bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the Associations Between the Liver Frailty Index and Karnofsky Performance Status With Waitlist Mortality
Authors: Xu Chelsea Q. , Yao Frederick , Mohamad Yara , Wong Randi , Kent Dorothea , Seetharaman Srilakshmi , Srisengfa Yanin , Lai Jennifer C.
Published: February 2021

Background.

Frailty has emerged as a critical determinant of mortality in patients with cirrhosis. Currently, the United Network for Organ Sharing registry only includes the Karnofsky Performance Status (KPS) scale, which captures a single component of frailty. We determined the associations between frailty, as measured by the Liver Frailty Index (LFI), and KPS with waitlist mortality.

Methods.

Included were 247 adult patients with cirrhosis listed for liver transplantation without hepatocellular carcinoma from February 2014 to June 2019, who underwent outpatient assessments using the LFI and KPS within 30 days of listing. “Frail” was defined using the established LFI cutoff of ≥4.4. Competing risk models assessed associations between the LFI and KPS with waitlist mortality (death/delisting for sickness).

Results.

At a median 8 months follow-up, 25 (10%) patients died/were delisted. In this cohort, median Model for End-Stage Liver Disease-Sodium was 17, LFI was 3.9 (interquartile range 3.4–4.5), and KPS was 80 (interquartile range 70–90). In multivariable analysis, LFI (sub-hazard ratio 1.07, per 0.1 unit; 95% confidence interval, 1.01-1.12) was associated with waitlist mortality while KPS was not (sub-hazard ratio 1.00, per 10 units; 95% confidence interval, 0.78-1.29).

Conclusions.

Our data suggest that frailty, as measured by the LFI, may be more appropriate at capturing mortality risk than KPS and provide evidence in support of using the LFI more broadly in clinical transplant practice in the outpatient setting.
Precision Medicine in Kidney Transplantation: Just Hype or a Realistic Hope?
Authors: Nobakht Ehsan , Jagadeesan Muralidharan , Paul Rohan , Bromberg Jonathan , Dadgar Sherry
Published: February 2021

Desirable outcomes including rejection- and infection-free kidney transplantation are not guaranteed despite current strategies for immunosuppression and using prophylactic antimicrobial medications. Graft survival depends on factors beyond human leukocyte antigen matching such as the level of immunosuppression, infections, and management of other comorbidities. Risk stratification of transplant patients based on predisposing genetic modifiers and applying precision pharmacotherapy may help improving the transplant outcomes. Unlike certain fields such as oncology in which consistent attempts are being carried out to move away from the “error and trial approach,” transplant medicine is lagging behind in implementing personalized immunosuppressive therapy. The need for maintaining a precarious balance between underimmunosuppression and overimmunosuppression coupled with adverse effects of medications calls for a gene-based guidance for precision pharmacotherapy in transplantation. Technologic advances in molecular genetics have led to increased accessibility of genetic tests at a reduced cost and have set the stage for widespread use of gene-based therapies in clinical care. Evidence-based guidelines available for precision pharmacotherapy have been proposed, including guidelines from Clinical Pharmacogenetics Implementation Consortium, the Pharmacogenomics Knowledge Base National Institute of General Medical Sciences of the National Institutes of Health, and the US Food and Drug Administration. In this review, we discuss the implications of pharmacogenetics and potential role for genetic variants-based risk stratification in kidney transplantation. A single score that provides overall genetic risk, a polygenic risk score, can be achieved by combining of allograft rejection/loss-associated variants carried by an individual and integrated into practice after clinical validation.
Twisted gastrulation signaling modulator 1 promotes the ability of glioma cell through activating Akt pathway
Authors: Liu Zhuohang , Li Hang
Published: February 2021

Glioblastoma is one of the most common primary nervous system tumors and has a high mortality rate. It is necessary to explore a novel biological target and treatment approach. Twisted gastrulation signaling modulator 1 (TWSG1) is expressed in many tumors and closely related to tumor growth and proliferation. However, there is almost no report about the mechanism of TWSG1 in glioma. We used a glioma chip to detect the expression level of TWSG1 by Immunohistochemistry. The overexpression and silence experiments of TWSG1 were performed to assay the biological function of TWSG1 in LN229 and U251 cells. Subcutaneous xenograft mouse model presented the effect of TWSG1 expression on the malignant behavior of tumor cells. Experimental results displayed that the expression level for TWSG1 was substantially elevated in gliomas compared to that in normal brain tissue. The expression knockdown of TWSG1 caused inhibition of glioma cell proliferation. Besides, TWSG1 overexpression enhanced proliferation in glioma cells, and the capacity of proliferation was partly abolished by the PI3K inhibitor LY294002. We found that TWSG1 affected the activity of Akt signaling pathway. In conclusion, TWSG1 is overexpressed in glioma tissue and promotes tumor proliferation through Akt signaling pathway, may serve as a potential target for glioma diagnosis and therapy.
TRPA1 involved in miR-141-5p-alleviated neuropathic pain induced by oxaliplatin
Authors: Zhang Haowen , Chen Hongping
Published: February 2021

