bluuebunny/crossref_metadata_2025 huggingface dataset:
Smoldering Myeloma Treatment
Authors: Mejia Saldarriaga Mateo , Rossi Adriana
Published: May 2021

Smoldering multiple myeloma (MM) is a clonal plasma cell disorder characterized by excess marrow involvement and immunoglobulin production. It is the precursor of MM, differing by the lack of end-organ damage. Smoldering MM encompasses a heterogeneous group of patients, with a median risk of progression to active disease of 50% in the first 5 years. Until recently, the standard of care would dictate observation off therapy until the development of end-organ damage. The recognition of high-risk and ultrahigh-risk subgroups of smoldering MM, with more likely evolution to MM, has led to earlier initiation of therapy in the disease course. Ongoing studies to define the ideal timing and patient population are underway, as well as identification of which agents would be of greatest benefit, as the armamentarium for MM continues to grow.
MDRO transmission in acute hospitals during the COVID-19 pandemic
Authors: Sun Jin Louisa , Fisher Dale
Published: May 2021

Purpose of review

The coronavirus disease (COVID-19) pandemic has resulted in necessary modifications of infection control policies and practices in acute healthcare facilities globally. This is often accompanied by infrastructure modifications, ward redesignations, as well as healthcare staff redeployments and changes to infection prevention and control (IPC) practices. We review the potential for both negative and positive impacts these major changes can have on nosocomial transmission of multidrug-resistant organisms (MDROs).

Recent findings

Healthcare facilities around the world have reported outbreaks of MDROs during the COVID-19 pandemic. In contrast some centres have reported a decrease in baseline rates due to a number of possible factors.

While implementing crucial preventive measures for COVID-19, is it important to consider any collateral effects of changes in IPC and antimicrobial stewardship program (ASP) practices. The disruption caused to IPC and ASP practices during the pandemic are likely to see a counter intuitive increase in transmission of MDROs.
Evaluating a Convolutional Neural Network Noise Reduction Method When Applied to CT Images Reconstructed Differently Than Training Data
Authors: Huber Nathan R. , Missert Andrew D. , Yu Lifeng , Leng Shuai , McCollough Cynthia H.
Published: May 2021

Objective

The aim of this study was to evaluate a narrowly trained convolutional neural network (CNN) denoising algorithm when applied to images reconstructed differently than training data set.

Methods

A residual CNN was trained using 10 noise inserted examinations. Training images were reconstructed with 275 mm of field of view (FOV), medium smooth kernel (D30), and 3 mm of thickness. Six examinations were reserved for testing; these were reconstructed with 100 to 450 mm of FOV, smooth to sharp kernels, and 1 to 5 mm of thickness.

Results

When test and training reconstruction settings were not matched, there was either reduced denoising efficiency or resolution degradation. Denoising efficiency was reduced when FOV was decreased or a smoother kernel was used. Resolution loss occurred when the network was applied to an increased FOV, sharper kernel, or decreased image thickness.

Conclusions

The CNN denoising performance was degraded with variations in FOV, kernel, or decreased thickness. Denoising performance was not affected by increased thickness.
Repurposing of synaptonemal complex proteins for kinetochores in Kinetoplastida
Authors: Tromer Eelco C. , Wemyss Thomas A. , Ludzia Patryk , Waller Ross F. , Akiyoshi Bungo
Published: May 2021

Chromosome segregation in eukaryotes is driven by the kinetochore, a macromolecular complex that connects centromeric DNA to microtubules of the spindle apparatus. Kinetochores in well-studied model eukaryotes consist of a core set of proteins that are broadly conserved among distant eukaryotic phyla. By contrast, unicellular flagellates of the class Kinetoplastida have a unique set of 36 kinetochore components. The evolutionary origin and history of these kinetochores remain unknown. Here, we report evidence of homology between axial element components of the synaptonemal complex and three kinetoplastid kinetochore proteins KKT16-18. The synaptonemal complex is a zipper-like structure that assembles between homologous chromosomes during meiosis to promote recombination. By using sensitive homology detection protocols, we identify divergent orthologues of KKT16-18 in most eukaryotic supergroups, including experimentally established chromosomal axis components, such as Red1 and Rec10 in budding and fission yeast, ASY3-4 in plants and SYCP2-3 in vertebrates. Furthermore, we found 12 recurrent duplications within this ancient eukaryotic SYCP
2–3
gene family, providing opportunities for new functional complexes to arise, including KKT16-18 in the kinetoplastid parasite
Trypanosoma brucei
. We propose the kinetoplastid kinetochore system evolved by repurposing meiotic components of the chromosome synapsis and homologous recombination machinery that were already present in early eukaryotes.
How best to quantify replication success? A simulation study on the comparison of replication success metrics
Authors: Muradchanian Jasmine , Hoekstra Rink , Kiers Henk , van Ravenzwaaij Don
Published: May 2021

