Hossain Mohammad Akhter , Petrie Emma J. , Bathgate Ross A. D. , Gooley Paul R.
Published: June 2021

Our poor understanding of the mechanism by which the peptide-hormone H2 relaxin activates its G protein coupled receptor, RXFP1 and the related receptor RXFP2, has hindered progress in its therapeutic development. Both receptors possess large ectodomains, which bind H2 relaxin, and contain an N-terminal LDLa module that is essential for receptor signalling and postulated to be a tethered agonist. Here, we show that a conserved motif (GDxxGWxxxF), C-terminal to the LDLa, is critical for receptor activity. Importantly, this motif adopts different structures in RXFP1 and RXFP2, suggesting distinct activation mechanisms. For RXFP1, the motif is flexible, weakly associates with the LDLa, and requires H2 relaxin binding to stabilize an active conformation. Conversely, the GDxxGWxxxF motif in RXFP2 is more closely associated with the LDLa, forming an essential binding interface for H2 relaxin. These differences in the activation mechanism will aid drug development targeting these receptors.
Resource-efficient pooled sequencing expands translational impact in solid tumors
Authors: DiNatale Renzo G. , Mano Roy , Makarov Vladimir , Rusk Nicole , Drill Esther , Winer Andrew , Sankin Alexander , Yoo Angela , Freeman Benjamin A. , Hsieh James J. , Chen Ying-Bei , Coleman Jonathan A. , Berger Michael , Ostrovnaya Irina , Chan Timothy A. , Russo Paul , Reznik Ed , Hakimi A. Ari
Published: June 2021

Intratumoral genetic heterogeneity (ITH) poses a significant challenge to utilizing sequencing for decision making in the management of cancer. Although sequencing of multiple tumor regions can address the pitfalls of ITH, it does so at a significant increase in cost and resource utilization. We propose a pooled multiregional sequencing strategy, whereby DNA aliquots from multiple tumor regions are mixed prior to sequencing, as a cost-effective strategy to boost translational value by addressing ITH while preserving valuable residual tissue for secondary analysis. Focusing on kidney cancer, we demonstrate that DNA pooling from as few as two regions significantly increases mutation detection while reducing clonality misattribution. This leads to an increased fraction of patients identified with therapeutically actionable mutations, improved patient risk stratification, and improved inference of evolutionary trajectories with an accuracy comparable to bona fide multiregional sequencing. The same approach applied to non-small-cell lung cancer data substantially improves tumor mutational burden (TMB) detection. Our findings demonstrate that pooled DNA sequencing strategies are a cost-effective alternative to address intrinsic genetic heterogeneity in clinical settings.
The role of the cannabinoid system in fear memory and extinction in male and female mice
Authors: Mizuno Ikumi , Matsuda Shingo , Tohyama Suguru , Mizutani Akihiro
Published: June 2021

The prevalence of post-traumatic stress disorder (PTSD) is higher in women than in men. Among both humans and mice, females exhibit higher resistance to fear extinction than males, suggesting that differences between sexes in processes of fear extinction are involved in the pathophysiology of such fear-related diseases. Sex differences in molecular mechanisms for fear memory and extinction are unclear. The cannabinoid (CB) system is well known to be involved in fear memory and extinction, but this involvement is based mainly on experiments using male rodents. It has been unclear whether there are sex differences in the role of the CB system in fear memory and extinction. To explore the possibility of such differences, we investigated the effects of pharmacological manipulations of the CB system on the retrieval and extinction of contextual fear memory in male and female mice. WIN55,212-2, a CB receptor (CBR) agonist, augmented the retrieval of fear memory in both sexes, but SR141716 (a CB1R antagonist) did not affect it in either sex. An enhancement of 2-arachidonylglycerol (2-AG, one of the two major endocannabinoids) via JZL184 [an inhibitor of the 2-AG hydrolase monoacylglycerol lipase (MAGL)], augmented the retrieval of fear memory through the activation of CB1R but not CB2R in female mice. In contrast, the enhancement of N-arachidonylethanolamine (AEA, the other major endocannabinoid) via URB597, an inhibitor of an AEA hydrolase (fatty acid amide hydrolase-1) did not show any effects on the retrieval or extinction of fear memory in either sex. WIN55,212-2, SR141716, and JZL184 inhibited fear extinction irrespective of sex. These results suggest that although the role of CB1R in the retrieval and extinction of contextual fear memory is common among males and females, the effects of an increase in the 2-AG level on the retrieval of contextual fear memory differ between the sexes.
Models of increased latent HIV reservoir turnover prior to cART initiation imply novel clearance strategies
Authors: Jagarapu Aditya , Mann Rajveer , Piovoso Michael J. , Zurakowski Ryan
Published: June 2021