Oxaliplatin (OXA) is widely used to treat advanced colorectal cancer, but it can induce severe peripheral neuropathy. Accumulating evidence has shown that microRNAs (miRNAs) are closely linked to neuropathic pain induced by sciatic nerve lesion and spinal cord injury. However, the study on the role of miRNAs in OXA-induced neuropathic pain is rare and needs to be further investigated. The study is aiming to investigate the effects of miR-141-5p on OXA-induced neuropathic pain and its underlying mechanisms. The neuropathic pain rat model was built through intraperitoneal injection of OXA. Mechanical withdrawal threshold and tail withdrawal latency were measured. The expressions of miR-141-5p and TRPA1 in dorsal root ganglion were detected by qRT-PCR, western blot, and immunohistochemistry. The results indicated that OXA down-regulated the expression of miR-141-5p. By contrast, OXA significantly up-regulated the expression of TRPA1 mRNA and protein. Besides, intrathecal injection of miR-141-5p mimic attenuated OXA-induced neuropathic pain and reduced the expression of TRPA1, a predicted target of miR-141-5p. Collectively, the results suggest that TRPA1 may mediate miR-141-5p-alleviated neuropathic pain induced by OXA. Our findings provide a potential therapeutic target for OXA-induced neuropathic pain.
Ageing with schizophrenia: an update
Authors: Solomon Haley V. , Sinopoli Martina , DeLisi Lynn E.
Published: February 2021

Purpose of review

The aim of this review was to summarize the recent literature on the clinical symptoms, functioning, outcomes and treatments for older adults with chronic schizophrenia.

Recent findings

The number and proportion of older adults with schizophrenia is rapidly increasing. Schizophrenia is a heterogeneous disorder and older adults with schizophrenia display significant variability in symptom severity, quality of life and overall outcomes. Many achieve stable disease remission, some display persistent nonremission and others experience fluctuating symptoms. Depression is commonly reported, and although rates of suicide are higher when compared with age-matched peers, the excess mortality seen in this population is mainly attributed to natural causes of death. Cognitive decline and reduced illness awareness have important implications for functional status and quality of life. Antipsychotics remain essential in the treatment regimen, although elderly patients with chronic disease may be good candidates for gradual dose reduction. Interdisciplinary treatment approaches as well as nonpharmacologic psychosocial interventions play a critical adjunctive role in the treatment of older adults with schizophrenia.

Research focusing on schizophrenia in late life is sparse. Too often, older patients are eliminated from research studies or averaged in with all age groups. Thus, there continues to be gaps in our understanding of modifiable predictors of remission and recovery, and the most efficacious and safest treatment approaches for this age group.
Neuron-derived extracellular vesicles extracted from plasma show altered size and miRNA cargo as a function of antidepressant drug response
Authors: Saeedi Saumeh , Nagy Corina , Théroux Jean-Francois , Wakid Marina , Fiori Laura M. , Ibrahim Pascal , Yang Jennie , Rotzinger Susan , Foster Jane A. , Mechawar Naguib , Kennedy Sidney H. , Turecki Gustavo
Published: February 2021

Previous work has demonstrated that microRNAs (miRNAs) change as a function of antidepressant treatment (ADT) response. However, it is unclear how representative these peripherally detected miRNA changes are to those occurring in the brain. This study aimed to use peripherally extracted neuron-derived extracellular vesicles (NDEVs) to circumvent these limitations and investigate neuronal miRNA changes associated with antidepressant response. Samples were collected at two time points (baseline and after 8 weeks of follow-up) from depressed patients who responded (N=20) and did not respond (N=20) to escitalopram treatment, as well as controls (N=20). Total extracellular vesicles (EVs) were extracted from plasma, and then further enriched for NDEVs by immunoprecipitation with L1CAM. EV size was measured using tunable resistive pulse sensing, and NDEV miRNA cargo was extracted and sequenced. Subsequently, studies in cell lines and postmortem tissue were conducted. Characterization of NDEVs revealed they were smaller than other EVs isolated from plasma (p<0.0001), had brain-specific neuronal markers, and contained miRNAs enriched for brain functions (p<0.0001) Furthermore, NDEVs from depressed patients were smaller than controls (p<0.05), and NDEV size increased with ADT response (p<0.01). Finally, changes in NDEV cargo, specifically changes in miR-21-5p, miR-30d-5p and miR-486-5p together (p<0.01), were associated with ADT response. Targets of these three miRNAs were altered in brain tissue from depressed individuals (p<0.05). Together, this study indicates that changes in peripherally isolated NDEVs can act as both a clinically accessible and informative biomarker of ADT response specifically through size and cargo.
Pulsed Focal ultrasound as a non-invasive method to deliver exosomes in the brain/stroke
Authors: Alptekin Ahmet , Khan Mohammad B , Ara Roxan , Rashid Mohammad H , Kong Fengchong , Parvin Mahrima , Frank Joseph A , Chopra Rajiv , Dhandapani Krishnan , Arbab Ali S.
Published: February 2021

Exosomes, a component of extracellular vesicles are shown to carry important small RNAs, mRNAs, protein, and bioactive lipid from parent cells and are found in most biological fluids. Investigators have demonstrated the importance of mesenchymal stem cells (MSCs) derived exosomes in repairing stroke lesions. However, exosomes from endothelial progenitor cells (EPCs) have not been tested in any stroke model nor has there been an evaluation of whether these exosomes target/home to areas of pathology. Targeted delivery of IV administered exosomes has been a great challenge and a targeted delivery system is lacking todeliver naïve (unmodified) exosomesfrom EPCs to the site of interest. Pulsed focused ultrasound (pFUS) is being used for therapeutic and experimental purposes. There has not been any report showing the use of pulsed low-intensity pFUS to deliver exosomes to the site of interest in models of stroke. In this proof of principle study, we have shown different parameters of pFUS to deliver exosomes in the intact and stroke brain with or without IV administration of nanobubbles. The study results showed that administration of nanobubbles is detrimental to the brain structures (micro bleeding and white matter destruction) at peak negative pressure (PNP) of >0.25 MPa, despite enhanced delivery of IV administered exosomes. However, without nanobubbles, pFUS PNP = 1 to 2 MPa enhances the delivery of exosomes in the stroke area without altering the brain structures.
Insertions and deletions as phylogenetic signal in an alignment-free context
Authors: Birth Niklas , Dencker Thomas , Morgenstern Burkhard
Published: February 2021