To overcome the frequently debated crisis of confidence, replicating studies is becoming increasingly more common. Multiple frequentist and Bayesian measures have been proposed to evaluate whether a replication is successful, but little is known about which method best captures replication success. This study is one of the first attempts to compare a number of quantitative measures of replication success with respect to their ability to draw the correct inference when the underlying truth is known, while taking publication bias into account. Our results show that Bayesian metrics seem to slightly outperform frequentist metrics across the board. Generally, meta-analytic approaches seem to slightly outperform metrics that evaluate single studies, except in the scenario of extreme publication bias, where this pattern reverses.
A new method to generate superoscillating functions and supershifts
Authors: Aharonov Yakir , Colombo Fabrizio , Sabadini Irene , Shushi Tomer , Struppa Daniele C. , Tollaksen Jeff
Published: May 2021

Superoscillations are band-limited functions that can oscillate faster than their fastest Fourier component. These functions (or sequences) appear in weak values in quantum mechanics and in many fields of science and technology such as optics, signal processing and antenna theory. In this paper, we introduce a new method to generate superoscillatory functions that allows us to construct explicitly a very large class of superoscillatory functions.
Stappia albiluteola sp. nov., isolated from marine sediment
Authors: Jiang Shan , Sun You-Yang , Lian Feng-Bai , Zhang Xiao-Kui , Du Zong-Jun
Published: May 2021

A Gram-stain negative, rod-shaped, facultatively aerobic, pale-beige-coloured bacterial strain, designated F7233T, was isolated from coastal sediment sampled at Jingzi Bay, Weihai, PR China. Cells of strain F7233T were 0.3–0.4 µm wide, 1.2–1.4 µm wide long, non-spore-forming and motile with one flagellum. Optimum growth occurred at 30 °C, with 1.0 % (w/v) NaCl and at pH 6.5–7.0. Positive for nitrate reduction, hydrolysis of Tweens and oxidase activity. The sole respiratory quinone of strain F7233T was ubiquinone-10 and the predominant cellular fatty acid was summed feature 8 (C18 : 1
 ω7c/C18 : 1
 ω6c). The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine and one unidentified aminophospholipid. The G+C content of the chromosomal DNA was 63.3 mol%. Phylogenetic analysis of the 16S rRNA gene sequence revealed that the newly isolate belonged to the genus

Stappia

, with 96.8 % sequence similarity to

Stappia indica

MCCC 1A01226T, 96.1 % similarity to

Stappia stellulata

JCM 20692T and 95.5% similarity to

Stappia taiwanensis

CC-SPIO-10-1T. On the basis of phylogenetic, phenotypic and chemotaxonomic data, it is considered that strain F7233T should represent a novel species within the genus

Stappia

, for which the name Stappia albiluteola sp. nov. is proposed. The type strain is F7233T (=MCCC 1H00419T=KCTC 72859T).
Joint analysis reveals shared autoimmune disease associations and identifies common mechanisms
Authors: Lincoln Matthew R , Connally Noah , Axisa Pierre-Paul , Gasperi Christiane , Mitrovic Mitja , Heel David van , Wijmenga Cisca , Withoff Sebo , Jonkers Iris H , Padyukov Leonid ,   International Multiple Sclerosis Genetics Consortium, Rich Stephen S , Graham Robert R , Gaffney Patrick M , Langefeld Carl D , Hafler David A , Chun Sung , Sunayev Shamil R , Cotsapas Chris
Published: May 2021

Autoimmune and inflammatory diseases are polygenic disorders of the immune system. Many genomic loci harbor risk alleles for several diseases, but the limited resolution of genetic mapping prevents determining if the same allele is responsible, indicating a shared underlying mechanism. Using a collection of 129,058 cases and controls across six diseases, we show that ∼40% of overlapping associations are due to the same allele. We improve fine-mapping resolution for shared alleles two-fold by combining cases and controls across diseases, allowing us to identify more eQTLs driven by the shared alleles. The patterns of sharing indicate widespread shared mechanisms, but not a single global autoimmune mechanism. Our approach can be applied to any set of traits, and is particularly valuable as sample collections become depleted.

One sentence summary

Genetic mapping in autoimmune diseases increases genetic mapping resolution and reveals shared mechanisms
Target Product Profiles for a Micronutrient Assessment Tool and Associated Blood Collection Device for Use in Population-Based Surveys: An Expert Consensus
Authors: Smith Emily R. , Lee Joanne , Allen Lindsay H. , Boyle David S. , Brindle Eleanor , Craft Neal E. , Dalmiya Nita , Erhardt Juergen , Garrett Dean , Jefferds Maria Elena , Kavishe Festo , Killilea David W. , Kung’u Jaqueline K. , Kurpad Anura , Loechl Cornelia U. , Moore Sophie E. , Namaste Sorrel ML , Pfeiffer Christine M. , Rohner Fabian , Schulze Kerry , Shaheen Nazma , Soofi Sajid , Winichagoon Pattanee , Thomas Bethanie , Osendarp Saskia , Rawat Rahul
Published: May 2021

