bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Acupressure on Relieving Cancer-Related Fatigue
Authors: Hsieh Shu-Hua , Wu Chia-Rung , Romadlon Debby Syahru , Hasan Faizul , Chen Pin-Yuan , Chiu Hsiao-Yean
Published: August 2021

Background

Fatigue, a common complaint reported by patients with cancer or in survivorship, has been negatively associated with quality of life, emotional health, and cognitive functions. Acupressure, a traditional Chinese medicine, has been increasingly practiced in clinical and community settings. However, little evidence supports the beneficial effects of acupressure on the reduction of general, physical, and mental fatigue in cancer survivors.

Objective

The aim of this study was to examine the effect of acupressure on fatigue in cancer survivors and the moderators of the effect of acupressure on cancer-related fatigue relief.

Methods

Databases, namely, PubMed, Embase, CINAHL, and ProQuest, were searched from their inception to July 17, 2020. No language and publication period restrictions were applied. Only randomized controlled trials that examined the effects of acupressure on cancer-related fatigue were included. A random-effects model was used for data analyses.

Results

Fourteen articles involving 776 participants with cancers were included. Acupressure considerably alleviated cancer-related general, physical, and mental fatigue (g = −0.87, −0.87, and −0.37) compared with controls. Increasing female percentage of participants significantly reduced the effects of acupressure on fatigue (B = −0.01, P < .001). The executor and operation approach as well as treatment period during chemotherapy did not moderate the effects of acupressure on fatigue relief.

Conclusion

Acupressure is effective at alleviating cancer-related fatigue.

Implications for Practice

Health professionals and patients can use acupressure to alleviate fatigue during and after chemotherapy. Nursing personnel could incorporate acupressure into clinical practice as part of a multimodal approach to alleviating fatigue in cancer survivors.
Possible Bioenergetic Biomarker for Chronic Cancer-Related Fatigue
Authors: Hsiao Chao-Pin , Daly Barbara , Chen Mei-Kuang , Veigl Marty , Dorth Jennifer , Ponsky Lee Evan , Hoppel Charles
Published: August 2021

Background

Cancer-related fatigue (CRF) is a highly prevalent, debilitating, and persistent symptom experienced by patients receiving cancer treatments. Up to 71% of men with prostate cancer receiving radiation therapy experience acute and persistent CRF. There is neither an effective therapy nor a diagnostic biomarker for CRF. This pilot study aimed to discover potential biomarkers associated with chronic CRF in men with prostate cancer receiving radiation therapy.

Methods

We used a longitudinal repeated-measures research design. Twenty men with prostate cancer undergoing radiation therapy completed all study visits. CRF was evaluated by a well-established and validated questionnaire, the Patient-Reported Outcomes Measurement Information System for Fatigue (PROMIS-F) Short Form. In addition, peripheral blood mononuclear cells were harvested to quantify ribonucleic acid (RNA) gene expression of mitochondria-related genes. Data were collected before, during, on completion, and 24 months postradiation therapy and analyzed using paired t-tests and repeated-measures analysis of variance.

Results

The mean of the PROMIS-F T score was significantly increased over time in patients with prostate cancer, remaining elevated at 24 months postradiation therapy compared to baseline. A significant downregulated BC1 ubiquinol-cytochrome c reductase synthesis-like (BCS1L) was observed over time during radiation therapy and at 24 months postradiation therapy. An increased PROMIS-F score was trended with downregulated BCS1L in patients 24 months after completing radiation therapy.

Discussion

This is the first evidence to describe altered messenger RNA for BCS1L in chronic CRF using the PROMIS-F measure with men receiving radiation therapy for prostate cancer.

Conclusion

Our results suggest that peripheral blood mononuclear cell messenger RNA for BCS1L is a potential biomarker and therapeutic target for radiation therapy-induced chronic CRF in this clinical population.
Be Prepared
Authors: Kishida Mizue , Daly Guris Rodrigo J. , Monachino AnneMarie , Hales Roberta , Benson Danielle C. , Good Grace , Hamburger Marjorie A. , Widmeier Keith , Dove Aleeshamonae , Ades Anne M. , Nadkarni Vinay M. , Nishisaki Akira
Published: August 2021

Introduction

The COVID-19 pandemic forced healthcare institutions to rapidly adapt practices for patient care, staff safety, and resource management. We evaluated contributions of the simulation center in a freestanding children's hospital during the early stages of the pandemic.

Methods

We reviewed our simulation center's activity for education-based and system-focused simulation for 2 consecutive academic years (AY19: 2018–2019 and AY20: 2019–2020). We used statistical control charts and χ2 analyses to assess the impact of the pandemic on simulation activity as well as outputs of system-focused simulation during the first wave of the pandemic (March–June 2020) using the system failure mode taxonomy and required level of resolution.

Results

A total of 1983 event counts were reported. Total counts were similar between years (994 in AY19 and 989 in AY20). System-focused simulation was more prevalent in AY20 compared with AY19 (8% vs. 2% of total simulation activity, P < 0.001), mainly driven by COVID-19–related simulation events. COVID-19–related simulation occurred across the institution, identified system failure modes in all categories except culture, and was more likely to identify macro-level issues than non–COVID-19–related simulation (64% vs. 44%, P = 0.027).