Most methods for phylogenetic tree reconstruction are based on sequence alignments; they infer phylogenies from substitutions that may have occurred at the aligned sequence positions. Gaps in alignments are usually not employed as phylogenetic signal. In this paper, we explore an alignment-free approach that uses insertions and deletions (indels) as an additional source of information for phylogeny inference. For a set of four or more input sequences, we generate so-calledquartet blocksof four putative homologous segments each. Forpairsof such quartet blocks involving the same four sequences, we compare the distances between the two blocks in these sequences, to obtain hints about indels that may have happened between the blocks since the respective four sequences have evolved from their last common ancestor. A prototype implementation is presented to infer phylogenetic trees from these data, using aquartet-treeapproach or, alternatively, under themaximum-parsimonyparadigm. This approach should not be regarded as an alternative to established methods, but rather as a complementary source of phylogenetic information. Interestingly, however, our software is able to produce phylogenetic trees from putative indels alone that are comparable to trees obtained with existing alignment-free methods.
The systemic inflammatory response and clinicopathological characteristics in patients admitted to hospital with COVID-19 infection: Comparison of 2 consecutive cohorts
Authors: Maguire Donogh , Richards Conor , Woods Marylynne , Dolan Ross , Veitch Jesse Wilson , Sim Wei MJ , Kemmett Olivia EH , Milton David C , Randall Sophie LW , Bui Ly D , Goldmann Nicola , Brown Amy , Gillen Eilidh , Cameron Allan , Laird Barry , Talwar Dinesh , Godber Ian M , Wadsworth John , Catchpole Anthony , Davidson Alan , McMillan Donald C
Published: February 2021

Background

In order to manage the COVID-19 systemic inflammatory response, it is important to identify clinicopathological characteristics across multiple cohorts.

Methods

Electronic patient records for 2 consecutive cohorts of patients admitted to two urban teaching hospitals with COVID-19 during two 7-week periods of the COVID-19 pandemic in Glasgow, U.K. (cohort 1: 17th March 2020 – 1st May 2020) and (cohort 2: 18th May 2020 – 6th July 2020) were examined for routine clinical, laboratory and clinical outcome data.

Results

Compared with cohort 1, cohort 2 were older (p<0.001), more likely to be female (p<0.05) and have less independent living circumstances (p<0.001). More patients in cohort 2 were PCR positive, CXR negative (both p<0.001) and had low serum albumin concentrations (p<0.001). 30-day mortality was similar between both cohorts (23% and 22%). Over the 2 cohorts, age ≥70 (p<0.001), male gender (p<0.05), hypertension (p<0.01), heart failure (p<0.05), cognitive impairment (p<0.001), frailty (p<0.001), COPD (p<0.05), delirium (p<0.001), elevated perioperative Glasgow Prognostic Score (p≤0.001), elevated neutrophil-lymphocyte ratio (p<0.001), low haematocrit (p<0.01), elevated urea (p<0.001), creatinine (p<0.001), glucose (p<0.05) and lactate (p<0.01); and the 4C score were associated with 30-day mortality. When compared with the 4C score, greater frailty (OR 10.2, 95% C.I. 3.4 – 30.6, p<0.01) and low albumin (OR 5.6, 95% C.I. 2.0 – 15.6, p<0.01) were strongly independently associated with 30-day mortality.

Conclusion

In addition to the 4C mortality score, frailty score and a low albumin were strongly independently associated with 30-day mortality in two consecutive cohorts of patients admitted to hospital with COVID-19.

Article summary

In two consecutive cohorts of patients with COVID-19 infection admitted to two urban teaching hospitals in Glasgow, UK, there were variations in a number of clinicopathological characteristics despite similar mortality (23 and 22%).

In these two cohorts, in a multivariate analysis that included the 4C mortality score, clinical frailty score >3, low serum albumin concentration (<35 g/L), high neutrophil-lymphocyte ratio (≥5), and abnormal serum sodium concentration (<133/>145 mmol/L) remained independently associated with 30-day mortality.
Comprehensive Study of Germline Mutations and Double-Hit Events in Esophageal Squamous Cell Cancer
Authors: Zeng Bing , Huang Peide , Du Peina , Sun Xiaohui , Huang Xuanlin , Fang Xiaodong , Li Lin
Published: February 2021

