bluuebunny/crossref_metadata_2025 huggingface dataset:
Laparoscopic management of recurrent ectopic pregnancy: A retrospective cohort study describing 10-years of experience in a tertiary care hospital
Authors: Yu Xiaoming , Zheng Xingbang , Lu Ying , Zhao Wei , Guan Jing
Published: April 2021

Objective

Recurrent ectopic pregnancy (REP) is rare, but can have severe consequences for patients. The aim of this study was to report outcomes of laparoscopic management of REP in our center.

Methods

Retrospective cohort study including REP treated surgically at a single, tertiary-care academic medical center between 2009 and 2018. All patients undergoing laparoscopic salpingostomy or salpingectomy were included. Patients were then followed up to monitor outcomes of future reproductive events.

Results

Of 41 eligible patients, 14 suffered from ipsilateral recurrence including 5 cases of tubal stump pregnancy. In the other 27 cases, the REP occurred in the contralateral tube that was previously unaffected. All patients with ipsilateral recurrence underwent salpingectomy. In patients with contralateral recurrence, salpingectomy was carried out in 21 patients (77.8%) and salpingostomy in 6 patients (22.2%). 32 patients (78%) subsequently sought to conceive either spontaneously or by in vitro fertilization. The subsequent live birth rates were 51.8% (14/27) in the salpingectomy group and 60.0% (3/5) in the salpingostomy group.

Conclusion

Where trained laparoscopists and adequate facilities are available, it is possible to achieve acceptable reproductive outcomes after REP irrespective of the surgical approach.
Associations Between Environmental and Sociodemographic Data and Hepatitis‐A Transmission in Pará State (Brazil)
Authors: Leal Philipe Riskalla , Guimarães Ricardo José de Paula Souza e , Kampel Milton
Published: April 2021

Hepatitis‐A is a waterborne infectious disease transmitted by the eponymous hepatitis‐A virus (HAV). Due to the disease's sociodemographic and environmental characteristics, this study applied public census and remote sensing data to assess risk factors for hepatitis‐A transmission. Municipality‐level data were obtained for the state of Pará, Brazil. Generalized linear and nonlinear models were evaluated as alternative predictors for hepatitis‐A transmission in Pará. The Histogram Gradient Boost (HGB) regression model was deemed the best choice (= 2.36, and higher  = 0.95) among the tested models. Partial dependence analysis and permutation feature importance analysis were used to investigate the partial dependence and the relative importance values of the independent variables in the disease transmission prediction model. Results indicated a complex relationship between the disease transmission and the sociodemographic and environmental characteristics of the study area. Population size, lack of sanitation, urban clustering, year of notification, insufficient public vaccination programs, household proximity to open‐air dumpsites and storm‐drains, and lack of access to healthcare facilities and hospitals were sociodemographic parameters related to HAV transmission. Turbidity and precipitation were the environmental parameters closest related to disease transmission. Based on HGB model, a hepatitis‐A risk map was built for Pará state. The obtained risk map can be thought of as an auxiliary tool for public health strategies. This study reinforces the need to incorporate remote sensing data in epidemiological modelling and surveillance plans for the development of early prevention strategies for hepatitis‐A.
Quantum optics with swift electrons
Authors: Talebi Nahid
Published: April 2021

Stimulated and spontaneous interactions of electron wavepackets with optical near fields were explored with complementary techniques. In striking agreement with theory, scientists have demonstrated the dependence of spontaneous and stimulated quantum mechanical processes on the spatial distribution of optical modes.
Electric field, temperature and light-triggered triple dynamic circularly polarized luminescence switching in fluorescent cholesteric liquid crystals with a large dissymmetry factor
Authors: Lu Peng , Chen Youde , Chen Zhong , Yuan Yongjie , Zhang Hailiang
Published: April 2021

Triple stimuli-responsive circularly polarized luminescent materials with largeglumvalues and high fluorescence quantum yields were successfully prepared.
Cosmic-ray production from neutron escape in microquasar jets
Authors: Escobar G. J. , Pellizza L. J. , Romero G. E.
Published: April 2021

Context. The origin of Galactic cosmic rays remains a matter of debate, but supernova remnants are commonly considered to be the main place where high-energy cosmic rays are accelerated. Nevertheless, current models predict cosmic-ray spectra that do not match observations and the efficiency of the acceleration mechanism is still undetermined. On the other hand, the contribution of other kinds of sources to the Galactic cosmic-ray population is still unclear, and merits investigation.

Aims. In this work we explore a novel mechanism through which microquasars might produce cosmic rays. In this scenario, microquasar jets generate relativistic neutrons, which escape and decay outside the system; protons and electrons, created when these neutrons decay, escape to the interstellar medium as cosmic rays.

Methods. We introduce the relativistic neutron component through a coupling term in the transport equation that governs the jet proton population. We compute the escape rate and decay distribution of these neutrons, and follow the propagation of the decay products until they escape the system and become cosmic rays. We then compute the spectra of these cosmic rays.

