bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic review and meta-analysis of the efficacy of benzodiazepines for dyspnea in patients with cancer
Authors: Yasuda Shuntaro , Sugano Koji , Matsuda Yoshinobu , Kako Jun , Takagi Yusuke , Watanabe Hiroaki , Kasahara Yoko , Goya Sho , Kohara Hiroyuki , Mori Masanori , Nakayama Takeo , Yamaguchi Takashi
Published: January 2023

Objective

the role of benzodiazepines in relieving dyspnea in patients with cancer has not yet been established. This systematic review and meta-analysis aimed to determine the efficacy and safety of benzodiazepines alone or in combination with opioids for dyspnea in patients with cancer.

Methods

Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and Ichushi-Web were searched for articles published from database inception to 23 September 2019. Studies of benzodiazepines alone or in combination with opioids for dyspnea were included. The primary outcome measure was the relief of dyspnea. The secondary outcome measures were anxiety, somnolence and severe adverse events.

Results

of 505 publications initially identified, two trials and one trial were included in the meta-analysis of midazolam alone and in combination with morphine, respectively. With regard to the relief of dyspnea, midazolam alone showed no significant difference compared with morphine alone, with a relative risk of 0.95 (95% confidence interval: 0.47–1.89). Meanwhile, midazolam plus morphine was significantly more effective than morphine alone, with a relative risk of 1.33 (95% confidence interval: 1.02–1.75). For anxiety relief, a meta-analysis could not be performed because of insufficient data. The incidence of somnolence and severe adverse events was not significantly different between the experimental and control groups for either midazolam alone or in combination with morphine.

Conclusions

benzodiazepines alone do not significantly improve dyspnea compared with opioids alone, but a combination of benzodiazepines and opioids may be more effective. Evidence from randomized controlled trials focusing on patients with cancer has not been generated in recent years. Further appropriately designed randomized controlled trials are required.
Well-Founded Fear of Algorithms or Algorithms of Well-Founded Fear? Hybrid Intelligence in Automated Asylum Seeker Interviews
Authors: McNamara Robert G , Tikka Pia
Published: January 2023

Growing numbers of asylum seekers across Europe have created heightened pressure on governments to employ technologies to assist immigration systems in meeting humanitarian standards of international law. This article analyses the potential of hybrid intelligence (HI)—a machine learning (ML) utility supervised by and supervising human intelligence—for assisting both asylum seekers and immigration officers in performing fair and just assessments, while addressing theoretical underpinnings of what hybridity entails from the perspective of stakeholders and humanitarian systems. While aspects of ML demonstrate promise in reducing bias in immigration decisions, such technology itself suffers from various inherent biases. In addition, technological mediation poses several unforeseen, unintended, and subtle threats to humanitarian missions. By analysing ML algorithms currently employed in refugee status determination pilot programs and immigration control, this article synthesizes universal complications of using assistive technology in Refugee Status Determinations, with special focus on evaluating resultant theoretical refugee identity reconfigurations. Conceptually, this article expands on the theoretical model of what has been termed ‘ID entity’ by biometrics researchers and ethnographers by analysing potential latent consequences from technological mediation in asylum cases, while addressing use cases such as German and Canadian immigration services’ pilot programs, along with automated pilot border screening projects such as Iborderctrl, among others. In addition, several hypothetical scenarios are presented to concretize and further theoretical inquiry of using HI in asylum seeker interviews, with special focus on the requisite criterion of possessing a well-founded fear of persecution.
The association between sexual dysfunction and prostate cancer: a systematic review and meta-analysis
Authors: Dilixiati Diliyaer , Kadier Kaisaierjiang , Laihaiti Duolikun , Lu Jian-De , Azhati Baihetiya , Rexiati Mulati
Published: January 2023

Background

Whether there is a connection between sexual dysfunction (SD) and prostate cancer (PCa) is controversial.

Aim

We sought to review the interrelationship between SD and PCa and to determine whether there is a definitive risk of men developing PCa after suffering from SD.

Methods

A complete search of the PubMed, Web of Science, Ovid MEDLINE, Embase, and Cochrane Library databases was performed to search for eligible studies published up to October 2022. The protocol for this meta-analysis is available from PROSPERO (ID: CRD42022342381).

Outcomes

The associations between SD and the risk of PCa were assessed by calculating pooled ORs with 95% CIs, and the standard mean difference (SMD) and its 95% CI were used to assess the relationship between SD and prostate-specific antigen (PSA) levels or prostate volume (PV). Random-effects models were used to account for potential heterogeneity, and the Newcastle–Ottawa Scale (NOS) was used to evaluate the quality of the included studies.