Esophageal squamous cell cancer (ESCC) is the eighth most common cancer around the world. Several reports have focused on somatic mutations and common germline mutations in ESCC. However, the contributions of pathogenic germline alterations in cancer susceptibility genes (CSGs), highly frequently mutated CSGs, and pathogenically mutated CSG-related pathways in ESCC remain unclear. We obtained data on 571 ESCC cases from public databases and East Asian from the 1000 Genomes Project database and the China Metabolic Analytics Project database to characterize pathogenic mutations. We detected 157 mutations in 75 CSGs, accounting for 25.0% (143/571) of ESCC cases. Six genes had more than five mutations: TP53 (n = 15 mutations), GJB2 (n = 8), BRCA2 (n = 6), RECQL4 (n = 6), MUTYH (n = 6), and PMS2 (n = 5). Our results identified significant differences in pathogenic germline mutations of TP53, BRCA2, and RECQL4 between the ESCC and control cohorts. Moreover, we identified 84 double-hit events (16 germline/somatic double-hit events and 68 somatic/somatic double-hit events) occurring in 18 tumor suppressor genes from 83 patients. Patients who had ESCC with germline/somatic double-hit events were diagnosed at younger ages than patients with the somatic/somatic double-hit events, although the correlation was not significant. Fanconi anemia was the most enriched pathway of pathogenically mutated CSGs, and it appeared to be a primary pathway for ESCC predisposition. The results of this study identified the underlying roles that pathogenic germline mutations in CSGs play in ESCC pathogenesis; increased our awareness about the genetic basis of ESCC; and provided suggestions for using highly mutated CSGs and double-hit features in the early discovery, prevention, and genetic counseling of ESCC.
Assessing the performance of a serological point-of-care test in measuring detectable antibodies against SARS-CoV-2
Authors: Coyle Peter V. , Kahlout Reham Awni El , Dargham Soha R. , Chemaitelly Hiam , Kacem Mohamed Ali Ben Hadj , Al-Mawlawi Naema Hassan Abdulla , Gilliani Imtiaz , Younes Nourah , Kanaani Zaina Al , Khal Abdullatif Al , Kuwari Einas Al , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Rahim Hanan F. Abdul , Nasrallah Gheyath K. , Yassine Hadi M. , Kuwari Mohamed G. Al , Al Romaihi Hamad Eid , Tang Patrick , Bertollini Roberto , Al-Thani Mohamed H. , Abu-Raddad Laith J.
Published: February 2021

Objective

To investigate the performance of a rapid point-of-care antibody test, the BioMedomics COVID-19 IgM/IgG Rapid Test, in comparison with a high-quality, validated, laboratory-based platform, the Roche Elecsys Anti-SARS-CoV-2 assay.

Methods

Serological testing was conducted on 708 individuals. Concordance metrics were estimated. Logistic regression was used to assess associations with seropositivity.

Results

SARS-CoV-2 seroprevalence was 63.4% (449/708; 95% CI 59.8%-66.9%) using the BioMedomics assay and 71.9% (509/708; 95% CI 68.5%-75.1%) using the Elecsys assay. There were 62 discordant results between the two assays. One specimen was seropositive in the BioMedomics assay, but seronegative in the Elecsys assay, while 61 specimens were seropositive in the Elecsys assay, but seronegative in the BioMedomics assay. Positive, negative, and overall percent agreements between the two assays were 88.0% (95% CI 84.9%-90.6%), 99.5% (95% CI 97.2%-99.9%), and 91.2% (95% CI 88.9%-93.1%), respectively, with a Cohen’s kappa of 0.80 (95% CI 0.77-0.83), indicating excellent agreement. Excluding specimens with lower antibody titers, the agreement improved with positive, negative, and overall percent concordance of 91.2% (95% CI 88.2%-93.6%), 99.5% (95% CI 97.2%-99.9%), and 93.9% (95% CI 91.7%-95.5%), respectively, and a Cohen’s kappa of 0.87 (95% CI 0.84-0.89). Logistic regression confirmed better agreement with higher antibody titers.

Conclusion

The BioMedomics COVID-19 IgM/IgG Rapid Test demonstrated excellent performance in measuring detectable antibodies against SARS-CoV-2, supporting the utility of such rapid point-of-care serological testing to guide the public health responses and possible vaccine prioritization.
Epigenome-wide scan identifies differentially methylated regions for lung cancer using pre-diagnostic peripheral blood
Authors: Zhao Naisi , Ruan Mengyuan , Koestler Devin C. , Lu Jiayun , Marsit Carmen J. , Kelsey Karl T. , Platz Elizabeth A. , Michaud Dominique S.
Published: February 2021

Background

To reduce lung cancer burden in the US, a better understanding of biological mechanisms in early disease development could provide new opportunities for risk stratification.

Methods

In a nested case-control study, we measured blood leukocyte DNA methylation levels in pre-diagnostic samples collected from 430 men and women in the 1989 CLUE II cohort. Median time from blood drawn to diagnosis was 14 years for all participants. We compared DNA methylation levels by case/control status to identify novel genomic regions, both single CpG sites and differentially methylated regions (DMRs), while controlling for known DNA methylation changes associated with smoking using a previously described pack-years based smoking methylation score. Stratification analyses were conducted by time from blood draw to diagnosis, histology, and smoking status.

Results

We identified sixteen single CpG sites and forty DMRs significantly associated with lung cancer risk (q < 0.05). The identified genomic regions were associated with genes includingH19, HOXA4, RUNX3, BRICD5, PLXNB2, andRP13. For the single CpG sites, the strongest association was noted for cg09736286 in theDIABLOgene (OR [for 1 SD] = 2.99, 95% CI: 1.95-4.59, P-value = 4.81 × 10−7). For the DMRs, we found that CpG sites in theHOXA4region were hypermethylated in cases compared to controls.