Conclusions

Our simulation center pivoted to deliver substantial system-focused simulation across the hospital during the first wave of the COVID-19 pandemic. Our experience suggests that simulation centers are essential resources in achieving safe and effective hospital-wide improvement.
Cardiometabolic and Kidney Protection in Kidney Transplant Recipients With Diabetes: Mechanisms, Clinical Applications, and Summary of Clinical Trials
Authors: Sridhar Vikas S. , Ambinathan Jaya Prakash N. , Gillard Pieter , Mathieu Chantal , Cherney David Z.I. , Lytvyn Yuliya , Singh Sunita K.
Published: August 2021

Abstract. Kidney transplantation is the therapy of choice for patients with end-stage renal disease. Preexisting diabetes is highly prevalent in kidney transplant recipients (KTR), and the development of posttransplant diabetes is common because of a number of transplant-specific risk factors such as the use of diabetogenic immunosuppressive medications and posttransplant weight gain. The presence of pretransplant and posttransplant diabetes in KTR significantly and variably affect the risk of graft failure, cardiovascular disease (CVD), and death. Among the many available therapies for diabetes, there are little data to determine the glucose-lowering agent(s) of choice in KTR. Furthermore, despite the high burden of graft loss and CVD among KTR with diabetes, evidence for strategies offering cardiovascular and kidney protection is lacking. Recent accumulating evidence convincingly shows glucose-independent cardiorenal protective effects in non-KTR with glucose-lowering agents, such as sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists. Therefore, our aim was to review cardiorenal protective strategies, including the evidence, mechanisms, and rationale for the use of these glucose-lowering agents in KTR with diabetes.
Streptomyces genisteinicus sp. nov., a novel genistein-producing actinomycete isolated from a Chinese medicinal plant and proposal of Streptomyces michiganensis Corbaz et al. 1957 as a later heterotypic synonym of Streptomyces xanthochromogenes Arishima et al. 1956
Authors: Hu Siren , Li Kaiqin , Wang Yinfeng , Guo Yihui , Zhou Meiliang , Tang Xinke , Gao Jian
Published: August 2021

A novel genistein-producing actinobacterial strain, designated strain CRPJ-33T, was isolated from the healthy leaves of a medicinal plant Xanthium sibiricum collected from Hunan Province, PR China. 16S rRNA gene sequence analysis indicated strain CRPJ-33T belonged to the genus

Streptomyces

and had 99.7, 99.0, 98.9, 98.9, 98.8 and 98.7% sequence similarities to

Streptomyces zhihengii

YIM T102T,

Streptomyces eurocidicus

NRRL B-1676T,

Streptomyces xanthochromogenes

NRRL B-5410T,

Streptomyces michiganensis

NBRC 12797T,

Streptomyces mauvecolor

LMG 20100T and

Streptomyces lavendofoliae

NBRC 12882T, respectively. Phylogenetic analysis of 16S rRNA gene sequences showed that strain CRPJ-33T was most closely related to

S. zhihengii

YIM T102T. However, digital DNA–DNA hybridization (dDDH) and average nucleotide identity (ANI) values between them were much less than the recommended threshold values. Furthermore, differential comparisons of the phenotypic characteristics were enough to distinguish strain CRPJ-33T from

S. zhihengii

YIM T102T. Meanwhile, the ANI and dDDH values or MLSA distances between strain CRPJ-33T and other type strains, which exhibited ≥98.7 % 16S rRNA gene sequence similarities to strain CRPJ-33T, were far away from the recommended threshold values. Based on these results, it is thought that strain CRPJ-33T should represent a novel species of the genus

Streptomyces

, for which the name Streptomyces genisteinicus sp. nov. is proposed. The type strain is CRPJ-33T (=MCCC 1K04965T=JCM 34526T). In addition, the phenotypic, chemotaxonomic and genotypic characteristics, as well as phylogenetic information revealed that the type strains of

S. xanthochromogenes

and

S. michiganensis

should belong to same genomic species. Consequently, it is proposed that

S. michiganensis

is a heterotypic synonym of

S. xanthochromogenes

for which an emended description is given.
Drug repurposing of metformin for Alzheimer’s disease: Combining causal inference in medical records data and systems pharmacology for biomarker identification
Authors: Charpignon Marie-Laure , Vakulenko-Lagun Bella , Zheng Bang , Magdamo Colin , Su Bowen , Evans Kyle , Rodriguez Steve , Sokolov Artem , Boswell Sarah , Sheu Yi-Han , Somai Melek , Middleton Lefkos , Hyman Bradley T. , Betensky Rebecca A. , Finkelstein Stan N. , Welsch Roy E. , Tzoulaki Ioanna , Blacker Deborah , Das Sudeshna , Albers Mark W.
Published: August 2021

Metformin, an antidiabetic drug, triggers anti-aging cellular responses. Aging is the principal risk factor for dementia, but previous observational studies of the diabetes drugs metformin vs. sulfonylureas have been mixed. We tested the hypotheses that metformin improves survival and reduces the risk of dementia, relative to the sulfonylureas, by emulating target trials in electronic health records of diabetic patients at an academic-centered healthcare system in the US and a wide-ranging group of primary care practices in the UK. To address metformin’s potentially dual influences on dementia risk—that it might reduce the hazard of death and put more people at risk of developing dementia while reducing the hazard of dementia by slowing biological aging, we used a competing risks approach and carefully grounded that within a causal inference emulated trial framework. To identify candidate biomarkers of metformin’s actions in the brain that might mediate reduced dementia risk, we conducted an in-vitro systems pharmacology evaluation of metformin and glyburide on differentiated human neural cells through differential gene expression. We named our multi-dimensional approach DRIAD-EHR (Drug Repurposing in Alzheimer’s Disease-Electronic Health Records). In intention-to-treat analyses, metformin was associated with a lower hazard of all-cause mortality than sulfonylureas in both cohorts. In competing risks analyses, there was also a lower cause-specific hazard of dementia onset among metformin initiators. In in-vitro studies, metformin reduced human neural cell expression ofSPP1andAPOE, two secreted proteins that have been implicated in Alzheimer’s disease pathogenesis and whose levels can be quantified in the CSF. Together, our findings suggest that metformin might prevent dementia in patientswithouttype II diabetes. In addition, our results inform the design of clinical trials of metformin in non-diabetics and suggest a pharmacodynamic CSF biomarker, SPP1, for metformin’s action in the brain.
Pleural fluid analysis in neutropenia
Authors: Budnick Isadore M. , Oliver Samuel F. , Barros Andrew J. , Sturek Jeffrey M.
Published: August 2021