Results

Twenty studies involving 215,626 individuals were included in our meta-analysis. Compared with controls, subjects with SD had a 1.62-fold increased risk of PCa (OR = 1.62, 95% CI, 1.77-2.23, P = .003; heterogeneity: I2 = 97.8%, P < .001). Patients with SD had higher PSA levels than controls (SMD =0.07, 95% CI, 0.00 to 0.13, P = .041; heterogeneity: I2 = 55.6%, P = .027). However, there was no association between SD and PV (SMD = 0.03, 95% CI, −0.05 to 0.11, P = .122; heterogeneity: I2 = 48.5%, P = .100).

Clinical Implications

Current evidence confirms a potential link between SD and the risk of PCa and that SD in PCa patients should be of concern to clinicians.

Strengths and Limitations

The strength of this study is that it is to our knowledge the first meta-analysis of studies on the risk of PCa in men with SD. A limitation is that most of the studies included in this meta-analysis focused on ED.

Conclusion

Our systematic review and meta-analysis results suggest that men with SD have a higher risk of PCa and higher PSA levels than men without SD. However, this is merely inferential, and causality cannot be determined based on the current data. Further longitudinal studies should be performed to validate our preliminary findings.
Stricter treat-to-target in RA does not result in less radiographic progression: a longitudinal analysis in RA BIODAM
Authors: Ramiro Sofia , Landewé Robert , van der Heijde Désirée , Sepriano Alexandre , FitzGerald Oliver , Østergaard Mikkel , Homik Joanne , Elkayam Ori , Thorne J Carter , Larché Maggie J , Ferraccioli Gianfranco , Backhaus Marina , Boire Gilles , Combe Bernard , Schaeverbeke Thierry , Saraux Alain , Dougados Maxime , Rossini Maurizio , Govoni Marcello , Sinigaglia Luigi , Cantagrel Alain G , Allaart Cornelia F , Barnabe Cheryl , Bingham Clifton O , van Schaardenburg Dirkjan , Hammer Hilde B , Dadashova Rana , Hutchings Edna , Paschke Joel , Maksymowych Walter P
Published: January 2023

Objectives

To investigate whether meticulously following a treat-to-target (T2T)-strategy in daily clinical practice will lead to less radiographic progression in patients with active RA who start (new) DMARD-therapy.

Methods

Patients with RA from 10 countries starting/changing conventional synthetic or biologic DMARDs because of active RA, and in whom treatment intensification according to the T2T principle was pursued, were assessed for disease activity every 3 months for 2 years (RA-BIODAM cohort). The primary outcome was the change in Sharp-van der Heijde (SvdH) score, assessed every 6 months. Per 3-month interval DAS44-T2T could be followed zero, one or two times (in a total of two visits). The relation between T2T intensity and change in SvdH-score was modelled by generalized estimating equations.

Results

In total, 511 patients were included [mean (s.d.) age: 56 (13) years; 76% female]. Mean 2-year SvdH progression was 2.2 (4.1) units (median: 1 unit). A stricter application of T2T in a 3-month interval did not reduce progression in the same 6-month interval [parameter estimates (for yes vs no): +0.15 units (95% CI: −0.04, 0.33) for 2 vs 0 visits; and +0.08 units (−0.06; 0.22) for 1 vs 0 visits] nor did it reduce progression in the subsequent 6-month interval.

Conclusions

In this daily practice cohort, following T2T principles more meticulously did not result in less radiographic progression than a somewhat more lenient attitude towards T2T. One possible interpretation of these results is that the intention to apply T2T already suffices and that a more stringent approach does not further improve outcome.
Proprietary estoppel and the position of the stranger
Authors: Palser Elaine
Published: January 2023

This article examines the position of a stranger in two principal scenarios, and the implications for strangers of the possible outcomes to these scenarios. First, if A makes a promise to B that C will receive A’s property if B advances monies to A, can the promise be enforced to benefit C who is a stranger to the promise? Secondly, if A makes a promise to B that B will receive A’s 50% share in a property if B advances monies to A, but A then enters into a declaration of trust with D (with whom A then purchases the property), is B bound by that declaration (to which B is a stranger)? Is B then excluded from a constructive or resulting trust claim, and left solely with a proprietary estoppel claim?
Is there added value from using three serial samples when surveying the occurrence of intestinal parasites in children?
Authors: Jerez Puebla Luis Enrique , Núñez-Fernández Fidel A , La Rosa Osoria Edel , Atencio Millán Iraís , Cruz Rodríguez Iredys , Rojas Rivero Lázara , Fresco Sampedro Yanet , Rodríguez Moreno Laura , Robertson Lucy J
Published: January 2023

Background

Surveys for intestinal parasitic infections (IPIs) often involve samples from three sampling dates analysed by various microscopy techniques. However, analysis of three samples per individual is a huge burden on time and resources. We compared the value from analysing three or fewer samples.