Conclusion

The single CpG sites and DMRs that we identified represented significant measurable differences in lung cancer risk, providing new insights into the biological processes of early lung cancer development and potential biomarkers for lung cancer risk stratification.
A Quantitative Data-Driven Analysis (QDA) Framework for Resting-state fMRI: a Study of the Impact of Adult Age
Authors: Li Xia , Fischer Håkan , Manzouri Amirhossein , Månsson Kristoffer N.T. , Li Tie-Qiang
Published: February 2021

Purpose

The objective of this study is to introduce a new quantitative data-driven analysis (QDA) framework for the analysis of resting-state fMRI (R-fMRI) and use it to investigate the effect of adult age on resting-state functional connectivity (RFC).

Methods

Whole-brain R-fMRI measurements were conducted on a 3T clinical MRI scanner in 227 healthy adult volunteers (N=227, aged 18-74 years old, male/female=99/128). With the proposed QDA framework we derived two types of voxel-wise RFC metrics: the connectivity strength index (CSI) and connectivity density index (CDI) utilizing the convolutions of the cross-correlation (CC) histogram with different kernels. Furthermore, we assessed the negative and positive portions of these metrics separately.

Results

With the QDA framework we found age-related declines of RFC metrics in the superior and middle frontal gyrus (MFG), posterior cingulate cortex (PCC), right insula and inferior parietal lobule (IPL) of the default mode network (DMN), which resembles previously reported results using other types of RFC data processing methods. Importantly, our new findings complement previously undocumented results in the following aspects: 1) the PCC and right insula are anti-correlated and tend to manifest simultaneously declines of both the negative and positive connectivity strength with subjects’ age; 2) separate assessment of the negative and positive RFC metrics provides enhanced sensitivity to the aging effect; 3) the sensorimotor network depicts enhanced negative connectivity strength with the adult age.

Conclusion

The proposed QDA framework can produce threshold-free, voxel-wise analysis of R-fMRI data the RFC metrics. The detected adult age effect is largely consistent with previously reported studies using different R-fMRI analysis approaches. Moreover, the separate assessment of the negative and positive contributions to the RFC metrics can enhance the RFC sensitivity and clarify some of the mixed results in the literature regarding to the DMN and sensorimotor network involvement in adult aging.

Highlights

A quantitative data-driven analysis (QDA) framework was proposed to analysis resting-state fMRI data.

Threshold-free resting-state functional connectivity (RFC) metrics were derived to assess brain changes with adult age.

Separate assessment of the positive and negative correlations improve sensitivity of the RFC metrics.

The posterior cingulate and right insula cortices are anti-correlated and tend to manifest declines in both the negative and positive connectivity strength with adult age.

Negative connectivity strength enhances with adult age in sensorimotor network.
Interleukin-33 regulates metabolic reprogramming of the retinal pigment epithelium in response to immune stressors
Authors: Scott Louis M , Vincent Emma E , Hudson Natalie , Neal Chris , Jones Nicholas , Lavelle Ed , Campbell Matthew , Halestrap Andrew P , Dick Andrew D , Theodoropoulou Sofia
Published: February 2021

It remains unresolved how retinal pigment epithelial (RPE) cell metabolism is regulated following immune activation to maintain retinal homeostasis and retinal function. We exposed RPE to several stress signals, particularly toll-like receptor stimulation, and uncovered an ability of RPE to adapt their metabolic preference on aerobic glycolysis or oxidative glucose metabolism in response to different immune stimuli. We have identified interleukin-33 (IL-33) as a key metabolic checkpoint that antagonises the Warburg effect to ensure the functional stability of the RPE. The identification of IL-33 as a key regulator of mitochondrial metabolism suggests roles for the cytokine that go beyond its extracellular “alarmin” activities. IL-33 exerts control over mitochondrial respiration in RPE by facilitating oxidative pyruvate catabolism. We have also revealed that in the absence of IL-33, mitochondrial function declines and resultant bioenergetic switching is aligned with altered mitochondrial morphology. Our data not only sheds new light in the molecular pathway of activation of mitochondrial respiration in RPE in response to immune stressors, but also uncovers a novel role of nuclear intrinsic IL-33 as a metabolic checkpoint regulator.
Fentanyl binds to the μ-opioid receptor via the lipid membrane and transmembrane helices
Authors: Sutcliffe Katy J , Corey Robin A , Charlton Steven J , Sessions Richard B , Henderson Graeme , Kelly Eamonn
Published: February 2021

Overdose deaths from synthetic opioids, such as fentanyl, have reached epidemic proportions in the USA and are increasing worldwide. Fentanyl is a potent opioid agonist, that is less well reversed by naloxone than morphine. Due to fentanyl’s high lipophilicity and elongated structure we hypothesised that its unusual pharmacology may be explained by a novel binding mode to the μ-opioid receptor (MOPr).

By employing coarse-grained molecular dynamics simulations and free energy calculations, we determined the routes by which fentanyl and morphine access the orthosteric pocket of MOPr.

Morphine accesses MOPr via the aqueous pathway; first binding to an extracellular vestibule, then diffusing into the orthosteric pocket. In contrast, fentanyl takes a novel route; first partitioning into the membrane, before accessing the orthosteric site by diffusing through a ligand-induced gap between the transmembrane helices.

This novel lipophilic route may explain the high potency and lower susceptibility of fentanyl to reversal by naloxone.
Differentiation of human adult-derived stem cells towards a neural lineage involves a de-differentiation event prior to re-differentiation to neural phenotypes
Authors: Bueno Carlos , Martínez-Morga Marta , García-Bernal David , Moraleda José M , Martínez Salvador
Published: February 2021

Although it has been reported that mesenchymal stem cells isolated from adult tissues can be induced to overcome their mesenchymal fate and transdifferentiate into neural cells, the findings and their interpretation have been challenged. The main argument against this process is that the cells rapidly adopt neuron-like morphologies through retraction of the cytoplasm rather than active neurite extension.