Results. Neutrons can drain only a small fraction of the jet power as cosmic rays. The most promising scenarios arise in extremely luminous systems (Ljet ∼ 1040 erg s−1), in which the fraction of jet power deposited in cosmic rays can reach ∼0.001. Slow jets (Γ ≲ 2, where Γ is the bulk Lorentz factor) favour neutron production. The resulting cosmic-ray spectrum is similar for protons and electrons, which share the power in the ratio given by neutron decay. The spectrum peaks at roughly half the minimum energy of the relativistic protons in the jet; it is soft (spectral index ∼3) above this energy, and almost flat below.

Conclusions. The proposed mechanism produces more energetic cosmic rays from microquasars than those presented by previous works in which the particles escape through the jet terminal shock. Values of spectral index steeper than 2 are possible for cosmic rays in our model and these indeed agree with those required to explain the spectral signatures of Galactic cosmic rays, although only the most extreme microquasars provide power comparable to that of a typical supernova remnant. The mechanism explored in this work may provide stronger and softer cosmic-ray sources in the early Universe, and therefore contribute to the heating and reionisation of the intergalactic medium.
Syzygium malaccense (Malay apple).
Authors: Datiles Marianne Jennifer
Published: April 2021

A datasheet on Syzygium malaccense covering, as an economically important tree, its taxonomy, importance, silviculture, distribution, biology and ecology, uses, products and pests.
Descriptive analysis of the unwarranted continuation of antipsychotics for the management of ICU delirium during transitions of care: A multicenter evaluation across New Jersey
Authors: Dixit Deepali , Barbarello Andrews Liza , Radparvar Sara , Adams Christopher , Kumar Samir T , Cardinale Maria
Published: April 2021

Purpose

Nearly half of intensive care unit (ICU) patients will develop delirium. Antipsychotics are used routinely for the management of ICU delirium despite limited reliable data supporting this approach. The unwarranted continuation of antipsychotics initiated for ICU delirium is an emerging transitions of care concern, especially considering the adverse event profile of these agents. We sought to evaluate the magnitude of this issue across 6 centers in New Jersey and describe risk factors for continuation.

Methods

This multicenter, retrospective study examined adult ICU patients who developed ICU delirium from June 2016 to June 2018. Patients were included in the study if they received at least 3 doses of antipsychotics while in the ICU with presence of either a clinical diagnosis of delirium or a positive Confusion Assessment Method score. Patients were excluded if they were on an antipsychotic before ICU admission.

Results

Of the 300 patients included and initiated on antipsychotics for ICU delirium, 157 (52.3%) were continued on therapy upon transfer from the ICU to another level of inpatient care. The number of patients continued on newly initiated antipsychotics further increased to 183 (61%) upon discharge from the hospital.

Conclusion

The continuation of antipsychotics for the management of delirium during transitions of care was a common practice across ICUs in New Jersey. Several risk factors for continuation of antipsychotics were identified. Efforts to reduce unnecessary continuation of antipsychotics at transitions of care are warranted.
Creation of a regional hazardous drug handling task force
Authors: Duty Ashley , Robinson Joanna , Bahmandar Della , Hanson Nathan , Lucas Amber J
Published: April 2021

Purpose

A regional task force of health-system pharmacy leaders was created to assist with successful adoption of United States Pharmacopeia (USP) general chapter <800>.

A group of pharmacy leaders in the Kansas City region identified potential benefits to healthcare personnel and patients if hazardous drug handling procedures were standardized. A task force was created, a preimplementation survey was distributed, and meetings were held monthly to discuss sections of USP <800> identified as the most challenging to implement. The task force focused on an assessment of risk tool, hot topics, cleanroom design, and a detailed analysis of controversial medications. After the first year of meetings, a postimplementation survey was distributed, and the results were analyzed. The task force created significant value for the participants and achieved the goal of facilitating efficient USP <800> implementation resulting in greater compliance and consistency across the multiple health systems represented. Over 5,100 beds and 200 clinic sites were affected by this task force’s efforts. Nearly three-fourths (73%) of respondents reported that the task force was “extremely helpful,” and the majority (64%) of respondents adopted most or all (81%-100%) of the task force’s assessment of risk choices. Prioritization of tasks, information sharing, and decision-making were areas where the individual leaders were most supported.

Conclusion

Creating a structure to eliminate barriers and facilitate collaboration among regional pharmacy leaders provided a framework for successful implementation of USP <800> requirements. This interdependent leadership model produced innovative and standardized solutions and should be considered when addressing complicated initiatives that impact the profession.
stPlus: a reference-based method for the accurate enhancement of spatial transcriptomics
Authors: Shengquan Chen , Boheng Zhang , Xiaoyang Chen , Xuegong Zhang , Rui Jiang
Published: April 2021

Motivation

Single-cell RNA sequencing (scRNA-seq) techniques have revolutionized the investigation of transcriptomic landscape in individual cells. Recent advancements in spatial transcriptomic technologies further enable gene expression profiling and spatial organization mapping of cells simultaneously. Among the technologies, imaging-based methods can offer higher spatial resolutions, while they are limited by either the small number of genes imaged or the low gene detection sensitivity. Although several methods have been proposed for enhancing spatially resolved transcriptomics, inadequate accuracy of gene expression prediction and insufficient ability of cell-population identification still impede the applications of these methods.