CD4+ T cells with a naive or memory phenotype carrying a replication-competent HIV provirus are recognized as the major component of the persistent HIV reservoir. These cells only minimally express viral protein, reducing viral cytotoxicity effects and making them difficult targets for immune responses as well as every available antiretroviral drug. In patients on suppressive antiretroviral therapy, the half-life of these cells is approximately 4-5 years, balanced by clonal expansion of the cells resulting in an overall reservoir half-life in excess of 40 years. A recent study has shown that prior to the initiation of antiretroviral therapy, the half-life of these cells is instead on the order of two weeks. We present two models explaining the wide disparity in the on- and off-treatment half-lives of the quiescent infected T cells. In the first model, generalized (antigen non-specific) immune activation due to the high HIV viral loads explains the high latent reservoir turnover rates in the absence of treatment. If this mechanism dominates, we demonstrate that reduction of the latent reservoir size is possible, either through the administration of exogenous antigen or through the use of timed treatment interruptions. In the second model, direct killing of reservoir cells by HIV drives the increased turnover off-treatment. If this mechanism dominates, modulation of the reservoir size is not possible by the methods described above. Previously published models of the immune response to HIV show the possibility of inducing post-treatment control by reducing the latent reservoir size; by incorporating the same immune response dynamics in our first model, it is shown that it may be possible to induce post-treatment control using either exogenous antigen administration or timed treatment interruptions.
RNA polymerases from Low G+C Gram Positive Bacteria
Authors: Miller Michael , Oakley Aaron J. , Lewis Peter J.
Published: June 2021

The low G+C Gram positive bacteria represent some of the most medically and industrially important microorganisms. They are relied on for the production of food and dietary supplements, enzymes and antibiotics, as well as being responsible for the majority of nosocomial infections and serving as a reservoir for antibiotic resistance. Control of gene expression in this group is more highly studied than in any bacteria other than the Gram negative model Escherichia coli, yet until recently no structural information on RNA polymerase (RNAP) from this group was available. This review will summarise recent reports on the high resolution structure of RNAP from the model low G+C representative Bacillus subtilis, including the role of auxiliary subunits δ and ε, and outline approaches for the development of antimicrobials to target RNAP from this group.
TRIB1 regulates tumour growth via controlling tumour-associated macrophage phenotypes and is associated with breast cancer survival and treatment response
Authors: Kim Taewoo , Johnston Jessica , Felipe Francisco J. C. , Hamby Stephen , Castillo-Lluva Sonia ,   The Cardiogenics Consortium, Goodall Alison H , Velasco Guillermo , Ocana Alberto , Muthana Munitta , Kiss-Toth Endre
Published: June 2021

Molecular mechanisms that regulate tumour-associated macrophage (TAM) phenotype and function are incompletely understood. Here, we show that the pseudokinase TRIB1 is highly expressed by TAMs in breast cancer and that its expression correlates with response to chemotherapy and patient survival. We used immune-competent murine models of breast cancer to characterise the consequences of altered (reduced or elevated) myeloid Trib1 expression on tumour growth and composition of stromal immune cells. We found that both overexpression and knockout of myeloid Trib1 promote tumour growth, albeit through distinct molecular mechanisms. Myeloid Trib1 deficiency resulted in an early accelearation of tumour growth, paired with a selective reduction in perivascular macrophage numbers in vivo and enhanced oncogenic cytokine expression in vitro. In contrast, elevated levels of Trib1 in myeloid cells led to an increase in mammary tumour volume at late stages, together with a reduction of NOS2 expressing macrophages and an overall reduction of these cells in hypoxic tumour regions. In addition, we show that myeloid Trib1 is a previously unknown, negative regulator of the anti-tumour cytokine IL-15 and that increased expression of myeloid Trib1 leads to reduced IL-15 levels in mammary tumours, with a consequent reduction in the number of T-cells, that are key to anti-tumour immune responses.

Together, these results define the different roles of TRIB1 in human breast cancer and provide a mechanistic understanding for the importance of myeloid TRIB1 expression levels in the development of this disease.