In this study, we examined the sequence of biological events during neural differentiation of human periodontal ligament-derived stem cells (hPDLSCs), human bone marrow-derived stem cells (hBMSCs) and human dental pulp-derived stem cells (hDPSCs) by time-lapse microscopy.

We have demonstrated that hPDLSCs, hBMSCs and hDPSCs can directly differentiate into neuron-like cells without passing through a mitotic stage and that they shrink dramatically and change their morphology to that of neuron-like cells through active neurite extension. Furthermore, we observed micronuclei movement and transient cell nuclei lobulation concurrent to in vitro neurogenesis from hBMSCs and hDPSCs.

Our results demonstrate that the differentiation of hPDLSCs, hBMSCs and hDPSCs towards a neural lineage occurs through a de-differentiation step followed by re-differentiation to neural phenotypes, and therefore we definitively confirm that the rapid acquisition of the neural phenotype is via a differentiation trait.
The molecular clockwork of the suprachiasmatic nucleus is sufficient to co-ordinate phasing and stabilisation of sleep-wake cycles and enhance memory deficits in a clockless mouse
Authors: Maywood Elizabeth S. , Chesham Johanna E. , Winsky-Sommerer Raphaelle , Hastings Michael H.
Published: February 2021

The timing and quality of sleep-wake cycles are regulated by interacting circadian and homeostatic mechanisms. Although the suprachiasmatic nucleus (SCN) is the principal circadian clock, local clocks are active across the brain and the respective sleep-regulatory roles of SCN and extra-SCN clocks are unclear. To determine the specific contribution(s) of the SCN, we used virally mediated genetic complementation, expressing Cryptochrome1 (Cry1) to restore circadian molecular competence to the SCN of globally clocklessCry1/Cry2-null mice. Under free-running conditions, the rest/activity behaviour ofCry1/Cry2-null controls which received EGFP (SCNCon) was arrhythmic, whereas Cry1-complemented mice (SCNCry1) had circadian behaviour comparable to that of Cry1,2-competent wild-types (WT). In SCNConmice, sleep-wakefulness, assessed by electroencephalography/electromyography, also lacked circadian organisation. In SCNCry1mice, however, it was comparable to WT, with consolidated vigilance states (wake, REM and NREM sleep) and rhythms in NREMS delta power and expression of REMS within total sleep. Wakefulness in SCNConmice was more fragmented than in WT, with more wake-NREMS-wake transitions. This disruption was corrected in SCNCry1mice. Following sleep deprivation, all mice showed an initial homeostatic increase in NREMS delta power. The SCNConmice, however, had reduced, non-consolidated NREMS during the inactive phase of the recovery period. In contrast, the dynamics of homeostatic responses in the SCNCry1mice were equivalent to WT. Finally, SCNConmice exhibited poor sleep-dependent memory but this was corrected in SCNCry1mice. Therefore, the SCN clock is sufficient for circadian control of sleep-wake, facilitating initiation and maintenance of wake, promoting sleep consolidation, homeostatic dynamics, and sleep-dependent memory.

Significance statement

The circadian timing system regulates sleep-wake cycles. The hypothalamic suprachiasmatic nucleus (SCN) is the principal circadian clock, but local clocks are also active across the brain and the respective roles of SCN and local clocks in regulating sleep are unclear. To determine, explicitly, the contribution of the SCN, we used virally mediated genetic complementation to restore SCN molecular circadian functions in otherwise genetically clockless mice. This initiated circadian activity-rest cycles, accompanied by circadian sleep-wake cycles, circadian patterning to the intensity of NREM sleep and circadian control of REM sleep as a proportion of total sleep. Consolidation of sleep-wake established normal dynamics of sleep homeostasis and enhanced sleep-dependent memory. Thus, the SCN is the principal and sufficient circadian regulator of sleep-wake.
Interaction between decision-making and interoceptive representations of bodily arousal in frontal cortex
Authors: Fujimoto Atsushi , Murray Elisabeth A. , Rudebeck Peter H.
Published: February 2021

Decision-making and representations of arousal are intimately linked. Behavioral investigations have classically shown that either too little or too much bodily arousal is detrimental to decision-making, indicating that there is an inverted ‘U’ relationship between bodily arousal and performance. How these processes interact at the level of single neurons as well as the neural circuits involved are unclear. Here we recorded neural activity from orbitofrontal cortex (OFC) and dorsal anterior cingulate cortex (dACC) of macaque monkeys while they made reward-guided decisions. Heart rate (HR) was also recorded and used as a proxy for bodily arousal. Recordings were made both before and after subjects received excitotoxic lesions of the bilateral amygdala. In intact monkeys, higher HR facilitated reaction times (RTs). Concurrently, a set of neurons in OFC and dACC selectively encoded trial-by-trial variations in HR independent of reward value. After amygdala lesions, HR increased and the relationship between HR and RTs was reversed. Concurrent with this change, there was an increase in the proportion of dACC neurons encoding HR. Applying a novel population-coding analysis, we show that after bilateral amygdala lesions the balance of encoding in dACC is skewed away from signaling either reward value or choice direction towards HR coding around the time that choices are made. Taken together, the present results provide insight into how bodily arousal and decision-making are signaled in frontal cortex.