Micronutrient deficiencies are a significant public health problem affecting a large portion of the world’s population. Disproportionately affected populations—infants, young children, adolescents and women of reproductive age including pregnant women — are especially susceptible to the health consequences of insufficient micronutrient intakes. However, assessment of micronutrient deficiencies is not routinely included in population health surveys. This nutrition data gap hampers policy, program, and promotion efforts to prevent and treat micronutrient deficiencies. To address one of the barriers to micronutrient assessment, an expert group created a consensus of a target product profile (TPP) for a micronutrient assessment tool and associated blood collection device for use in population surveys. Experts in laboratory medicine, micronutrient assessment, population-based surveys, and product development reviewed proposed TPP standards and collaboratively established minimum and optimal characteristics. These experts defined the target population as infants and children from 6-59 months, adolescents and women of reproductive age 12-49 years including pregnant women. At minimum, the assessment tool should be a multiplex ELISA formatted for >1 analyte that uses a serum or plasma sample prepared from venous blood obtained by a phlebotomist with a 2-week training. Given the use case was specific for population surveys, experts agreed the minimum tool could be semi-quantitative, with analytical specificity of 99%. The TPP also considers the variable field environments for testing (e.g. storage conditions and time to results). The consensus TPP developed can be used to guide selection of existing technologies into population-based surveys, as well as future investment in product development. Partnerships focused on research and development—including industry, public sector, nonprofit, and academic institutions—can help advance the field and fill the micronutrient data gap.
Patient Characteristics in Cases of Reinfection or Prolonged viral shedding in SARS-CoV-2
Authors: Yoo Richard M. , Romero Roland A. , Mabajen Joseph , Mehrotra Suchit , Kohane Isaac S. , Sheils Natalie E
Published: May 2021

Importance

As testing options increase for COVID-19, their interpretability is challenged by the increasing variety of clinical contexts in which results are obtained. In particular, positive COVID-19 diagnostic (RT-PCR) tests that occur after a patient has seroconverted may be indicative of reinfection. However, in the absence of SARS-CoV-2 sequence data, the possibility of prolonged viral shedding may not be excluded. We highlight a testing pattern that identifies such cases and study its statistical power in identifying potential reinfection. We also study the medical records of patients that matched the pattern.

Objective

To describe the frequency and demographic information of people with a testing pattern indicative of SARS-CoV-2 reinfection.

Design

We examined 4.2 million test results from a large national health insurer in the United States. Specifically, we identified the pattern of a positive RT-PCR test followed by a positive IgG test, again followed by a positive RT-PCR.

Setting

Data from outpatient laboratories across the United States was joined with claims data from a single large commercial insurer’s administrative claims database.

Participants

Study participants are those whose insurance, either commercial or Medicare, is provided by a single US based insurer.

Exposures

People who received at least two positive diagnostic tests via RT-PCR for SARS-Cov-2 separated by 42 or more days with at least one serological test (IgG) indicating the presence of antibodies between diagnostic tests.

Main Outcomes and Measures

Count and characteristics of people with the timeline of three tests as described in Exposures.

Results

We identified 79 patients who had two positive RT-PCR tests separated by more than six weeks, with a positive IgG test in between. These patients tended to be older than those COVID-19 patients without this pattern (median age 56 vs. 42), and they exhibited comorbidities typically attributed to a compromised immune system and heart disease.

Conclusions and Relevance

While the testing pattern alone was not sufficient to distinguish potential reinfection from prolonged viral shedding, we were able to identify common traits of the patients identified through the pattern.
Body mass index and birth weight improve polygenic risk score for type 2 diabetes
Authors: Moldovan Avigail , Waldman Yedael Y. , Brandes Nadav , Linial Michal
Published: May 2021

One of the major challenges in the post-genomic era is elucidating the genetic basis of human diseases. In recent years, studies have shown that polygenic risk scores (PRS), based on aggregated information from millions of variants across the human genome, can estimate individual risk for common diseases. In practice, the current medical practice still predominantly relies on physiological and clinical indicators to assess personal disease risk. For example, caregivers mark individuals with high body mass index (BMI) as having an increased risk to develop type 2 diabetes (T2D). An important question is whether combining PRS with clinical metrics can increase the power of disease prediction in particular from early life. In this work we examined this question, focusing on T2D. We show that an integrated approach combining adult BMI and PRS achieves considerably better prediction than each of the measures on unrelated Caucasians in the UK Biobank (UKB, n=290,584). Likewise, integrating PRS with self-reports on birth weight (n=172,239) and comparative body size at age ten (n=287,203) also substantially enhance prediction as compared to each of its components. While the integration of PRS with BMI achieved better results as compared to the other measurements, the latter are early-life measurements that can be integrated already at childhood, to allow preemptive intervention for those at high risk to develop T2D. Our integrated approach can be easily generalized to other diseases, with the relevant early-life measurements.
Maliqua: A study within Malakit, a project on malaria and gold miners in French Guiana
Authors: Parent André-Anne , Galindo Muriel Suzanne , Lambert Yann , Douine Maylis
Published: May 2021