Significance

TRIB1 expression is strongly associated with response to chemotherapy in breast cancer patients with aggressive tumours. This protein is also highly expressed by tumour-associated macrophages. Thus, we used myeloid-specific alterations of Trib1 expression in mice (Trib1mKO and Trib1mTg), and characterised consequent changes in the growth rate and tumour microenvironment of mammary tumours. Both Trib1mKO and Trib1mTg enhanced tumour growth, but at different stages of tumour growth and via distinct mechanisms. Trib1mKO significantly increased the expression of oncogenic cytokines, such as IL6, IL10, CCL20, PD-L1, and VEGF. In contrast, Trib1mTg accelerated at the later stage of tumour growth via inhibition of hypoxic TAMs in the TME, as well as by reduced IL-15 expression thus leading to impaired naïve and cytotoxic T cell infiltration. These data define TRIB1 as a potential novel marker of therapeutic responses in breast cancer, as well as a key mechanistic regulator of the anti-tumour cytokine, IL-15 in myeloid cells.
DNA transposon expansion is associated with genome size increase in mudminnows
Authors: Lehmann Robert , Kovařík Aleš , Ocalewicz Konrad , Kirtiklis Lech , Zuccolo Andrea , Tegner Jesper N. , Wanzenböck Josef , Bernatchez Louis , Lamatsch Dunja K. , Symonová Radka
Published: June 2021

Genome sizes of eukaryotic organisms vary substantially, with whole genome duplications (WGD) and transposable element expansion acting as main drivers for rapid genome size increase. The two North American mudminnows, Umbra limi and U. pygmaea, feature genomes about twice the size of their sister lineage Esocidae (e.g., pikes and pickerels). However, it is unknown whether all Umbra species share this genome expansion and which causal mechanisms drive this expansion. Using flow cytometry, we find that the genome of the European mudminnow is expanded similarly to both North American species, ranging between 4.5-5.4 pg per diploid nucleus. Observed blocks of interstitially located telomeric repeats in Umbra limi suggest frequent Robertsonian rearrangements in its history. Comparative analyses of transcriptome and genome assemblies show that the genome expansion in Umbra is driven by extensive DNA transposon expansion without WGD. Furthermore, we find a substantial ongoing expansion of repeat sequences in the Alaska blackfish Dallia pectoralis, the closest relative to the family Umbridae, which might mark the beginning of a similar genome expansion. Our study suggests that the genome expansion in mudminnows, driven mainly by transposon expansion, but not WGD, occurred before the separation into the American and European lineage.

Significance Statement

North American mudminnows feature genomes about twice the size of their sister lineage Esocidae (e.g., pikes and pickerels). However, neither the mechanism underlaying this genome expansion, nor whether this feature is shared amongst all mudminnows is currently known. Using cytogenetic analyses, we find that the genome of the European mudminnow also expanded and that extensive chromosome fusion events have occurred in some Umbra species. Furthermore, comparative genomics based on de-novo assembled transcriptomes and genome assemblies, which have recently become available, indicates that DNA transposon activity is responsible for this expansion.
Evidence of subjective, but not objective, cognitive deficit in new mothers at one-year postpartum
Authors: Orchard Edwina R , Ward Phillip GD , Egan Gary F , Jamadar Sharna D
Published: June 2021

The experience and even existence of cognitive deficits in the postpartum period is uncertain, with only a few scientific studies, reporting inconsistent results. Here we investigate cognition in 86 women (43 first-time mothers one year postpartum, and 43 non-mothers). Mothers and non-mothers showed no significant differences on measures of objective cognition (verbal memory, working memory, processing speed or theory of mind). Despite the absence of objective differences, mothers self-reported significantly worse subjective memory than non-mothers. To interpret the difference between objective and subjective measures of memory, we investigated relationships between subjective memory, objective memory, and wellbeing. Mothers, but not non-mothers, showed a positive correlation between subjective and objective measures of memory, indicating mothers are ‘in-tune’ with their memory performance. Mothers also demonstrated a positive relationship between subjective memory and wellbeing (sleep, anxiety and depression), where better wellbeing correlated with higher subjective memory. This relationship was not apparent in non-mothers. The results suggest that poorer sleep, higher anxiety and higher depression are related to reports of poorer self-reported memory in mothers. Our results add to our growing understanding of maternal cognition at one year postpartum, with no evidence of cognitive differences between mothers and non-mothers.
Lying in a 3T MRI Scanner Induces Neglect-Like Spatial Attention Bias
Authors: Lindner Axel , Wiesen Daniel , Karnath Hans-Otto
Published: June 2021