Results

We propose stPlus, a reference-based method that leverages information in scRNA-seq data to enhance spatial transcriptomics. Based on an auto-encoder with a carefully tailored loss function, stPlus performs joint embedding and predicts spatial gene expression via a weighted k-nearest-neighbor. stPlus outperforms baseline methods with higher gene-wise and cell-wise Spearman correlation coefficients. We also introduce a clustering-based approach to assess the enhancement performance systematically. Using the data enhanced by stPlus, cell populations can be better identified than using the measured data. The predicted expression of genes unique to scRNA-seq data can also well characterize spatial cell heterogeneity. Besides, stPlus is robust and scalable to datasets of diverse gene detection sensitivity levels, sample sizes and number of spatially measured genes. We anticipate stPlus will facilitate the analysis of spatial transcriptomics.

Availability and implementation

stPlus with detailed documents is freely accessible at http://health.tsinghua.edu.cn/software/stPlus/ and the source code is openly available on https://github.com/xy-chen16/stPlus.
A variant selection framework for genome graphs
Authors: Jain Chirag , Tavakoli Neda , Aluru Srinivas
Published: April 2021

Motivation

Variation graph representations are projected to either replace or supplement conventional single genome references due to their ability to capture population genetic diversity and reduce reference bias. Vast catalogues of genetic variants for many species now exist, and it is natural to ask which among these are crucial to circumvent reference bias during read mapping.

Results

In this work, we propose a novel mathematical framework for variant selection, by casting it in terms of minimizing variation graph size subject to preserving paths of length α with at most δ differences. This framework leads to a rich set of problems based on the types of variants [e.g. single nucleotide polymorphisms (SNPs), indels or structural variants (SVs)], and whether the goal is to minimize the number of positions at which variants are listed or to minimize the total number of variants listed. We classify the computational complexity of these problems and provide efficient algorithms along with their software implementation when feasible. We empirically evaluate the magnitude of graph reduction achieved in human chromosome variation graphs using multiple α and δ parameter values corresponding to short and long-read resequencing characteristics. When our algorithm is run with parameter settings amenable to long-read mapping (α = 10 kbp, δ = 1000), 99.99% SNPs and 73% SVs can be safely excluded from human chromosome 1 variation graph. The graph size reduction can benefit downstream pan-genome analysis.

Availability and implementation

https://github.com/AT-CG/VF.

Supplementary information

Supplementary data are available at Bioinformatics online.
Fatal myopericarditis complicated with coronary vein perforation under the triple antithrombotic therapy: a case report
Authors: Takasaki Akihiro , Okamoto Ryuji , Sugimoto Hiroko , Dohi Kaoru
Published: April 2021

Background 

Acute pericarditis generally follows a mild clinical course and is rarely fatal. Coronary vein involvement is rarely reported.

Case summary 

We report an autopsy case of cardiac tamponade from idiopathic myopericarditis due to coronary venous perforation under the triple antithrombotic therapy. A 69-year-old man was admitted to our hospital with abnormal findings on electrocardiography, bloody pericardial effusion, and mild elevation of troponin I. Oral anti-inflammatories were started and the patient followed a benign course. However, on hospital Day 5, he suddenly suffered cardiogenic shock with pulseless electric activity due to cardiac tamponade under the combination use of the dual antiplatelet drugs and an anticoagulant drug. He died despite intense medical treatment. Autopsy revealed cardiac tamponade caused by perforation in the coronary venous wall. To the best of our knowledge, this is the first description of fatal myopericarditis as a complication of coronary venous perforation.

Discussion 

The aetiology and mechanism remain unknown; however, we should take care for this rare complication in patients with acute myopericarditis and bloody effusion under the triple antithrombotic therapy.
Random matrices and controllability of dynamical systems
Authors: Leventides John , Poulios Nick , Poulios Costas
Published: April 2021

We introduce the concept of $\epsilon $-uncontrollability for random linear systems, i.e. linear systems in which the usual matrices have been replaced by random matrices. We also estimate the $\varepsilon $-uncontrollability in the case where the matrices come from the Gaussian orthogonal ensemble. Our proof utilizes tools from systems theory, probability theory and convex geometry.
Drying Operation Effects on the Pigments and Phytochemical Properties of Rose Cultivars
Authors: Kim Sujung , Kim Seongmin , Shim Iesung , Hong Eunhye , Kim Sunhyung
Published: April 2021

Background

Roses are flowers which contain various phytochemicals and have been used for food and medicinal purposes in many countries. Materials, including flowers, are available for limited periods when plants can be cultivated.

Objective

To evaluate the quality of rose petals on the basis of cultivars and drying methods, chromaticity, phytochemical contents, and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity.

Method

Petals of three rose cultivars were dried by hot air drying (HD) and freeze drying (FD). Subsequently, the chromaticity and the contents of pigment, total flavonoids, and ascorbic acid, and DPPH radical scavenging activity were analyzed.