Light’s criteria is the standard for determining the etiology of pleural effusions. Test characteristics of Light’s criteria varies in different populations, and Light’s criteria may misclassify effusions in patients with impaired immunity such as in neutropenia. This study evaluates the test characteristics of Light’s criteria and other clinically available pleural fluid tests in a cohort of patients with neutropenia. Cases were defined as a thoracentesis performed with an absolute neutrophil count of less than 1000 cells/µl documented at least 24 hours prior to the procedure. The etiology of the effusion was adjudicated by independent review of the case data and hospital course by two board certified pulmonologists. Categories for final diagnosis included exudate due to infection, exudate due to malignancy, exudate due to other, and transudate. A total of 83 thoracenteses from 80 patients were identified. Comorbidities included hematologic and solid tumor malignancies, recipients of allogeneic stem cell and solid organ transplants, heart failure, chronic kidney disease, and decompensated cirrhosis. Light’s criteria had a sensitivity of 92% and a specificity of 55% for identifying exudates, LR+ 2.07 and LR-0.14. A pleural fluid protein value of >2.9 g/dl had a sensitivity of 42% and a specificity of 96%, LR+11.12 and LR-0.61. When comparing exudative effusions, the percentage of neutrophils in the pleural fluid was significantly higher in infection, despite peripheral neutropenia. Together these results show a reduced specificity of Light’s criteria in neutropenia, and underscore the complexity of pleural effusions in this setting.
Geospatial Variability in Excess Death Rates during the COVID-19 Pandemic in Mexico: Examining Socio Demographic and Population Health Characteristics
Authors: Dahal Sushma , Luo Ruiyan , Swahn Monica H. , Chowell Gerardo
Published: August 2021

Background

Mexico has suffered one of the highest COVID-19 mortality rates in the world. In this study we examined how socio demographic and population health characteristics shape the geospatial variability in excess mortality patterns during the COVID-19 pandemic in Mexico.

Methods

Weekly all-cause mortality time series for all 32 Mexican states, from January 4, 2015 to April 10, 2021, were analyzed to estimate the excess mortality rates using Serfling regression models. The association between socio-demographic, health indicators and excess mortality rates were determined using multiple linear regression analyses. Finally, we used functional data analysis to characterize clusters of states with distinct mortality growth rate curves.

Results

The overall all-cause excess deaths rate during the COVID-19 pandemic in Mexico until April 10, 2021 was estimated at 39.66 per 10 000 population. The lowest excess death rates were observed in southeastern states including Chiapas (12.72), Oaxaca (13.42) and Quintana Roo (19.41) whereas Mexico City had the highest excess death rate (106.17), followed by Tlaxcala (51.99) and Morelos (45.90). We found a positive association of excess mortality rates with aging index (P value<.0001), marginalization index (P value<.0001), and average household size (P value=0.0003) in the final adjusted model (Model R2=76%). We identified four distinct clusters with qualitatively similar excess mortality curves.

Conclusion

Central states exhibited the highest excess mortality rates whereas the distribution of aging index, marginalization index, and average household size explained the variability in excess mortality rates across Mexico. Our findings can help tailor interventions to mitigate the mortality impact of the pandemic.

Key message

This study quantified and examined spatial patterns of excess mortality across states of Mexico, with lower rates of excess mortality in southeastern states and higher rates in central states.

Mexico City recorded 1 in 5 of all excess deaths in reported in Mexico, which accounted for 19% of total excess deaths across the country.

Findinds indicate that aging index, marginalization index, and average household size played a significant role on excess death rates across Mexican states during the COVID-19 pandemic.

Four distinct clusters characterized the excess mortality curves across Mexican states.
Open reading frame correction using antisense oligonucleotides for the treatment of cystic fibrosis caused by CFTR-W1282X
Authors: Michaels Wren E. , Pena-Rasgado Cecilia , Kotaria Rusudan , Bridges Robert J. , Hastings Michelle L.
Published: August 2021

CFTRgene mutations that result in the introduction of premature termination codons (PTCs) are common in cystic fibrosis (CF). This mutation type causes a severe form of the disease, likely because of lowCFTRmRNA expression as a result of nonsense mediated mRNA decay (NMD), as well as production of a non-functional, truncated CFTR protein. Current therapeutics for CF, which target residual protein function, are less effective in patients with these types of mutations, due in part to low CFTR protein levels. Splice-switching antisense oligonucleotides (ASOs) designed to induce skipping of exons in order to restore the mRNA open reading frame have shown therapeutic promise pre-clinically and clinically for a number of diseases. We hypothesized that ASO-mediated skipping of CFTR exon 23 would recover CFTR activity associated with terminating mutations in the exon, includingCFTRp.W1282X, the 5thmost common mutation in CF. Here, we show that CFTR lacking the amino acids encoding exon 23 is partially functional and responsive to corrector and modulator drugs currently in clinical use. ASO-induced exon 23 skipping rescued CFTR expression and chloride current in primary human bronchial epithelial cells isolated from homozygote CFTR-W1282X patients. These results support the use of ASOs in treating CF patients withCFTRclass I mutations in exon 23 that result in unstableCFTRmRNA and truncations of the CFTR protein.