The static magnetic field of MRI scanners can induce a magneto-hydrodynamic stimulation of the vestibular organ (MVS). In common fMRI settings, this MVS effect leads to a vestibular ocular reflex (VOR). We asked whether – beyond inducing a VOR – putting a healthy subject in a 3T MRI scanner would also alter goal-directed spatial behavior, as is known from other types of vestibular stimulation. We investigated 17 healthy volunteers, all of which exhibited a rightward VOR inside the MRI-scanner as compared to outside-MRI conditions. More importantly, when probing the distribution of overt spatial attention inside the MRI using a visual search task, subjects scanned a region of space that was significantly shifted towards the right. An additional estimate of subjective straight-ahead orientation likewise exhibited an MVC-induced rightward shift. Hence, putting a subject in a 3T MRI-scanner induces a bias of spatial attention, which closely mimics that of stroke patients with spatial neglect.
Immuno-EM characterization of vasopressin neurons in macaques by use of formaldehyde-fixed tissues stored for several years
Authors: Otubo Akito , Maejima Sho , Oti Takumi , Satoh Keita , Ueda Yasumasa , Morris John F. , Sakamoto Tatsuya , Sakamoto Hirotaka
Published: June 2021

Translational research often requires the testing of experimental therapies in primates, but research in non-human primates is now stringently controlled by law around the world. Tissues fixed in formaldehyde without glutaraldehyde have been thought to be inappropriate for use in electron microscopic analysis, particularly those of the brain. Here we report the immunoelectron microscopic characterization of arginine vasopressin (AVP)-producing neurons in macaque hypothalamo-pituitary axis tissues fixed with 4% formaldehyde and stored at –25°C for several years. The size difference of dense-cored vesicles between magnocellular and parvocellular AVP neurons was detectable in their cell bodies and perivascular nerve endings located, respectively, in the posterior pituitary and median eminence. Furthermore, glutamate and the vesicular glutamate transporter 2 were colocalized with AVP in perivascular nerve endings of both the posterior pituitary and the external layer of the median eminence, suggesting that both magnocellular and parvocellular AVP neurons are glutamatergic in primates. Both ultrastructure and immunoreactivity can therefore be sufficiently preserved in macaque brain tissues stored long-term for light microscopy. Taken together, these results suggest that this methodology could be applied to the human post-mortem brain and be very useful in translational research.
In-vitro Reconstitution of Membrane Contact Sites between the Endoplasmic Reticulum and Lipid Droplets
Authors: Kamerkar Sukrut , Singh Jagjeet , Tripathy Subham , Bhonsle Hemangi , Kumar Mukesh , Mallik Roop
Published: June 2021

Coordinated cell function requires inter-organelle communication across Membrane Contact Sites (MCS). Here we deposit ER-enriched microsomes purified from rat liver or from cultured cells on a coverslip in the form of a continuous planar membrane. We visualize real-time protein and lipid exchanges across MCS that form between this ER-mimicking membrane and lipid droplets purified from rat liver. An Optical trap is used to demonstrate physical tethering of individual lipid droplets to the ER-mimicking membrane at MCS, and to directly measure the strength of this tether. In-vitro MCS formation changes dramatically in response to metabolic state and immune activation in the animal. Surprisingly, we find that the Rab18 GTPase and Phosphatidic acid are common molecular factors to control both of these pathways. This assay could possibly be adapted to interrogate MCS formation between other membranes (e.g. mitochondria, peroxisomes, endosomes etc.), and abnormalities therein that cause neurological, metabolic and pathogenic diseases.
Modelling Porcine NAFLD by Deletion of Leptin and defining the role of AMPK in hepatic fibrosis
Authors: Tan Tan , Song Zhiyuan , Wang Runming , Jiang Shuheng , Liang Zuoxiang , Wang Qi , Hu Xiaoxiang , Li Ning , Xing Yiming
Published: June 2021

Liver fibrosis occurs during chronic liver disease. Advanced liver fibrosis results in cirrhosis, liver failure and often requires liver transplantation. However, due to the lack of human models, mechanisms underlining the pathogenesis of liver fibrosis remain unclear. Recent studies implicated a central role of deranged lipid metabolism in its pathogenesis. In this study, we generated LEPTIN-deficient (LEPTIN-/-) pigs using zinc finger nuclease technology to investigate the mechanisms of liver fibrosis associated with obesity. The LEPTIN-/- pigs showed increased body fat and significant insulin resistance by 12 months of age. To resemble non-alcoholic fatty liver disease (NAFLD) patients, LEPTIN-/- pig developed the phenotypic features of fatty liver, non-alcoholic steatohepatitis (NASH) and hepatic fibrosis with age. Meanwhile, LEPTIN absence reduced phosphorylation of JAK2-STAT3 and AMPK. The alteration of JAK2-STAT3 enhanced fatty acid β-oxidation, whereas inactivation of AMPK led to mitochondrial autophagy, and both contributed to increased oxidative stress in hepatocytes. Although Leptin deletion in the rat liver altered JAK2-STAT3 phosphorylation, it activated the AMPK pathway and prevented liver fibrogenesis in contrast with the LEPTIN-/- pig. To our knowledge, the LEPTIN-/- pig provides the first model recapitulating the full pathogenesis of NAFLD and its progression toward liver fibrosis. The activity of AMPK signaling pathway suggests a potential target for development of new strategies for the diagnosis and treatment of NAFLD.
Effects of early life adversity on immediate early gene expression: systematic review and 3-level meta-analysis of rodent studies
Authors: Schuler Heike , Bonapersona Valeria , Joëls Marian , Sarabdjitsingh R. Angela
Published: June 2021