Malaria is endemic in French Guiana, especially within the gold mining community working illegally. Gold miners travel to remote camps in the forest to carry out their activities, exposing themselves to the presumed contamination area. This paper presents the results of a qualitative case study of the Malakit project, a free distribution of self-diagnosis and self-treatment kits, along with appropriate training/information from health facilitators, at resting sites in Brazil and Suriname on the borders with French Guiana. This study documents how Malakit is part of the care trajectory of gold miners. The data was collected using three methods: 1) on-site observation; 2) semi-structured individual interviews (n=26); 3) semi-structured group interviews (n=2). The results inform us that Malakit responds to the need for treatment and facilitates access to care. Gold miners say they trust the facilitators and receive accurate explanations. The majority of participants find the kit easy to use and to carry and explanations given were sufficient, although some people needed to be reminded how to use it once in the forest. Results remind us that malaria among illegal gold miners in French Guiana is a question of social inequalities in health, where the interaction of the health, social, economic and political contexts of Brazil and French Guiana influence exposure to numerous risk factors. Thus, malaria intervention practices such as Malakit cannot be carried out without considering the complexity generated by social inequalities in health.
THE US MIDLIFE MORTALITY CRISIS CONTINUES: EXCESS CAUSE-SPECIFIC MORTALITY DURING 2020
Authors: Glei Dana A.
Published: May 2021

COVID-19 prematurely ended many lives, particularly among the oldest Americans, but the pandemic also had an indirect effect on health and non-COVID mortality among the working-age population, who suffered the brunt of the economic consequences. This analysis investigates whether monthly excess mortality in the US during 2020 varied by age and cause of death. Based on national-level death counts and population estimates for 1999-2020, negative binomial regression models—fit separately by sex— were used to estimate monthly cause-specific excess mortality by age group during 2020. Among males, 71% non-COVID excess deaths occurred at working ages (25-64), but those ages accounted for only 36% of non-COVID excess deaths in females. The results revealed substantial numbers of excess deaths from external causes (particularly among males), heart disease, diabetes, Alzheimer’s disease (particularly among women), and cerebrovascular disease. For males, the largest share of non-COVID excess deaths resulted from external causes, nearly 80% of which occurred at working ages. Although incorrectly classified COVID-19 deaths may explain some excess non-COVID mortality, misclassification is unlikely to explain the increase in external causes of mortality. Auxiliary analyses suggested that drug-related mortality may be driving the rise in external mortality, but drug overdoses were already increasing for a full year prior to the pandemic. The oldest Americans bore the brunt of COVID-19 mortality, but working-age Americans, particularly men, suffered substantial numbers of excess non-COVID deaths, most commonly from external causes and heart disease.
Reduction in COPD exacerbations during COVID-19: a systematic review and meta-analysis
Authors: Alqahtani Jaber S. , Oyelade Tope , Aldhahir Abdulelah M. , Mendes Renata Gonçalves , Alghamdi Saeed M. , Miravitlles Marc , Mandal Swapna , Hurst John R.
Published: May 2021

Background

Reports have suggested a reduction in exacerbations of chronic obstructive pulmonary disease (COPD) during the coronavirus (COVID-19) pandemic, particularly hospital admissions for severe exacerbations. However, the magnitude of this reduction varies between studies.

Method

Electronic databases were searched from January 2020 to May 2021. Two independent reviewers screened titles and abstracts and, when necessary, full text to determine if studies met inclusion criteria. A modified version of the Newcastle-Ottawa Scale was used to assess study quality. A narrative summary of eligible studies was synthesised, and meta-analysis was conducted using a random effect model to pool the rate ratio and 95% confidence intervals (95% CI) for hospital admissions. Exacerbation reduction was compared against the COVID-19 Containment and Health Index.

Results

A total of 13 of 745 studies met the inclusion criteria and were included in this review, with data from nine countries. Seven studies could be included in the meta-analysis. The pooled rate ratio of hospital admissions for COPD exacerbations during the pandemic period was 0.50 (95% CI 0.42-0.58). Findings on the rate of community-treated exacerbations were inconclusive. Three studies reported a significant decrease in the incidence of respiratory viral infections compared with the pre-pandemic period. There was not a significant relationship between exacerbation reduction and the COVID-19 Containment and Health Index.

Conclusion

There was a 50% reduction in admissions for COPD exacerbations during the COVID-19 pandemic period, associated with a reduction in respiratory viral infections that trigger exacerbations. We provide pooled evidence supporting the potential effectiveness of COVID-19 preventive interventions in reducing the risk of admissions for COPD exacerbations.
Complexities in the role of acetylation dynamics in modifying inducible gene activation parameters
Authors: Carrera Samantha , O’Donnell Amanda , Li Yaoyong , Nowicki-Osuch Karol , Baker Syed Murtuza , Spiller David , Sharrocks Andrew D.
Published: May 2021

High levels of histone acetylation are associated with the regulatory elements of active genes, suggesting a link between acetylation and gene activation. However, several studies have shown that histone acetylation dynamics rather than hyperacetylation per se are important determinants in gene activation, particularly at inducible genes. We revisited this model, in the context of EGF-inducible gene expression and found that rather than a simple unifying model, there are two broad classes of genes; one in which high lysine acetylation activity is required for efficient gene activation, and a second group where the opposite occurs and high acetylation activity is inhibitory. We examined the latter class in more detail using EGR2 as a model gene and found that lysine acetylation levels are critical for several activation parameters, including the timing of expression onset, and overall amplitudes of the transcriptional response. In contrast, DUSP1 responds in the canonical manner and its transcriptional activity is promoted by acetylation. Single cell approaches demonstrate heterogenous DUSP1 activation kinetics and that acetylation levels influence allele activation frequencies. Our data therefore point to a complex interplay between acetylation dynamics and target gene induction, which cannot simply be explained by a unified response to acetylation activity. Instead, acetylation level thresholds are an important determinant of transcriptional induction dynamics that are sensed in a gene-specific manner.
MiR-135-5p alleviates bone cancer pain by regulating astrocyte-mediated neuroinflammation in spinal cord through JAK2/STAT3 signaling pathway
Authors: Liu Ming , Cheng Xuefeng , Yan Hong , Chen Jingli , Liu Caihua , Chen Zhonghui
Published: May 2021