Significance Statement

Frameshift and nonsense mutations pose a major problem for disease therapeutic development. Eliminating these mutations from the mRNA by inducing exon skipping is a relatively unexplored treatment approach, though it has shown promise for some diseases. Here, we show that eliminating a common stop mutation associated with cystic fibrosis by inducing skipping of the exon it is located in, results in a restoration of the open reading frame and recovers CFTR protein function in a manner expected to be therapeutic in CF patients who don’t currently have effective treatment options. These results are an important advancement for the cystic fibrosis community but also have implications for other diseases where terminating mutations are responsible for dysfunction.
Structural Differences In 3C-like protease (Mpro) From SARS-CoV and SARS-CoV-2: Molecular Insights For Drug Repurposing Against COVID-19 Revealed by Molecular Dynamics Simulations
Authors: Parmar Meet , Thumar Ritik , Patel Bhumi , Athar Mohd , Jha Prakash C. , Patel Dhaval
Published: August 2021

A recent fatal outbreak of novel coronavirus SARS-CoV-2, identified preliminary as a causative agent for series of unusual pneumonia cases in Wuhan city, China has infected more than 20 million individuals with more than 4 million mortalities. Since, the infection crossed geographical barriers, the WHO permanently named the causing disease as COVID-2019 by declaring it a pandemic situation. SARS-CoV-2 is an enveloped single-stranded RNA virus causing a wide range of pathological conditions from common cold symptoms to pneumonia and fatal severe respiratory syndrome. Genome sequencing of SARS-CoV-2 has revealed 96% identity to the bat coronavirus and 79.6% sequence identity to the previous SARS-CoV. The main protease (known as 3C-like proteinase/ Mpro) plays a vital role during the infection with the processing of replicase polyprotein thus offering an attractive target for therapeutic interventions. SARS-CoV and SARS-CoV-2 Mpro shares 97% sequence identity, with 12 variable residues but none of them present in the catalytic and substrate binding site. With the high level of sequence and structural similarity and absence of any drug/vaccine against SARS-CoV-2, drug repurposing against Mpro is an effective strategy to combat COVID-19. Here, we report a detailed comparison of SARS-CoV-2 Mpro with SARS-CoV Mpro using molecular dynamics simulations to assess the impact of 12 divergent residues on the molecular microenvironment of Mpro. A structural comparison and analysis is made on how these variable residues affects the intra-molecular interactions between key residues in the monomer and biologically active dimer form of Mpro. The present MD simulations study concluded the change in microenvironment of active-site residues at the entrance (T25, T26, M49 and Q189), near the catalytic region (F140, H163, H164, M165 and H172) and other residues in substrate binding site (V35T, N65S, K88R and N180K) due to 12 mutation incorporated in the SARS-CoV-2 Mpro. It is also evident that SARS-CoV-2 dimer is more stable and less flexible state compared to monomer which may be due to these variable residues, mainly F140, E166 and H172 which are involved in dimerization. This also warrants a need for inhibitor design considering the more stable dimer form. The mutation accumulated in SARS-CoV-2 Mpro indirectly reconfigures the key molecular networks around the active site conferring a potential change in SARS-CoV-2, thus posing a challenge in drug repurposing SARS drugs for COVID-19. The new networks and changes in microenvironment identified by our work might guide attempts needed for repurposing and identification of new Mpro inhibitors.
Organization and dynamics of the cortical complexes controlling insulin secretion in β-cells
Authors: Noordstra Ivar , van den Berg Cyntha M. , Boot Fransje W. J. , Katrukha Eugene A. , Yu Ka Lou , Tas Roderick P. , Portegies Sybren , Viergever Bastiaan J. , de Graaff Esther , Hoogenraad Casper C. , de Koning Eelco J. P. , Carlotti Françoise , Kapitein Lukas C. , Akhmanova Anna
Published: August 2021

Insulin secretion in pancreatic β-cells is regulated by cortical complexes that are enriched at the sites of adhesion to extracellular matrix facing the vasculature. Many components of these complexes, including Bassoon, RIM, ELKS and liprins, are shared with neuronal synapses. Here, we show that insulin secretion sites also contain non-neuronal proteins LL5β and KANK1, which in migrating cells organize exocytotic machinery in the vicinity of integrin-based adhesions. Depletion of LL5β or focal adhesion disassembly triggered by myosin II inhibition perturbed the clustering of secretory complexes and attenuated the first wave of insulin release. While previous analyses in vitro and in neurons suggested that secretory machinery might assemble through liquid-liquid phase separation, analysis of endogenously labeled ELKS in pancreatic islets indicated that its dynamics is inconsistent with such a scenario. Instead, fluorescence recovery after photobleaching and single molecule imaging showed that ELKS turnover is driven by binding and unbinding to low-mobility scaffolds. Both the scaffold movements and ELKS exchange were stimulated by glucose treatment. Our findings help to explain how integrin-based adhesions control spatial organization of glucose-stimulated insulin release.
The Microtubule Associated Protein Tau Regulates KIF1A Pausing Behavior and Motility
Authors: Lessard DV , Berger CL
Published: August 2021