Results

The total color difference (△E)values of rose red (RR, Calypso) and rose orange (RO, Lambada) were low in FD. In contrast, in rose yellow (RY, Ileos), there was no significant difference in chromaticity regulation regardless of the drying methods. The pigment contents were generally increased by drying. The carotenoid content in the RR and anthocyanin and carotenoid contents in RO were higher in FD than in HD. The drying operations increased the flavonoid and ascorbic acid content and antioxidant activity in roses, but the difference between the drying methods was not significant. Correlation coefficient analysis revealed ascorbic acid and anthocyanin to have a high positive correlation (r = 0.843), followed by flavonoid and DPPH radical scavenging activity.

Conclusions

This study showed that the drying operations increased the flavonoid and ascorbic acid contents, and the chromaticity and pigment content of some cultivars was higher in FD.

Highlights

Comparison of the color change, phytochemical content, and antioxidant activity by the drying methods (FD and HD treatment) in the three rose cultivars with red, orange, and yellow petals showed the increased phytochemical contents and antioxidant activity after drying, and chromaticity and pigment content were more stable and higher in FD.
“More than Scabs and Stitches”: An Interview Study of Burn Survivors’ Perspectives on Treatment and Recovery
Authors: Dukes Kimberly , Baldwin Stephanie , Hagedorn Joshua , Ruba Emily , Christel Katherine , Assimacopoulos Evangelia , Grieve Brian , Wibbenmeyer Lucy A
Published: April 2021

Sustaining a burn injury often results in a life-long recovery process. Survivors are impacted by changes in their mobility, appearance, and ability to carry out activities of daily living. In this study, we examined survivors’ accounts of their treatment and recovery in order to identify specific factors that have had significant impacts on their well-being. With this knowledge, we may be better equipped to optimize the care of burn patients. We conducted inductive, thematic analysis on transcripts of in-depth, semistructured interviews with 11 burn survivors. Participants were purposefully selected for variability in age, gender, injury size and mechanism, participation in peer support, and rurality. Survivors reported varied perceptions of care quality and provider relationships. Ongoing issues with skin and mobility continued to impact their activities of daily living. Many survivors reported that they did not have a clear understanding or realistic expectations of the recovery process. Wound care was often described as overwhelming and provoked fear for many. Even years later, trauma from burn injury can continue to evolve, creating fears and impediments to daily living for survivors. To help patients understand the realistic course of recovery, providers should focus on communicating the nature of injury and anticipated recovery, developing protocols to better identify survivors facing barriers to care, and referring survivors for further support.
Integrated dominance mechanisms regulate reproductive architecture inArabidopsis thalianaandBrassica napus
Authors: Walker Catriona H , Wheeldon Cara D , Bennett Tom
Published: April 2021

The production of seed in flowering plants is complicated by the need to first invest in reproductive shoots, inflorescences, flowers, and fruit. Furthermore, in many species, it will be months between plants generating flowers and setting seed. How can plants therefore produce an optimal seed-set relative to environmental resources when the “reproductive architecture” that supports seed-set needs to be elaborated so far in advance? Here, we address this question by investigating the spatio-temporal control of reproductive architecture in Arabidopsis (Arabidopsis thaliana) and Brassica napus. We show that resource and resource-related signals such as substrate volume play a key role in determining the scale of reproductive effort, and that this is reflected in the earliest events in reproductive development, which broadly predict the subsequent reproductive effort. We show that a series of negative feedbacks both within and between developmental stages prevent plants from over-committing to early stages of development. These feedbacks create a highly plastic, homeostatic system in which additional organs can be produced in the case of reproductive failure elsewhere in the system. We propose that these feedbacks represent an “integrated dominance” mechanism that allows resource use to be correctly sequenced between developmental stages to optimize seed set.
3D bioprinting of integral ADSCs-NO hydrogel scaffolds to promote severe burn wound healing
Authors: Wu Yu , Liang Tangzhao , Hu Ying , Jiang Shihai , Luo Yuansen , Liu Chang , Wang Guo , Zhang Jing , Xu Tao , Zhu Lei
Published: April 2021

Severe burns are challenging to heal and result in significant death throughout the world. Adipose-derived mesenchymal stem cells (ADSCs) have emerged as a promising treatment for full-thickness burn healing but are impeded by their low viability and efficiency after grafting in vivo. Nitric oxide (NO) is beneficial in promoting stem cell bioactivity, but whether it can function effectively in vivo is still largely unknown. In this study, we bioprinted an efficient biological scaffold loaded with ADSCs and NO (3D-ADSCs/NO) to evaluate its biological efficacy in promoting severe burn wound healing. The integral 3D-ADSCs/NO hydrogel scaffolds were constructed via 3D bioprinting. Our results shown that 3D-ADSCs/NO can enhance the migration and angiogenesis of Human Umbilical Vein Endothelial Cells (HUVECs). Burn wound healing experiments in mice revealed that 3D-ADSCs/NO accelerated the wound healing by promoting faster epithelialization and collagen deposition. Notably, immunohistochemistry of CD31 suggested an increase in neovascularization, supported by the upregulation of vascular endothelial growth factor (VEGF) mRNA in ADSCs in the 3D biosystem. These findings indicated that 3D-ADSC/NO hydrogel scaffold can promote severe burn wound healing through increased neovascularization via the VEGF signalling pathway. This scaffold may be considered a promising strategy for healing severe burns.
Estimating the total morbidity burden of COVID-19
Authors: Smith Maia P.
Published: April 2021