Bone cancer pain (BCP) was associated with microRNA dysregulation. In this study, we intended to clarify the potential role of miR-135-5p in a BCP mouse model, which was established by tumor cell implantation (TCI) in the medullary cavity of the mouse femur. The BCP related behaviors were tested, including the paw withdrawal mechanical threshold (PWMT) and number of spontaneous flinches (NSF). The miRNA expression profiles in astrocytes of the sham and tumor groups were compared, and miRNA microarray and quantitative real-time PCR (qRT-PCR) assays confirmed that the amount of expression of miR-135-5p was significantly decreased in astrocytes of the tumor group. Gain- and loss-of-function studies showed that miR-135-5p could inhibit astrocytes activation and inflammation cytokines (TNF-α and IL-1β) expression. The relation between miR-135-5p and JAK2 was detected by bioinformatic analysis and dual luciferase reporter gene assay. By conducting in vitro experiments, it was shown that the miR-135-5P mimics lowered the level of JAK2/STAT3 proteins and inflammatory factors in astrocytes. Moreover, in vivo analysis on BCP mice model indicated that the miR-135-5p agonist could sufficiently increase PWMT and decrease NSF. Meanwhile, reduced activation of astrocytes in the spinal cord, as well as decreased expression of JAK2/STAT3 and inflammatory mediators, were found after miR-135-5p agonist treatment. Collectively, the results showed that miR-135-5p could potentially reduce BCP in mice through inhibiting astrocyte-mediated neuroinflammation and blocking of the JAK2/STAT3 signaling pathway, indicating that the upregulation of miR-135-5P could be a therapeutic focus in BCP treatment.
Inference of tissue relative proportions of the breast epithelial cell types luminal progenitor, basal, and luminal mature
Authors: Bartlett Thomas E. , Jia Peiwen , Chandna Swati , Roy Sandipan
Published: May 2021

Single-Cell Analysis has revolutionised genomic science in recent years. However, due to cost and other practical considerations, single-cell analyses are impossible for studies based on medium or large patient cohorts. For example, a single-cell analysis usually costs thousands of euros for one tissue sample from one volunteer, meaning that typical studies using single-cell analyses are based on very few individuals. While single-cell genomic data can be used to examine the phenotype of individual cells, cell-type deconvolution methods are required to track the quantities of these cells in bulk-tissue genomic data. Hormone receptor negative breast cancers are highly aggressive, and are thought to originate from a subtype of epithelial cells called the luminal progenitor. In this paper, we show how to quantify the number of luminal progenitor cells as well as other epithelial subtypes in breast tissue samples using DNA and RNA based measurements. We find elevated levels of cells which resemble these hormone receptor negative luminal progenitor cells in breast tumour biopsies of hormone receptor negative cancers, as well as in healthy breast tissue samples from BRCA1 (FANCS) mutation carriers. We also find that breast tumours from carriers of heterozygous mutations in non-BRCA Fanconi Anaemia pathway genes are much more likely to be hormone receptor negative. These findings have implications for understanding hormone receptor negative breast cancers, and for breast cancer screening in carriers of heterozygous mutations of Fanconi Anaemia pathway genes.
Metabolic Reprogramming from Glycolysis to Fatty Acid Uptake and beta-Oxidation in Platinum-Resistant Cancer Cells
Authors: Li Junjie , Tan Yuying , Zhao Guangyuan , Huang Kai-Chih , Cardenas Horacio , Matei Daniela , Cheng Ji-Xin
Published: May 2021

Increased aerobic glycolysis is widely considered as a hallmark of cancer. Yet, cancer cell metabolic reprograming during development of therapeutic resistance is under-studied. Here, through high-throughput stimulated Raman scattering imaging and single cell analysis, we found that cisplatin-resistant cells exhibit increased uptake of exogenous fatty acids, accompanied with decreased glucose uptake and de novo lipogenesis, indicating a reprogramming from glucose and glycolysis dependent to fatty acid uptake and beta-oxidation dependent anabolic and energy metabolism. A metabolic index incorporating measurements of glucose derived anabolism and fatty acid uptake correlates linearly to the level of resistance to cisplatin in ovarian cancer cell lines and in primary cells isolated from ovarian cancer patients. Mechanistically, the increased fatty acid uptake facilitates cancer cell survival under cisplatin-induced oxidative stress by enhancing energy production through beta-oxidation. Consequently, blocking fatty acid beta-oxidation by a small molecule inhibitor in combination with cisplatin or carboplatin synergistically suppressed ovarian cancer proliferation in vitro and growth of patient-derived xenograft in vivo. Collectively, these findings support a new way for rapid detection of cisplatin-resistance at single cell level and a new strategy for treatment of cisplatin-resistant tumors.
Effect of Covid-19 on inequalities in premature mortality in England: an analysis of excess mortality by deprivation and ethnicity
Authors: Barnard Sharmani , Fryers Paul , Fitzpatrick Justine , Fox Sebastian , Baker Allan , Burton Paul , Newton John , Doyle Yvonne , Goldblatt Peter
Published: May 2021

Objectives

To examine the impact of the Covid-19 pandemic on inequalities in premature mortality in England by deprivation and ethnicity.