Many neurodegenerative diseases result from dysfunction of axonal transport, a highly regulated cellular process responsible for site-specific neuronal cargo delivery. The kinesin-3 family member KIF1A is a key mediator of this process by facilitating long-distance cargo delivery in a spatiotemporally regulated manner. While misregulation of KIF1A cargo delivery is observed in many neurodegenerative diseases, the regulatory mechanisms responsible for KIF1A cargo transport are largely unexplored. Our lab has recently characterized a mechanism for a unique pausing behavior of KIF1A in between processive segments on the microtubule. This behavior, mediated through an interaction between the KIF1A K-loop and the polyglutamylated C-terminal tails of tubulin, helps us further understand how KIF1A conducts long-range cargo transport. However, how this pausing behavior is influenced by other regulatory factors on the microtubule is an unexplored concept. The microtubule associated protein Tau is one potential regulator, as altered Tau function is a pathological marker in many neurodegenerative diseases. However, while the effect of Tau on kinesin-1 and -2 has been extensively characterized, its role in regulating KIF1A transport is greatly unexplored at the behavioral level. Using single-molecule imaging, we have identified Tau-mediated regulation of KIF1A pausing behavior and motility. Specifically, our findings imply a competitive interaction between Tau and KIF1A for the C-terminal tails of tubulin. We introduce a new mechanism of Tau-mediated kinesin regulation by inhibiting the ability of KIF1A to use C-terminal tail reliant pauses to connect multiple processive segments into a longer run length. Moreover, we have correlated this regulatory mechanism to the behavioral dynamics of Tau, further elucidating the function of Tau diffusive and static behavioral state on the microtubule surface. In summary, we introduce a new mechanism of Tau-mediated motility regulation, providing insight on how disruptions in axonal transport can lead to disease state pathology.

SIGNIFICANCE

KIF1A mediated cargo transport is essential in many cellular processes such as axonal transport and neuronal development. Defects in KIF1A transport have been implicated in neurodegenerative diseases including Alzheimer’s disease and frontotemporal dementia. However, the mechanism of KIF1A’s pathological misregulation remains elusive, highlighting the importance of identifying regulators of KIF1A function. The microtubule associated protein Tau is an attractive potential regulator of KIF1A motility as Tau dysfunction is a hallmark of these neurodegenerative diseases. Here, we demonstrate a direct connection between Tau and KIF1A motility, revealing a unique form of Tau-mediated regulation of axonal transport. Our results provide a molecular foundation for understanding the role of motor protein misregulation in neurodegenerative disease progression.
Predicting epitopes Based on TCR sequence using an embedding deep neural network artificial intelligence approach
Authors: Kubick Norwin , Klimovich Pavel , Sacharczuk Mariusz , Mickael Michel-Edwar
Published: August 2021

T cells receptors are fundamental in recognizing antigens and mediating an appropriate specific immune response against them. Today TCR sequencing has contributed to forming a large repertoire for different immune-associated pathologies. However, predicting epitopes based on TCR sequences has not been satisfactory achieved. We formed a deep neural network using a combination of an embedding autoencoder and selu and relu layers to predict epitopes based on TCR TCR β-chain CDR3. We trained our model using the VDJ database (VDJdb) and validated it using the manually curated catalog of pathology-associated T cell receptor sequences (McPAS-TCR). We used various metrics to measure the accuracy of our tool. We found that our tool can achieve an accuracy of 98 %. Overall our approach presents a step toward identifying microbes crosslinking epitopes that could be playing an important role in various immune diseases.
Soma and Neurite Density MRI (SANDI) of the in-vivo mouse brain
Authors: Ianuş Andrada , Carvalho Joana , Fernandes Francisca F. , Cruz Renata , Chavarrias Cristina , Palombo Marco , Shemesh Noam
Published: August 2021

Diffusion MRI (dMRI) provides unique insights into the neural tissue milieu by probing interaction of diffusing molecules and tissue microstructure. Most dMRI techniques focus on white matter tissues (WM) due to the relatively simpler modelling of diffusion in the more organized tracts; however, interest is growing in gray matter characterisations. The Soma and Neurite Density MRI (SANDI) methodology harnesses a model incorporating water diffusion in spherical objects (assumed to be associated with cell bodies) and in impermeable “sticks” (representing neurites), which potentially enables the characterisation of cellular and neurite densities. Recognising the importance of rodents in animal models of development, aging, plasticity, and disease, we here sought to develop SANDI for preclinical imaging and provide a validation of the methodology by comparing its metrics with the Allen mouse brain atlas. SANDI was implemented on a 9.4T scanner equipped with a cryogenic coil, and experiments were carried out on N=6 mice. Pixelwise, ROI-based, and atlas comparisons were performed, and results were also compared to more standard Diffusion Kurtosis MRI (DKI) metrics. We further investigated effects of different pre-processing pipelines, specifically the comparison of magnitude and real-valued data, as well as different acceleration factors. Our findings reveal excellent reproducibility of the SANDI parameters, including the sphere and stick fraction as well as sphere size. More strikingly, we find a very good rank correlation between SANDI-driven soma fraction and Allen brain atlas contrast (which represents the cellular density in the mouse brain). Although some DKI parameters (FA, MD) correlated with some SANDI parameters in some ROIs, they did not correlate nearly as well as SANDI parameters with the Allen atlas, suggesting a much more specific nature of the SANDI parameters. We conclude that SANDI is a viable preclinical MRI technique that can greatly contribute to research on brain tissue microstructure.
Identification of the 216kbp gene cluster and structure elucidation of gargantulides B and C, new complex 52-membered macrolides fromAmycolatopsissp
Authors: Carretero-Molina Daniel , Ortiz-López Francisco Javier , Gren Tetiana , Oves-Costales Daniel , Martín Jesús , Román-Hurtado Fernando , Jørgensen Tue Sparholt , de la Cruz Mercedes , Díaz Caridad , Vicente Francisca , Blin Kai , Reyes Fernando , Weber Tilmann , Genilloud Olga
Published: August 2021