Background

Calculations of disease burden of COVID-19 are used to allocate scarce resources and historically have focused on mortality, with little attention to morbidity such as postviral ‘post-COVID,’ similar to chronic fatigue syndrome (CFS), which strikes 4 and 16% of male and female survivors. This paper quantifies post-COVID disability burden and combines it with case fatality to estimate total morbidity per COVID-19 case.

Methods

Healthy life years lost per COVID-19 case were computed as the sum of (incidence*disability weight*remaining lifespan) for death and post-COVID (modeled as CFS) by sex and 10-year age category. In addition to death, the main model considered lifelong mild, moderate or severe CFS; Model 2, CFS which resolved in ten years; Model 3, no CFS but 10% risk of death 10 years later.

Results

In all models, acute mortality was only a small share of total morbidity. For lifelong moderate CFS symptoms, healthy years lost per COVID-19 case ranged from 0.92 (male in his 30s) to 5.71 (girl under 10) and were 3.5 and 3.6 for the oldest females and males. At higher symptom severities, young people and females bore larger shares of total morbidity; if symptoms were persistent or survivors’ later mortality increased, young people of both sexes were at highest risk.

Conclusions

Compared to post-COVID, acute mortality contributes only a small share of total COVID-19 morbidity. Total burden falls heavily on the young, who are currently deprioritized for preventive interventions such as vaccines. To fairly allocate scarce resources, decisionmakers should consider all morbidity.
County-Level Estimates of Excess Mortality Associated with COVID-19 in the United States
Authors: Ackley Calvin A. , Lundberg Dielle J. , Ma Lei , Elo Irma T. , Preston Samuel H. , Stokes Andrew C.
Published: April 2021

Background

The COVID-19 pandemic in the U.S. has been largely monitored on the basis of death certificates containing reference to COVID-19. However, prior analyses reveal that a significant percentage of excess deaths associated with the pandemic were not directly assigned to COVID-19.

Methods

In the present study, we estimate a generalized linear model of expected mortality in 2020 based on historical trends in deaths by county of residence between 2011 and 2019. We use the results of the model to generate estimates of excess mortality and excess deaths not assigned to COVID-19 for 1,470 county-sets in the U.S. representing 3,138 counties.

Results

During 2020, more than one-fourth of U.S. residents (91.2 million) lived in counties where less than 75% of excess deaths were assigned to COVID-19. Across the country, we estimated that 439,698 excess deaths occurred in 2020, among which 86.7% were assigned to COVID-19. Some regions (Mideast, Great Lakes, New England, and Far West) reported the most excess deaths in large central metros, whereas other regions (Southwest, Southeast, Plains, and Rocky Mountains) reported the highest excess mortality in nonmetro areas. The proportion assigned to COVID-19 was lowest in large central metro areas (79.3%) compared to medium or small metros (87.4%), nonmetro areas (89.4%) and large fringe metros (95.2%). Regionally, the proportion of excess deaths assigned to COVID-19 was lowest in the Southeast (81.1%), Far West (81.2%), Southwest (82.6%), and Rocky Mountains (85.2%). Across the regions, the number of excess deaths exceeded the number of directly assigned COVID-19 deaths in the majority of counties. The exception to this was in New England, which reported more directly assigned COVID-19 deaths than excess deaths in large central metro areas, large fringe metros, and medium or small metros.

Conclusions

Across the U.S., many counties had substantial numbers of excess deaths that were not accounted for in direct COVID-19 death counts. Estimates of excess mortality at the local level can inform the allocation of resources to areas most impacted by the pandemic and contribute to positive protective behavior feedback loops (i.e. increases in mask-wearing and vaccine uptake).
A ganglioside-based senescence-associated immune checkpoint
Authors: Iltis Charlène , Seguin Laetitia , Cervera Ludovic , Duret Lou , Hamidouche Tynhinane , Kunz Sarah , Croce Olivier , Delannoy Clément , Gueŕardel Yann , Allain Fabrice , Moudombi Lyvia , Hofman Paul , Cosson Estelle , Guglielmi Julien , Pourcher Thierry , Braud Véronique M. , Shkreli Marina , Michallet Marie-Cécile , Feral Chloé C. , Gilson Eric , Cherfils-Vicini Julien
Published: April 2021