Design

A statistical model to estimate increased mortality in population sub-groups during the Covid-19 pandemic by comparing observed with expected mortality in each group based on trends over the previous five years.

Setting

Information on deaths registered in England since 2015 was used, including age, sex, area of residence, and cause of death. Ethnicity was obtained from Hospital Episode Statistics (HES) records linked to death registration data.

Participants

Population study of England, including all 569,824 deaths from all causes registered between 21 March 2020 and 26 February 2021.

Main outcome measures

Excess mortality in each sub-group over and above the number expected based on trends in mortality in that group over the previous five years.

Results

The gradient in excess mortality by deprivation was greater in the under 75s (most deprived had 1.25 times as many deaths as expected, least deprived 1.14) than in all ages (most deprived had 1.24 times as many deaths as expected, least deprived 1.20). Among the Black and Asian groups, all deprivation quintiles had significantly larger excesses than the most deprived White group and there were no clear gradients across quintiles. Among the White group, only the most deprived had more excess deaths than deaths directly involving Covid-19. Among the Black group all deprivation quintiles experienced more excess deaths than deaths directly involving Covid-19.

Conclusion

The Covid-19 pandemic has widened inequalities in premature mortality by deprivation. Among those under 75, the direct and indirect effects of the pandemic on deaths have disproportionately impacted ethnic minority groups irrespective of deprivation, and the most deprived White group. Statistics limited to deaths directly involving Covid-19 understate the pandemic’s impact on inequalities by deprivation and ethnic group at younger ages.

Key Messages

What is already known on this topic

Estimates of excess mortality for all ages combined for the period March 2020 to February 2021 show a small difference in the relative impact of Covid-19 on excess mortality between the most deprived and the least deprived

Throughout the pandemic estimates of excess mortality have been greater for ethnic minority groups compared with the white group.

What this study adds

Among the under 75s the gradient of excess mortality across the deprivation spectrum indicates a stark increase in already established inequalities in premature mortality

Independent of deprivation, excess mortality in Black and Asian ethnic groups is much higher than that of the white group, indicating that ethnicity is a determinant of excess mortality, regardless of level of area-based deprivation.
Preserved metacognition despite impaired perception of intentionality cues in schizophrenia
Authors: Muthesius Ana , Grothey Farina , Cunningham Carter , Hölzer Susanne , Vogeley Kai , Schultz Johannes
Published: May 2021

Social cognition and metacognition are frequently impaired in schizophrenia, and these impairments complicate recovery. Recent work suggests that different aspects of metacognition may not be impaired to the same degree. Furthermore, metacognition and the cognitive capacity being monitored need not be similarly impaired. Here, we assessed performance in detecting cues of intentional behaviour as well as metacognition about detecting those cues in schizophrenia. Thirty patients and controls categorized animations of moving dots into those displaying a dyadic interaction demonstrating a chase or no chase and indicated their confidence in these judgments. Perception and metacognition were assessed using signal detection theoretic measures, which were analysed using frequentist and Bayesian statistics. Patients showed a deficit compared to controls in detecting intentionality cues, but showed preserved metacognitive performance into this task. Our study reveals a selective deficit in the perception of intentionality cues, but preserved metacognitive insight into the validity of this perception. It thus appears that impairment of metacognition in schizophrenia varies across cognitive domains - metacognition should not be considered a monolithic stone that is either impaired or unimpaired.

Highlights

-

Impaired detection of chasing between two moving objects in schizophrenia

-

No impairment in metacognition during this task in schizophrenia

-

Preserved metacognition into social perception despite impaired social perception
Glycine-Rich RNA-Binding Protein 7 interacts with and potentiates effector-induced immunity by Gpa2 and Rx1 based on an intact RNA Recognition Motif
Authors: Sukarta Octavina C. A. , Zheng Qi , Slootweg Erik J. , Mekken Mark , Mendel Melanie , Putker Vera , Overmars Hein , Pomp Rikus , Roosien Jan , Boeren Sjef , Smant Geert , Goverse Aska
Published: May 2021

The activity of intracellular plant Nucleotide-Binding Leucine-Rich Repeat (NB-LRR) immune receptors is fine-tuned by interactions between the receptors and their partners. Identifying NB-LRR interacting proteins is, therefore, crucial to advance our understanding of how these receptors function.

A Co-Immunoprecipitation/Mass-Spectrometry screening was performed inNicotiana benthamianato identify host proteins associated with the Gpa2 CC-NB-LRR, which confers resistance against the potato cyst nematodeGlobodera pallida. A combination of biochemical, cellular, and functional assays was used to assess the role of a candidate interactor in defence.