Gargantulides B and C, two new and highly complex 52-membered glycosylated macrolactones, were isolated fromAmycolatopsissp. strain CA-230715 during an antibacterial screening campaign. The structures of these giant macrolides were elucidated by 2D NMR spectroscopy and shown to be related to gargantulide A, although containing additionalβ-glucopyranose and/orα-arabinofuranose monosaccharides separately attached to their backbones. Genome sequencing allowed the identification of a strikingly large 216 kbp biosynthetic gene cluster, among the largest type I PKS clusters described so far, and the proposal of a biosynthetic pathway for gargantulides A-C. Additionally, genes putatively responsible for the biosynthesis of the amino sugarβ-3,6-deoxy-3-methylamino glucose, reported exclusively in gargantulide macrolides, were also found in the cluster and described in this work. The absolute configurations of gargantulides B and C were assigned based on a combination of NMR and bioinformatics analysis of ketoreductase and enoylreductase domains within the multimodular type I PKS. Furthermore, the absolute stereochemistry of the related macrolide gargantulide A has now been revised and completed. Gargantulides B and C display potent antibacterial activity against a set of drug-resistant Gram-positive bacteria and moderate activity against the clinically relevant Gram-negative pathogenAcinetobacter baumannii.
A novel SATB1 protein isoform with different biophysical properties
Authors: Zelenka Tomas , Papamatheakis Dionysios-Alexandros , Tzerpos Petros , Panagopoulos Giorgos , Tsolis Konstantinos C. , Papadakis Vassilis M. , Mariatos Metaxas Dimitris , Papadogkonas George , Mores Eleftherios , Kapsetaki Manouela , Papamatheakis Joseph , Stanek David , Spilianakis Charalampos
Published: August 2021

Intra-thymic T cell development is coordinated by the regulatory actions of SATB1 genome organizer. In this report, we show that SATB1 is involved in the regulation of transcription and splicing, both of which displayed deregulation inSatb1knockout murine thymocytes. More importantly, we characterized a novel SATB1 protein isoform and described its distinct biophysical behavior, implicating potential functional differences compared to the commonly studied isoform. SATB1 utilized its prion-like domains to transition through liquid-like states to aggregated structures. This behavior was dependent on protein concentration as well as phosphorylation and interaction with nuclear RNA. Notably, the long SATB1 isoform was more prone to aggregate following phase separation. Thus, the tight regulation of SATB1 isoforms expression levels alongside with protein post-translational modifications, are imperative for SATB1’s mode of action in T cell development. Our data indicate that deregulation of these processes may also be linked to disorders such as cancer.
NSUN6, an RNA methyltransferase of 5-mC controls glioblastoma response to Temozolomide (TMZ) via NELFB and RPS6KB2 interaction
Authors: Awah Chidiebere U , Winter Jan , Mazdoom Claudiane M , Ogunwobi Olorunseun O.
Published: August 2021

Nop2/Sun RNA methyltransferase (NSUN6) is an RNA 5 - methyl cytosine (5mC) transferase with little information known of its function in cancer and response to cancer therapy. Here, we show that NSUN6 methylates both large and small RNA in glioblastoma and controls glioblastoma response to temozolomide with or without influence of the MGMT promoter status, with high NSUN6 expression conferring survival benefit to glioblastoma patients and in other cancers. Mechanistically, our results show that NSUN6 controls response to TMZ therapy via 5mC mediated regulation of NELFB and RPS6BK2. Taken together, we present evidence that show that NSUN6 mediated 5mC deposition regulates transcriptional pause (by accumulation of NELFB and the general transcription factor complexes (POLR2A, TBP, TFIIA, TFIIE) on the preinitiation complex at TATA binding site to control translation machinery in glioblastoma response to alkylating agents. Our findings open a new frontier into controlling of transcriptional regulation by RNA methyltransferase and 5mC.
Rab11 endosomes coordinate centrosome number and movement following mitotic exit
Authors: Krishnan Nikhila , Swoger Maxx , Bates Michael , Freshour Judy , Fioramonti Peter J. , Patteson Alison , Hehnly Heidi
Published: August 2021

The last stage of cell division involves two daughter cells remaining interconnected by a cytokinetic bridge that is cleaved in a process called abscission. During pre-abscission, we identified that the centrosome moves in a Rab11-dependent manner towards the cytokinetic bridge in human cells grown in culture and in an in vivo vertebrate model, Danio rerio (zebrafish). Rab11-endosomes are dynamically organized in a Rab11-GTP dependent manner at the centrosome during pre-abscission and this organization is required for the centrosome protein, pericentrin, to be enriched at the centrosome. Using zebrafish embryos, we found that reduction in pericentrin expression or optogenetically disrupting Rab11-endosome function inhibited centrosome movement towards the cytokinetic bridge and abscission resulting in daughter cells prone to being binucleated and/or having supernumerary centrosomes. These studies suggest that Rab11-endosomes contribute to centrosome function during pre-abscission by regulating pericentrin organization resulting in appropriate centrosome movement towards the cytokinetic bridge and subsequent abscission.
Forgetting Enhances Episodic Control with Structured Memories
Authors: Yalnizyan-Carson Annik , Richards Blake A.
Published: August 2021