Significance statement

How bodily arousal states influence decision-making has been a central question in psychology, but the neural mechanisms are unclear. We recorded heart rate, a measure of bodily arousal, while simultaneously monitoring neural activity in orbitofrontal cortex (OFC) and dorsal anterior cingulate cortex (dACC) of macaques making reward-guided decisions. In intact macaques higher HR was associated with shorter reaction times. Concurrently, the activity of a set of neurons in OFC and dACC selectively encoded HR. Following amygdala lesions, HR generally increased and now the relationship between HR and reaction times was reversed. At the neural level, the balance of encoding in dACC shifted towards signaling HR, suggesting a specific mechanism through which bodily arousal influences decision-making.
Multi-task deep learning for concurrent prediction of protein structural properties
Authors: Zhang Buzhong , Li Jinyan , Quan Lijun , Lyu Qiang
Published: February 2021

Protein structural properties are diverse and have the characteristics of spatial hierarchy, such as secondary structures, solvent accessibility and backbone angles. Protein tertiary structures are formed in close association with these features. Separate prediction of these structural properties has been improved with the increasing number of samples of protein structures and with advances in machine learning techniques, but concurrent prediction of these tightly related structural features is more useful to understand the overall protein structure and functions. We introduce a multi-task deep learning method for concurrent prediction of protein secondary structures, solvent accessibility and backbone angles (ϕ, ψ). The new method has main two deep network modules: the first one is designed as a DenseNet architecture a using bidirectional simplified GRU (GRU2) network, and the second module is designed as an updated Google Inception network. The new method is named CRRNN2.

CRRNN2 is trained on 14,100 protein sequences and its prediction performance is evaluated by testing on public benchmark datasets: CB513, CASP10, CASP11, CASP12 and TS1199. Compared with state-of-the-art methods, CRRNN2 achieves similar, or better performance on the prediction of 3- and 8-state secondary structures, solvent accessibility and backbone angles (ϕ, ψ). Online CRRN-N2 applications, datasets and standalone software are available athttp://qianglab.scst.suda.edu.cn/crrnn2/.
High fiber, whole foods dietary intervention alters the human gut microbiome but not fecal short-chain fatty acids
Authors: Oliver Andrew , Chase Alexander B. , Weihe Claudia , Orchanian Stephanie B. , Riedel Stefan F. , Hendrickson Clark , Lay Mi , Sewall Julia Massimelli , Martiny Jennifer B. H. , Whiteson Katrine
Published: February 2021

Dietary shifts can have a direct impact on the gut microbiome by preferentially selecting for microbes capable of utilizing the various dietary nutrients. Intake of dietary fiber has decreased precipitously in the last century, while consumption of processed foods has increased. Fiber, or microbiota-accessible carbohydrates (MACs), persist in the digestive tract and can be metabolized by specific bacteria encoding fiber degrading enzymes. Digestion of MACs results in the accumulation of short-chain fatty acids (SCFAs) and other metabolic byproducts that are critical to human health. Here, we implemented a two-week dietary fiber intervention aiming for 40-50 grams of fiber per day within the context of a course-based undergraduate research experience (CURE) (n = 20). By coupling shotgun metagenomic sequencing and targeted gas-chromatography mass spectrometry (GC/MS), we found that the dietary intervention significantly altered the composition of individual gut microbiomes, accounting for 8.3% of the longitudinal variability within subjects. Notably, microbial taxa that increased in relative abundance as a result of the diet change included known MAC degraders (i.e.,BifidobacteriumandLactobacillus). We further assessed the genetic diversity withinBifidobacterium, assayed by amplification of thegroELgene. Concomitant with microbial composition changes, we show an increase in the abundance of genes involved in inositol degradation. Despite these changes in gut microbiome composition, we did not detect a consistent shift in SCFA abundance. Collectively, our results demonstrate that on a short-term timescale of two weeks, increased fiber intake can induce compositional changes of the gut microbiome, including an increase in MAC degrading bacteria.

IMPORTANCE

A profound decrease in the consumption of dietary fiber in many parts of the world in the last century may be associated with the increasing prevalence of Type II diabetes, colon cancer, and other health problems. A typical U.S. diet includes about ∼15 grams of fiber per day, far less fiber than daily recommended allowance. Changes in dietary fiber intake affect human health not only through the uptake of nutrients directly, but also indirectly through changes in the microbial community and their associated metabolism. Here we conducted a two-week diet intervention in healthy young adults to investigate the impact of fiber consumption on the gut microbiome. Participants increased their average fiber consumption by 25 grams/day on average for two weeks. The high fiber diet intervention altered the gut microbiome of the study participants, including increases in known fiber degrading microbes such asBifidobacteriumandLactobacillus.
Brain transcriptional regulatory architecture and schizophrenia etiology converge between East Asian and European ancestral populations
Authors: Liu Sihan , Chen Yu , Wang Feiran , Jiang Yi , Duan Fangyuan , Xia Yan , Ning Zhilin , Li Miao , Qiu Wenying , Ma Chao , Yan Xiao-Xin , Bao Aimin , Dai Jiapei , Kopp Richard F. , Kuney Liz , Huang Jufang , Xu Shuhua , Tang Beisha , Liu Chunyu , Chen Chao
Published: February 2021