Early-life adversity (ELA) causes long-lasting structural and functional changes to the brain, rendering affected individuals vulnerable to the development of psychopathologies later in life. Immediate-early genes (IEGs) provide a potential marker for the observed alterations, bridging the gap between activity-regulated transcription and long-lasting effects on brain structure and function. Several heterogeneous studies have used IEGs to identify differences in cellular activity after ELA; systematically investigating the literature is therefore crucial for comprehensive conclusions. Here, we performed a systematic review on 39 pre-clinical studies in rodents to study the effects of ELA on IEG expression. Females and IEGs other than cFos were investigated in only a handful of publications. We meta-analyzed publications investigating specifically cFos expression. ELA increased cFos expression after an acute stressor only if the animals (control and ELA) had experienced multiple negative life events. At rest, ELA increased cFos expression irrespective of other life events, suggesting that ELA creates a phenotype similar to naïve, acutely stressed animals. We present a conceptual theoretical framework to interpret the unexpected results. Overall, ELA likely alters IEG expression across the brain, especially in interaction with other negative life events. The present review highlights current knowledge gaps and provides guidance to aid the design of future studies.
Structural, spectroscopic and DFT theoretical studies of phosphorescent CuIP2S-containing cuprous complexes
Authors: Liang Yu , Wang Jian-Teng , Song Li , Dai Ding-Qiu , Wang You-Yu , Chai Wen-Xiang
Published: June 2021

Luminescent cuprous complexes are important coordination compounds due to their relative abundance, low cost and ability to display excellent luminescence. The structures of two CuIP2S-type cuprous complexes, namely, iodido(thiourea-κS)bis(triphenylphosphane-κP)copper(I), [CuI(CH4N2S)(C18H15P)2] or [CuI(TU)(TPP)2] (I), and (2,3-dihydrobenzimidazole-2-thione-κS)iodidobis(triphenylphosphane-κP)copper(I), [CuI(C7H6N2S)(C18H15P)2] or [CuI(DHBIT)(TPP)2] (II), are described. In these two structures, the complex molecules of both are constructed by one copper(I) centre, one iodide ion, two TPP ligands and one thione ligand (TU forIand DHBIT forII). The copper(I) centres ofIandIIare both located in a distorted CuIP2S tetrahedron and are coordinated by two P atoms from two TPP ligands, one S atom from the thione ligand and the I atom. The UV–Vis absorption and photoluminescence properties of these CuIP2S-type cuprous complexes have been studied using crystalline powder samples. Detailed time-dependent density functional theory (TD-DFT) calculations and wavefunction analysis reveal that the pale-blue–green phosphorescence emission should originate from intra-ligand (TPP forIand DHBIT forII) charge transfer, with a small component of the metal-to-ligand charge transfer3(IL+ML)CT excited state.
Organizational career management and turnover intentions: mediating role of trust in management
Authors: Haridas Jyothilakshmy , Ture Rameshwar Shivadas , Nayanpally Ajith Kumar
Published: June 2021

Purpose

The contemporary career development models argued more for self-management of careers, yet few researchers emphasized importance of organizational career management. The purpose of this paper is to check association between perceived organizational career management practices, trust in management and turnover intentions.

Design/methodology/approach

In this study, authors proposed a model based on social exchange theory. Data for this study were collected from 405 IT professionals employed in India. The proposed model was tested using structural equation modelling.

Findings

Results showed significant direct and indirect negative effect of perceived informal organizational career management on turnover intention. In case of perceived formal organizational career management only indirect effect was significant. Trust in management mediated relationship between both types of organizational career management and turnover intentions.

Originality/value

First, this study delineated effect of formal and informal perceived organizational career management practices on turnover intentions. Second, this study introduced trust in management as mediator to explain relationship between organizational career management practice and outcome.