Forgetting is a normal process in healthy brains, and evidence suggests that the mammalian brain forgets more than is required based on limitations of mnemonic capacity. Episodic memories, in particular, are liable to be forgotten over time. Researchers have hypothesized that it may be beneficial for decision making to forget episodic memories over time. Reinforcement learning offers a normative framework in which to test such hypotheses. Here, we show that a reinforcement learning agent that uses an episodic memory cache to find rewards in maze environments can forget a large percentage of older memories without any performance impairments, if they utilize mnemonic representations that contain structural information about space. Moreover, we show that some forgetting can actually provide a benefit in performance compared to agents with unbounded memories. Our analyses of the agents show that forgetting reduces the influence of outdated information and states which are not frequently visited on the policies produced by the episodic control system. These results support the hypothesis that some degree of forgetting can be beneficial for decision making, which can help to explain why the brain forgets more than is required by capacity limitations.
Sulfonylureas target the neurovascular response to decrease Alzheimer’s pathology
Authors: Macauley Shannon L. , Stanley Molly S. , Caesar Emily E. , Moritz William R. , Bice Annie R. , Cruz-Diaz Nildris , Carroll Caitlin M. , Day Stephen M. , Grizzanti John , Mahan Thomas E. , Snipes James A. , Orr Timothy E. , Culver Joseph P. , Remedi Maria S. , Nichols Colin G. , Karch Celeste M. , Cox Laura A. , Diz Debra I. , Bauer Adam Q. , Holtzman David M.
Published: August 2021

Hyperexcitability is a defining feature of Alzheimer’s disease (AD), where aberrant neuronal activity is both a cause and consequence of AD. Therefore, identifying novel targets that modulate cellular excitability is an important strategy for treating AD. ATP-sensitive potassium (KATP) channels are metabolic sensors that modulate cellular excitability. Sulfonylureas are KATPchannel antagonists traditionally used to combat hyperglycemia in diabetic patients by inhibiting pancreatic KATPchannels, thereby stimulating insulin release. However, KATPchannels are not limited to the pancreas and systemic modulation of KATPchannels has pleotropic physiological effects, including profound effects on vascular function. Here, we demonstrate that human AD patients have higher cortical expression of vascular KATPchannels, important modulators of vasoreactivity. We demonstrate that peripheral treatment with the sulfonylurea and KATPchannel inhibitor, glyburide, reduced the aggregation and activity-dependent production of amyloid-beta (Aβ), a hallmark of AD, in mice. Since glyburide does not readily cross the blood brain barrier, our data suggests that glyburide targets vascular KATPchannel activity to reduce arterial stiffness, improve vasoreactivity, and normalize pericyte-endothelial cell morphology, offering a novel therapeutic target for AD.

Graphical abstract

Targeting vascular KATPchannel activity for the treatment of Alzheimer’s disease pathology.
A temporally controlled sequence of X-chromosome inactivation and reactivation defines female mouse in vitro germ cells with meiotic potential
Authors: Severino Jacqueline , Bauer Moritz , Mattimoe Tom , Arecco Niccolò , Cozzuto Luca , Lorden Patricia , Hamada Norio , Nosaka Yoshiaki , Nagaoka So , Heyn Holger , Hayashi Katsuhiko , Saitou Mitinori , Payer Bernhard
Published: August 2021

The early mammalian germ cell lineage is characterized by extensive epigenetic reprogramming, which is required for the maturation into functional eggs and sperm. In particular, the epigenome needs to be reset before parental marks can be established and then transmitted to the next generation. In the female germ line, reactivation of the inactive X-chromosome is one of the most prominent epigenetic reprogramming events, and despite its scale involving an entire chromosome affecting hundreds of genes, very little is known about its kinetics and biological function.

Here we investigate X-chromosome inactivation and reactivation dynamics by employing a tailor-made in vitro system to visualize the X-status during differentiation of primordial germ cell-like cells (PGCLCs) from female mouse embryonic stem cells (ESCs). We find that the degree of X-inactivation in PGCLCs is moderate when compared to somatic cells and characterized by a large number of genes escaping full inactivation. Nevertheless, PGCLCs that fail to undergo X-inactivation show an abnormal gene expression signature and deficiencies in meiotic entry. Subsequent to X-inactivation we observe gradual step-wise X-reactivation, which is mostly completed by the end of meiotic prophase I. Cells deviating from these progressive kinetics and undergoing X-reactivation too rapidly fail to enter a meiotic trajectory. Our data reveals that a fine-tuned X-inactivation and -reactivation cycle is a critical feature of female germ cell developmental competence towards meiosis and oogenesis
Nuclear SUN1 Stabilizes Endothelial Cell Junctions via Microtubules to Regulate Blood Vessel Formation
Authors: Buglak Danielle B , Kulikauskas Molly R , Liu Ziqing , Gold Ariel L , Marvin Allison P , Burciu Andrew , Tanke Natalie T , Ricketts Shea N , Kinghorn Karina , Oatley Morgan , Johnson Bryan N , Bougaran Pauline , Shiau Celia E , Rogers Stephen L , Bautch Victoria L
Published: August 2021