Understanding the genetic architecture of gene expression and splicing in human brain is critical to unlocking the mechanisms of complex neuropsychiatric disorders like schizophrenia (SCZ). Large-scale brain transcriptomic studies are based primarily on populations of European (EUR) ancestry. The uniformity of mono-racial resources may limit important insights into the disease etiology. Here, we characterized brain transcriptional regulatory architecture of East Asians (EAS; n=151), identifying 3,278 expression quantitative trait loci (eQTL) and 4,726 spliceQTL (sQTL). Comparing these to PsychENCODE/BrainGVEX confirmed our hypothesis that the transcriptional regulatory architecture in EAS and EUR brains align. Furthermore, distinctive allelic frequency and linkage disequilibrium impede QTL translation and gene-expression prediction accuracy. Integration of eQTL/sQTL with genome-wide association studies reveals common and novel SCZ risk genes. Pathway-based analyses showing shared SCZ biology point to synaptic and GTPase dysfunction as a prospective pathogenesis. This study elucidates the transcriptional landscape of the EAS brain and emphasizes an essential convergence between EAS and EUR populations.
Alternative architecture of theE. colichemosensory array
Authors: Burt Alister , Cassidy C. Keith , Stansfeld Phillip J. , Gutsche Irina
Published: February 2021

Chemotactic responses in motile bacteria are the result of sophisticated signal transduction by large, highly organized arrays of sensory proteins. Despite tremendous progress in the understanding of chemosensory array structure and function, a structural basis for the heightened sensitivity of networked chemoreceptors is not yet complete. Here we present cryo-electron tomography visualisations of native-state chemosensory arrays inE. coliminicells. Strikingly, these arrays exhibit a p2-symmetric array architecture that differs markedly from the p6-symmetric architecture previously described inE. coli. Based on this data, we propose molecular models of this alternative architecture and the canonical p6-symmetric assembly. We evaluate our observations and each model in the context of previously published data, assessing the functional implications of an alternative architecture and effects for future studies.
Protein N-glycosylation is essential for SARS-CoV-2 infection
Authors: Casas-Sanchez Aitor , Romero-Ramirez Alessandra , Hargreaves Eleanor , Ellis Cameron C. , Grajeda Brian I. , Estevao Igor , Patterson Edward I. , Hughes Grant L. , Almeida Igor C. , Zech Tobias , Acosta-Serrano Álvaro
Published: February 2021

SARS-CoV-2 extensively N-glycosylates its spike proteins, which are necessary for host cell invasion and the target of both vaccines and immunotherapies. These sugars are predicted to help mediate spike binding to the host receptor by stabilizing its ‘open’ conformation and evading host immunity. Here, we investigated both the essentiality of the host N-glycosylation pathway and SARS-CoV-2 N-glycans for infection. Inhibition of host N-glycosylation using RNAi or FDA-approved drugs reduced virus infectivity, including that of several variants. Under these conditions, cells produced less virions and some completely lost their infectivity. Furthermore, partial deglycosylation of intact virions showed that surface-exposed N-glycans are critical for cell invasion. Altogether, spike N-glycosylation is a targetable pathway with clinical potential for treatment or prevention of COVID-19.
Use of additives to regulate solute aggregation and direct conformational polymorph nucleation of pimelic acid
Authors: Shi Peng , Xu Shijie , Yang Huaiyu , Wu Songgu , Tang Weiwei , Wang Jingkang , Gong Junbo
Published: February 2021

Understanding the nucleation pathway and achieving regulation to produce the desired crystals are mutually beneficial. The authors previously proposed a nucleation pathway of conformational polymorphs in which solvation and solute self-assembly could affect the result of the conformational rearrangement and further nucleation outcomes. Based on this, herein α,ω-alkanedicarboxylic acids (DAn, wherenrepresents the number of carbon atoms in the molecule,n= 2–6, 8–11) were designed as homologous additives to interfere with the self-assembly of pimelic acid (DA7) to further induce the form II compound, which differs from form I only in conformation. Interestingly, longer-chain additives (DA6–11) have a stronger form II-inducing ability than short-chain ones (DA2–4). In addition, an apparent gradient of the degree of interference with solute self-assembly, consistent with form II-inducing ability, was detected by infrared and nuclear magnetic resonance spectroscopy. The calculated molecular electrostatic potential charges also clearly indicate that additive–solute electrostatic interactions gradually increase with increasing carbon chain length of the additives, reaching a maximum value with DA6–11. This novel use of additives demonstrates a direct link between solute aggregation and conformational polymorph nucleation.
Nitrosonium nitrate (NO+NO3
−) structure solution using in situ single-crystal X-ray diffraction in a diamond anvil cell
Authors: Laniel Dominique , Winkler Bjoern , Koemets Egor , Fedotenko Timofey , Chariton Stella , Milman Victor , Glazyrin Konstantin , Prakapenka Vitali , Dubrovinsky Leonid , Dubrovinskaia Natalia
Published: February 2021

At high pressures, autoionization – along with polymerization and metallization – is one of the responses of simple molecular systems to a rise in electron density. Nitrosonium nitrate (NO+NO3
−), known for this property, has attracted a large interest in recent decades and was reported to be synthesized at high pressure and high temperature from a variety of nitrogen–oxygen precursors, such as N2O4, N2O and N2–O2 mixtures. However, its structure has not been determined unambiguously. Here, we present the first structure solution and refinement for nitrosonium nitrate on the basis of single-crystal X-ray diffraction at 7.0 and 37.0 GPa. The structure model (P21/m space group) contains the triple-bonded NO+ cation and the NO3
−
sp
2-trigonal planar anion. Remarkably, crystal-chemical considerations and accompanying density-functional-theory calculations show that the oxygen atom of the NO+ unit is positively charged – a rare occurrence when in the presence of a less-electronegative element.