Senescent cells accumulate in aging tissues, and their elimination can favor healthy aging1-4. Therefore, therapeutic interventions targeting cellular senescence may be promising strategies for delaying or reversing a vast range of age-related diseases5. As cells of the immune system are responsible for senescent cell elimination6-11, a possible anti-aging and pro-healthspan treatment is the specific activation of the immune system to induce senescent cell clearance. However, whether this elimination is limited by an immune checkpoint leading to tolerance of senescence cells is currently unknown. Here, we show that cellular senescence, elicited by various stressors other than oncogenic activation, triggers immune escape toward natural killer (NK) cells, which may thus limit the use of anti-senescence immunotherapies. Moreover, using mass spectrometry, we reveal that senescent cells reshuffle their glycosphingosine composition, toward a marked increase in the ganglioside content, including the appearance of disialylated ganglioside GD3. This senescence associated GD3 overexpression results from transcriptional upregulation of the gene encoding the enzyme ST8SIA1, which is responsible for GD3 synthesis. The high level of GD3 leads to a strong immunosuppressive signal affecting NK cell-mediated immunosurveillance. In a mouse model of lung fibrosis, senescent cell-dependent NK cell immunosuppression is blunted byin vivoadministration of anti-GD3 monoclonal antibodies leading to a clear anti-fibrotic effect. These results demonstrate that GD3 upregulation in senescent cells drives a switch from immune clearance toward immune tolerance of senescent cells. Therefore, we propose that GD3 level acts as a senescence-associated immune checkpoint (SIC) that regulates NK cell functions toward senescent cells. Thus, targeting GD3 with specific antibodies may be a promising strategy for the development of effective anti-senescence immunotherapies.
An N-terminal Fusion Allele to Study Melanin Concentrating Hormone Receptor 1
Authors: Jasso Kalene R. , Kamba Tisianna K. , Zimmerman Arthur D. , Bansal Ruchi , Engle Staci E. , Everett Thomas , Wu Chang-Hung , Kulaga Heather , Reed Randal R. , Berbari Nicolas F. , McIntyre Jeremy C.
Published: April 2021

Cilia on neurons play critical roles in both the development and function of the central nervous system (CNS). While it remains challenging to elucidate the precise roles for neuronal cilia, it is clear that a subset of G-protein-coupled receptors (GPCRs) preferentially localize to the cilia membrane. Further, ciliary GPCR signaling has been implicated in regulating a variety of behaviors. Melanin concentrating hormone receptor 1 (MCHR1), is a GPCR expressed centrally in rodents known to be enriched in cilia. Here we have used MCHR1 as a model ciliary GPCR to develop a strategy to fluorescently tag receptors expressed from the endogenous locusin vivo.Using CRISPR/Cas9, we inserted the coding sequence of the fluorescent protein mCherry into the N-terminus ofMchr1. Analysis of the fusion protein (mCherryMCHR1) revealed its localization to neuronal cilia in the CNS, across multiple developmental time points and in various regions of the adult brain. Our approach simultaneously produced fortuitous in/dels altering theMchr1start codon resulting in a new MCHR1 knockout line. Functional studies using electrophysiology show a significant alteration of synaptic strength in MCHR1 knockout mice. A reduction in strength is also detected in mice homozygous for the mCherry insertion, suggesting that while the strategy is useful for monitoring the receptor, activity could be altered. However, both lines should aid in studies of MCHR1 function and contribute to our understanding of MCHR1 signaling in the brain. Additionally, this approach could be expanded to aid in the study of other ciliary GPCRs.
MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets
Authors: Qiu Xintao , Boufaied Nadia , Hallal Tarek , Feit Avery , de Polo Anna , Luoma Adrienne M. , Larocque Janie , Zadra Giorgia , Xie Yingtian , Gu Shengqing , Tang Qin , Zhang Yi , Syamala Sudeepa , Seo Ji-Heui , Bell Connor , O’Connor Edward , Liu Yang , Schaeffer Edward M. , Karnes R. Jeffrey , Weinmann Sheila , Davicioni Elai , Cejas Paloma , Ellis Leigh , Loda Massimo , Wucherpfennig Kai W. , Pomerantz Mark M. , Spratt Daniel E. , Corey Eva , Freedman Matthew L. , Liu X. Shirley , Brown Myles , Long Henry W. , Labbé David P.
Published: April 2021

c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Importantly, analyses of clinical specimens revealed that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq revealed an increased RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.

STATEMENT OF SIGNIFICANCE

AR and MYC are key to prostate cancer etiology but our current understanding of their interplay is scarce. Here we show that the oncogenic transcription factor MYC can pause the transcriptional program of the master transcription factor in prostate cancer, AR, while turning on its own, even more lethal program.
Sex-dependent effects of CYP46A1 overexpression on cognitive function during aging
Authors: Latorre-Leal María , Rodriguez-Rodriguez Patricia , Franchini Luca , Daniilidou Makrina , Eroli Francesca , Winblad Bengt , Blennow Kaj , Zetterberg Henrik , Kivipelto Miia , Pacciarini Manuela , Wang Yuqin , Griffiths William J. , Björkhem Ingemar , Sandebring Matton Anna , Merino-Serrais Paula , Cedazo-Minguez Angel , Maioli Silvia
Published: April 2021