AN. benthamianahomolog of the Glycine-Rich RNA-Binding Protein 7 (NbGRP7) protein was prioritized as a novel Gpa2-interacting protein for further investigations.NbGRP7 also associatesin plantawith the homologous Rx1 receptor, which confers immunity to Potato Virus X. We show thatNbGRP7 positively regulates extreme resistance by Rx1 and cell death by Gpa2. Mutating theNbGRP7 RNA recognition motif compromises its role in Rx1-mediated defence. Strikingly, ectopicNbGRP7 expression impacts the steady-state levels of Rx1, which relies on an intact RNA recognition motif.

Combined, our findings illustrate thatNbGRP7 is a novel pro-immune component in effector-triggered immunity by regulating Gpa2/Rx1 functioning at a post-transcriptional level.
Rieske head domain dynamics and indazole-derivative inhibition of Candida albicans complex III
Authors: Di Trani Justin M. , Liu Zhongle , Whitesell Luke , Brzezinski Peter , Cowen Leah E. , Rubinstein John L.
Published: May 2021

During cellular respiration, electron transfer between the integral membrane protein complexes of the electron transport chain is coupled to proton translocation across the inner mitochondrial membrane, which in turn powers synthesis of ATP and transmembrane transport processes. The homodimeric electron transport chain Complex III (CIII2) oxidizes ubiquinol (UQH2) to ubiquinone (UQ), transferring electrons to cytochrome c, and translocating protons through a mechanism known as the Q cycle. The Q cycle involves UQH2 oxidation and UQ reduction at two different sites within each CIII monomer, as well as movement of the head domain of the Rieske subunit. We used cryoEM to determine the structure of CIII2 from Candida albicans, revealing density for endogenous UQ in the structure and allowing us to directly visualize the continuum of conformations of the Rieske head domain. Analysis of these conformations does not indicate cooperativity in the position of the Rieske head domains or binding of ligands in the two CIIIs of the CIII2 dimer. CryoEM with the indazole derivative Inz-5, which inhibits fungal CIII2 and is fungicidal when administered with fungistatic azole drugs, showed that inhibition by Inz-5 alters the equilibrium of the Rieske head domain positions.
Somatosensory signals from the controllers of an extra robotic finger support motor learning
Authors: Amoruso Elena , Dowdall Lucy , Kollamkulam Mathew Thomas , Ukaegbu Obioha , Kieliba Paulina , NG Tammy , Dempsey-Jones Harriet , Clode Danielle , Makin Tamar Rebecca
Published: May 2021

Considerable resources are being invested to provide bidirectional control of substitutive and augmentative motor interfaces through artificial somatosensory feedback. Here, we investigated whether intrinsic somatosensory information, from body part(s) proportionally controlling an augmentation device, can be utilised to infer the device state and position, to better support motor control and learning. In a placebo-controlled design, we used local anaesthetic to attenuate somatosensory inputs to the big toes while participants learned to operate a toe-controlled robotic extra finger (Third Thumb) using pressure sensors. Motor learning outcomes were compared against a control group who received sham anaesthetic. The availability of somatosensory cues about the amount of exerted pressure generally facilitated acquisition, retention and transfer of motor skills, and performance under cognitive load. Motor performance was not impaired by anaesthesia when tasks involved close collaboration with the biological fingers, indicating that the brain could close the gap of the missing pressure signals by alternative means, including feedback from other body parts involved in the motor task. Together, our findings demonstrate that there are intrinsic natural avenues to provide surrogate position information to support motor control of an artificial body part, beyond artificial extrinsic signalling.
Targeted single-cell RNA sequencing of transcription factors enhances the identification of cell types and trajectories
Authors: Pokhilko Alexandra , Handel Adam E. , Curion Fabiola , Volpato Viola , Whiteley Emma S. , Bøstrand Sunniva , Newey Sarah E. , Akerman Colin J. , Webber Caleb , Clark Michael B. , Bowden Rory , Cader M. Zameel
Published: May 2021

Single-cell RNA sequencing (scRNA-seq) is a widely used method for identifying cell types and trajectories in biologically heterogeneous samples, but it is limited in its detection and quantification of lowly expressed genes. This results in missing important biological signals, such as the expression of key transcription factors (TFs) driving cellular differentiation. We show that targeted sequencing of ∼1000 TFs (scCapture-seq) in iPSC-derived neuronal cultures greatly improves the biological information garnered from scRNA-seq. Increased TF resolution enhanced cell type identification, developmental trajectories, and gene regulatory networks. This allowed us to resolve differences among neuronal populations, which were generated in two different laboratories using the same differentiation protocol. ScCapture-seq improved TF-gene regulatory network inference and thus identified divergent patterns of neurogenesis into either excitatory cortical neurons or inhibitory interneurons. Furthermore, scCapture-seq revealed a role for of retinoic acid signaling in the developmental divergence between these different neuronal populations. Our results show that TF targeting improves the characterization of human cellular models and allows identification of the essential differences between cellular populations, which would otherwise be missed in traditional scRNA-seq. scCapture-seq TF targeting represents a cost-effective enhancement of scRNA-seq, which could be broadly applied to improve scRNA-seq resolution.
Soft X-ray nanospectroscopy for quantification of X-ray linear dichroism on powders
Authors: Hageraats Selwin , Thoury Mathieu , Stanescu Stefan , Keune Katrien
Published: May 2021