Endothelial cells line all blood vessels, where they coordinate blood vessel formation and the blood-tissue barrier via regulation of cell-cell junctions. The nucleus also regulates endothelial cell behaviors, but it is unclear how the nucleus contributes to endothelial cell activities at the cell periphery. Here we show that the nuclear-localized LINC complex protein SUN1 regulates vascular sprouting and barrier function via effects on endothelial cell-cell junction morphology and function. Loss of murine endothelial Sun1 impaired blood vessel formation and destabilized junctions, angiogenic sprouts formed but retracted in SUN1-depleted sprouts, and zebrafish vessels lacking Sun1b had aberrant junctions and defective cell-cell connections. At the cellular level, SUN1 stabilized endothelial cell-cell junctions, promoted barrier function, and regulated contractility. Mechanistically, SUN1 depletion altered cell behaviors via the cytoskeleton without changing transcriptional profiles. Reduced peripheral microtubule density, fewer junction contacts and increased catastrophes accompanied SUN1 loss, and microtubule depolymerization phenocopied effects on junctions. Depletion of GEF-H1, a microtubule-regulated Rho activator, or the LINC complex protein nesprin-1 rescued defective junctions of SUN1-depleted endothelial cells. Thus, endothelial SUN1 regulates peripheral cell-cell junctions from the nucleus via LINC complex-based microtubule interactions that affect peripheral microtubule dynamics and Rho-regulated contractility, and this long-range regulation is important for proper blood vessel sprouting and barrier function.

The nuclear membrane protein SUN1 promotes blood vessel formation and barrier function by stabilizing endothelial cell-cell junctions. Communication between SUN1 and endothelial cell junctions relies upon proper microtubule dynamics and Rho signaling far from the nucleus, revealing long-range cellular communication from the nucleus to the cell periphery that is important for vascular development and function.
Physiologically based modeling of the effect of physiological and anthropometric variability on indocyanine green based liver function tests
Authors: Köller Adrian , Grzegorzewski Jan , König Matthias
Published: August 2021

Accurate evaluation of liver function is a central task in hepatology. Dynamic liver function tests (DLFT) based on the time-dependent elimination of a test substance provide an important tool for such a functional assessment. These tests are used in the diagnosis and monitoring of liver disease as well as in the planning of hepatobiliary surgery. A key challenge in the evaluation of liver function with DLFTs is the large inter-individual variability. Indocyanine green (ICG) is a widely applied test compound used for the evaluation of liver function. After an intravenous administration, pharmacokinetic (PK) parameters are calculated from the plasma disappearance curve of ICG which provide an estimate of liver function. The hepatic elimination of ICG is affected by physiological factors such as hepatic blood flow or binding of ICG to plasma proteins, anthropometric factors such as body weight, age, and sex, or the protein amount of the organic anion-transporting polypeptide 1B3 (OATP1B3) mediating the hepatic uptake of ICG. Being able to account for and better understand these various sources of inter-individual variability would allow to improve the power of ICG based DLFTs and move towards an individualized evaluation of liver function. Within this work we systematically analyzed the effect of various factors on ICG elimination by the means of computational modeling. For the analysis, a recently developed and validated physiologically based pharmacokinetics (PBPK) model of ICG distribution and hepatic elimination was utilized. Key results are (i) a systematic analysis of the variability in ICG elimination due to hepatic blood flow, cardiac output, OATP1B3 abundance, liver volume, body weight and plasma bilirubin level; (ii) the evaluation of the inter-individual variability in ICG elimination via a largein silicocohort of n=100000 subjects based on the NHANES cohort with special focus on stratification by age, sex, and body weight; (iii) the evaluation of the effect of various degrees of cirrhosis on variability in ICG elimination. The presented results are an important step towards individualizing liver function tests by elucidating the effects of confounding physiological and anthropometric parameters in the evaluation of liver function via ICG.
Position-dependent Codon Usage Bias in the Human Transcriptome
Authors: Subramanian Kaavya , Waugh Nathan , Shanks Cole , Hendrix David A
Published: August 2021

All life depends on the reliable translation of RNA to protein according to complex interactions between translation machinery and RNA sequence features. While ribosomal occupancy and codon frequencies vary across coding regions, well-established metrics for computing coding potential of RNA do not capture such positional dependence. Here, we investigate positiondependent codon usage bias (PDCUB), which dynamically accounts for the position of proteincoding signals embedded within coding regions. We demonstrate the existence of PDCUB in the human transcriptome, and show that it can be used to predict translation-initiating codons with greater accuracy than other models. We further show that observed PDCUB is not accounted for by other common metrics, including position-dependent GC content, consensus sequences, and the presence of signal peptides in the translation product. More importantly, PDCUB defines a spectrum of translational efficiency supported by ribosomal occupancy and tRNA adaptation index (tAI). High PDCUB scores correspond to a tAI-defined translational ramp and low ribosomal occupancy, while low PDCUB scores exhibit a translational valley and the highest ribosomal occupancy. Finally, we examine the relationship between PDCUB intensity and functional enrichment. We find that transcripts with start codons showing the highest PDCUB are enriched for functions relating to neuropeptide signaling and nucleosome assembly, as well as development of musculoskeletal, cardiovascular, neurological, gastrointestinal, sensory, and other body systems. Furthermore, transcripts with high PDCUB are depleted for functions related to immune response and detection of chemical stimulus. These findings lay important groundwork for advances in our understanding of the regulation of translation, the calculation of coding potential, and the classification of RNA transcripts.