Cholesterol turnover and CYP46A1 regulation are reported to be crucial for memory functions. An increasing body of evidence shows that CYP46A1 activation is able to reduce Alzheimer’s Disease (AD) pathological processes. In this study we report for the first time that CYP46A1 overexpression and increase of 24S-hydroxycholesterol (24OH) induces sex-specific changes in synaptic functions in aged mice, being beneficial in females while detrimental in males. The positive effects on cognition in aged CYP46A1 overexpressing female mice were accompanied by morphological changes in dendritic spines and enhancement of estrogen receptor signaling in hippocampus. In aged males, CYP46A1 overexpression leads to anxiety-like behavior and worsening of spatial memory, followed by decreased dendritic spine density and higher 5α-dihydrotestosterone (DHT) levels in hippocampus. Further, analysis of cerebrospinal fluid (CSF) from AD, mild cognitive impairment and healthy patients revealed that 24OH was negatively associated to markers of neurodegeneration in women but not in men. Based on our results, CYP46A1 activation may represent a pharmacological target that could specifically enhance brain estrogen receptor signaling in women at risk of developing AD. Finally, this study highlights the importance of taking into account the sex-dimension in both preclinical and clinical studies of neurodegenerative diseases like AD.
Sex-specific blood-brain barrier alterations and vascular biomarkers underlie chronic stress responses in mice and human depression
Authors: Dion-Albert Laurence , Cadoret Alice , Doney Ellen , Kaufmann Fernanda Neutzling , Dudek Katarzyna A. , Parise Lyonna F. , Cathomas Flurin , Samba Nalia , Hudson Natalie , Lebel Manon ,   Signature Consortium, Campbell Matthew , Turecki Gustavo , Mechawar Naguib , Menard Caroline
Published: April 2021

Prevalence, symptoms, and treatment of depression all point toward major sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice however it remains unknown if it contributes to this sexual dimorphism. Here, we report that chronic social and subchronic variable stress promoted sex-specific blood-brain barrier (BBB) molecular and morphological alterations in mood-related brain regions. Viral-mediated functional manipulation leading to a targeted disruption of the BBB induced anxiety- and depression-like behaviors including social avoidance and anhedonia. Endothelium cell-specific transcriptomic profiling revealed key pathways and novel genes involved in maladaptive stress responses vs resilience. We also confirmed BBB leakiness in the brain of stressed females which led us to explore and identify circulating vascular biomarkers of chronic stress that could inform on diagnosis and treatment. Importantly, these pre-clinical findings were validated in human blood andpostmortembrain samples from depressed women, thus highlighting their translational value. By revealing a sex-specific causal role of BBB dysfunction in stress responses and depression, our results implicate vascular impairment as a major factor underlying mood disorders.
Functional independence of endogenous μ- and δ-opioid receptors co-expressed in cholinergic interneurons
Authors: Arttamangkul Seksiri , Platt Emily J. , Carroll James , Farrens David L.
Published: April 2021

Class A G protein-coupled receptors (GPCRs) normally function as monomers, although evidence from heterologous expression systems suggests they may form homodimers and/or heterodimers. Detection of GPCR dimers in native tissues has however been challenging due to the lack of suitable tools. μ- and δ-Opioid receptors (MORs and DORs) co-expressed in transfected cells has been reported to form heterodimers. The co-localization of MORs and DORs in neurons has been studied in knock-in mice expressing genetically engineered receptors fused to fluorescent proteins. Here we report that single cholinergic neurons in the mouse striatum endogenously express both MORs and DORs. The receptors were fluorescently labeled in live brain slices with a ligand-directed labeling reagent, NAI-A594. The selective activation of MORs and DORs, with DAMGO (μ-agonist) and deltorphin (δ-agonist) inhibited spontaneous firing in all cells examined. In the continued presence of agonist, the firing rate returned to baseline with the application of deltorphin but was persistently inhibited with the application of DAMGO. In addition, agonist-induced internalization of DORs but not MORs was detected. When MORs and DORs were activated simultaneously with [Met5]enkephalin, desensitization of MORs was facilitated but internalization was not increased. Together, these results indicate that while MORs and DORs are expressed in single striatal cholinergic interneurons, the two receptors function independently.
Neural circuits for dynamics-based segmentation of time series
Authors: Teşileanu Tiberiu , Golkar Siavash , Nasiri Samaneh , Sengupta Anirvan M. , Chklovskii Dmitri B.
Published: April 2021

The brain must extract behaviorally relevant latent variables from the signals streamed by the sensory organs. Such latent variables are often encoded in the dynamics that generated the signal rather than in the specific realization of the waveform. Therefore, one problem faced by the brain is to segment time series based on underlying dynamics. We present two algorithms for performing this segmentation task that are biologically plausible, which we define as acting in a streaming setting and all learning rules being local. One algorithm is model-based and can be derived from an optimization problem involving a mixture of autoregressive processes. This algorithm relies on feedback in the form of a prediction error, and can also be used for forecasting future samples. In some brain regions, such as the retina, the feedback connections necessary to use the prediction error for learning are absent. For this case, we propose a second, model-free algorithm that uses a running estimate of the autocorrelation structure of the signal to perform the segmentation. We show that both algorithms do well when tasked with segmenting signals drawn from autoregressive models with piecewise-constant parameters. In particular, the segmentation accuracy is similar to that obtained from oracle-like methods in which the ground-truth parameters of the autoregressive models are known. We also test our methods on datasets generated by alternating snippets of voice recordings. We provide implementations of our algorithms athttps://github.com/ttesileanu/bio-time-series.
Characterization of α2-Adrenergic Receptors Mediated Vasoconstriction inex vivomodel
Authors: Yao Molly
Published: April 2021