X-ray linear dichroism (XLD) is a fundamental property of many ordered materials that can for instance provide information on the origin of magnetic properties and the existence of differently ordered domains. Conventionally, measurements of XLD are performed on single crystals, crystalline thin films, or highly ordered nanostructure arrays. Here, it is demonstrated how quantitative measurements of XLD can be performed on powders, relying on the random orientation of many particles instead of the controlled orientation of a single ordered structure. The technique is based on a scanning X-ray transmission microscope operated in the soft X-ray regime. The use of a Fresnel zone plate allows X-ray absorption features to be probed at ∼40 nm lateral resolution – a scale small enough to probe the individual crystallites in most powders. Quantitative XLD parameters were then retrieved by determining the intensity distributions of certain diagnostic dichroic absorption features, estimating the angle between their transition dipole moments, and fitting the distributions with four-parameter dichroic models. Analysis of several differently produced ZnO powders shows that the experimentally obtained distributions indeed follow the theoretical model for XLD. Making use of Monte Carlo simulations to estimate uncertainties in the calculated dichroic model parameters, it was established that longer X-ray exposure times lead to a decrease in the amplitude of the XLD effect of ZnO.
A simple vapor-diffusion method enables protein crystallization inside the HARE serial crystallography chip
Authors: Norton-Baker Brenna , Mehrabi Pedram , Boger Juliane , Schönherr Robert , von Stetten David , Schikora Hendrik , Kwok Ashley O. , Martin Rachel W. , Miller R. J. Dwayne , Redecke Lars , Schulz Eike C.
Published: May 2021

Fixed-target serial crystallography has become an important method for the study of protein structure and dynamics at synchrotrons and X-ray free-electron lasers. However, sample homogeneity, consumption and the physical stress on samples remain major challenges for these high-throughput experiments, which depend on high-quality protein microcrystals. The batch crystallization procedures that are typically applied require time- and sample-intensive screening and optimization. Here, a simple protein crystallization method inside the features of the HARE serial crystallography chips is reported that circumvents batch crystallization and allows the direct transfer of canonical vapor-diffusion conditions to in-chip crystallization. Based on conventional hanging-drop vapor-diffusion experiments, the crystallization solution is distributed into the wells of the HARE chip and equilibrated against a reservoir with mother liquor. Using this simple method, high-quality microcrystals were generated with sufficient density for the structure determination of four different proteins. A new protein variant was crystallized using the protein concentrations encountered during canonical crystallization experiments, enabling structure determination from ∼55 µg of protein. Additionally, structure determination from intracellular crystals grown in insect cells cultured directly in the features of the HARE chips is demonstrated. In cellulo crystallization represents a comparatively unexplored space in crystallization, especially for proteins that are resistant to crystallization using conventional techniques, and eliminates any need for laborious protein purification. This in-chip technique avoids harvesting the sensitive crystals or any further physical handling of the crystal-containing cells. These proof-of-principle experiments indicate the potential of this method to become a simple alternative to batch crystallization approaches and also as a convenient extension to canonical crystallization screens.
The missing link: covalent linkages in structural models
Authors: Nicholls Robert A. , Wojdyr Marcin , Joosten Robbie P. , Catapano Lucrezia , Long Fei , Fischer Marcus , Emsley Paul , Murshudov Garib N.
Published: May 2021

Covalent linkages between constituent blocks of macromolecules and ligands have been subject to inconsistent treatment during the model-building, refinement and deposition process. This may stem from a number of sources, including difficulties with initially detecting the covalent linkage, identifying the correct chemistry, obtaining an appropriate restraint dictionary and ensuring its correct application. The analysis presented herein assesses the extent of problems involving covalent linkages in the Protein Data Bank (PDB). Not only will this facilitate the remediation of existing models, but also, more importantly, it will inform and thus improve the quality of future linkages. By considering linkages of known type in the CCP4 Monomer Library (CCP4-ML), failure to model a covalent linkage is identified to result in inaccurate (systematically longer) interatomic distances. Scanning the PDB for proximal atom pairs that do not have a corresponding type in the CCP4-ML reveals a large number of commonly occurring types of unannotated potential linkages; in general, these may or may not be covalently linked. Manual consideration of the most commonly occurring cases identifies a number of genuine classes of covalent linkages. The recent expansion of the CCP4-ML is discussed, which has involved the addition of over 16 000 and the replacement of over 11 000 component dictionaries using AceDRG. As part of this effort, the CCP4-ML has also been extended using AceDRG link dictionaries for the aforementioned linkage types identified in this analysis. This will facilitate the identification of such linkage types in future modelling efforts, whilst concurrently easing the process involved in their application. The need for a universal standard for maintaining link records corresponding to covalent linkages, and references to the associated dictionaries used during modelling and refinement, following deposition to the PDB is emphasized. The importance of correctly modelling covalent linkages is demonstrated using a case study, which involves the covalent linkage of an inhibitor to the main protease in various viral species, including SARS-CoV-2. This example demonstrates the importance of properly modelling covalent linkages using a comprehensive restraint dictionary, as opposed to just using a single interatomic distance restraint or failing to model the covalent linkage at all.