Introduction

rat tail serves as a thermoregulatory organ by dilating or constricting tail blood vessels and rat tail lateral veins play a role in cutaneous circulation. However, this cutaneous vessel has never been examined and evaluated as a potential candidateex vivomodel to study peripheral vascular diseases. This study aims to investigate vascular tone mediated through α2-adenergic receptor on rat tail vein under different temperatures.

Methods

Vasoconstriction stimulated by α2-adrenergic receptor selective agonists UK14304, guanabenz was thoroughly examined in isolated rat tail lateral vein. Susceptibility of cutaneous vessel to temperature changes was investigated under 37 °C and 28 °C. Differentiated vascular reactivity exhibited at different temperature was further explored with different α2-adrenergic receptor selective agonists and validated with antagonism by α1-adrenergic receptor and α2-adrenergic receptor selective antagonist prazosin and RX821002, respectively.

Results

Vascular tone of freshly isolated vein remained same compared with that of stored in pre-gassed physiologic buffer at 4 °C overnight. Presence of endothelium and repeated administration of UK14304 did not alter contractile property. Vessels away from torso (distal) showed significantly different contractile character compared with portion close to torso (proximal) at 28 °C but kept uniform at 37 °C. Enhanced vasoconstriction along with increased potency of α2-adrenergic receptor agonists UK14304 and guanabenz was consistently present at 28 °C, independent of temperature change orders. Potentiated vasoconstriction present at 28 °C was later proved via α2-adrenergic receptor alone.

Discussion

Harvest and preparation of rat tail lateral vein was described in details. Contractile property of venous preparations stimulated by α2-adrenergic receptor selective agonists was first time examined. Differentiated vasoconstriction at moderate cooling temperature was described and confirmed to through α2-adrenergic receptor activation. Rat tail lateral vein is found valuable for studies of cutaneous circulation altered by temperature changes.
Activity-based cell sorting reveals resistance of functionally degenerateNitrospiraduring a press disturbance in nitrifying activated sludge
Authors: Madill Maxwell B.W. , Luo Yaqian , Sampara Pranav , Ziels Ryan M.
Published: April 2021

Managing and engineering activated sludge wastewater treatment microbiomes for low-energy nitrogen removal requires process control strategies to stop the oxidation of ammonium at nitrite. Our ability to out-select nitrite oxidizing bacteria (NOB) from activated sludge is challenged by their metabolic and physiological diversity, warranting measurements of theirin situphysiology and activity under selective growth pressures. Here, we examined the stability of nitrite oxidation in activated sludge during a press disturbance induced by treating a portion of return activated sludge with a sidestream flow containing free ammonia (FA) at 200 mg NH3-N/L. The nitrite accumulation ratio peaked at 42% by day 40 in the experimental bioreactor with the press disturbance, while it did not increase in the control bioreactor. A subsequent decrease in nitrite accumulation within the experimental bioreactor coincided with shifts in dominantNitrospira16S rRNA amplicon sequence variants (ASVs). We applied bioorthogonal non-canonical amino acid tagging (BONCAT) coupled with fluorescence activated cell sorting (FACS) to investigate changes in the translational activity of NOB populations throughout batch exposure to FA. BONCAT-FACS confirmed that the singleNitrospiraASV washed-out of the experimental bioreactor had reduced translational activity following exposure to FA, whereas the twoNitrospiraASVs that emerged after process acclimation were not impacted by FA. Thus, the coexistence of functionally degenerate and physiologically resistantNitrospirapopulations provided resilience to the nitrite-oxidizing function during the press disturbance. These results highlight how BONCAT-FACS can resolve ecological niche differentiations within activated sludge and inform strategies to engineer and control microbiome function.

Importance

Nitrogen removal from activated sludge wastewater treatment systems is an energy-intensive process due to the large aeration requirement for nitrification. This energy footprint could be minimized with engineering control strategies that wash-out nitrite oxidizing bacteria (NOB) to limit oxygen demands. However, NOB populations can have a high degree of physiological diversity, and it is currently difficult to decipher the behavior of individual taxa during applied selective pressures. Here, we utilized a new substrate analog probing approach to measure the activity of NOB at the cellular translational level in the face of an applied press disturbance to the activated sludge process. Substrate analog probing corroborated the time-series reactor sampling, showing that coexisting and functionally redundantNitrospiraprovided resilience to the nitrite oxidation process. Taken together, these results highlight how substrate analog approaches can illuminatein situecophysiologies within shared niches, and can inform strategies to improve microbiome engineering and management.