Methods

In this cross-sectional study, three faecal samples were collected every other day from 332 children from two locations in Guantanamo province, Cuba. Samples were analysed by wet mount with Lugol stain, Willis flotation method and Kato–Katz thick smear.

Results

Most parasites were detected by wet mount, although helminth eggs not found by wet smear were detected by the Willis flotation method (in particular) and Kato–Katz smear. Blastocystis spp. was the most commonly detected parasite (about 65%), then Giardia duodenalis and then Entamoeba spp. Although analysis of two stool samples significantly increased occurrence data for Blastocystis, this was not so for the other parasites. For none of the protozoan parasites were results from analysing three samples significantly higher than results from analysing just two samples.

Conclusions

Analysing two faecal samples by wet mount and the Willis flotation method provides useful data for estimating the prevalence of IPIs in relatively high prevalence settings. Analysing further samples provides limited additional information and adds an extra burden in terms of time and resources.
Study on Spatio-temporal Prevalence and Hematological Attributes of Bovine Babesiosis in Cattle Population of Layyah, Southern Punjab, Pakistan
Authors: Ahmad Absar , Ali Zulfiqar , Lashari Mushtaq Hussain
Published: January 2023

The objective of the present study was to investigate the spatiotemporal prevalence of bovine babesiosis in cattle population (n=376) of District Layyah, South Punjab, Pakistan as affected by location, age, breed, gender and seasons. Blood samples were collected aseptically and assessed for babesiosis through microscopy and PCR, and through automated analyzer for hematological attributes. Overall results of prevalence as attained through PCR in cattle population showed a significantly (P≤0.05) lower prevalence of 19.4% (n=72/376) as compared to 37.2% (n=140/276) through microscopy. None of the studied cattle from Cholistani breed were Babesia-positive. However, significantly (P≤0.05) higher prevalence was noticed for crossbred cattle (46.7%, n= 50/107) followed by that in Friesian (16.1%, n= 10/62), Jersey (7%, n= 5/71) and Sahiwal (6.9%, n= 7/101) cattle breeds. Female cattle (19.5%, n= 55/281) and age group 1 (Up to 2 years) (40%, n= 42/105) had higher prevalence of Babesia as ascertained through PCR in comparison to their counterpart groups. Significantly (P≤0.05) higher prevalence of 35.9% (n=60/167) was shown in summer as compared to that in winter season (5.7%, n= 12/209). All the positive samples produced the 490bp amplicons specific and typical for Babesia bigemina. Regarding hematology, hemoglobin concentration, erythrocytic count, hematocrit and mean corpuscular volume were significantly (P≤0.05) lower in babesia-positive cattle as compared to healthy ones. In a nutshell, indigenous cattle breeds are tick-resistant hardy breeds and do not show severe signs of babesiosis as compared to exotic and crossbred cattle. Furthermore, Southern Punjab area of Pakistan has a different spatiotemporal distribution of babesiosis with bigemina being predominant.
Wnt signaling regulates ion channel expression to promote smooth muscle and cartilage formation in developing mouse trachea
Authors: Russell Nicholas X. , Burra Kaulini , Shah Ronak , Bottasso-Arias Natalia , Mohanakrishnan Megha , Snowball John , Ediga Harshavardhana H. , Madala Satish K , Sinner Debora
Published: January 2023

Ion channels play critical roles in the physiology and function of the nervous system and contractile tissue; however, their role in non-contractile tissue and embryonic development has yet to be understood. Tracheobronchomalacia (TBM) and complete tracheal rings (CTR) are disorders affecting the muscle and cartilage of the trachea and bronchi, whose etiology remains poorly understood. We demonstrated that trachealis muscle organization and polarity are disrupted after epithelial ablation of Wls, a cargo receptor critical for the Wnt signaling pathway, in developing trachea. The phenotype resembles the anomalous trachealis muscle observed after deletion of ion channel encoding genes in developing mouse trachea. We sought to investigate whether and how the deletion ofWlsaffects ion channels during tracheal development. We hypothesize that Wnt signaling influences the expression of ion channels to promote trachealis muscle cell assembly and patterning. DeletingWlsin developing trachea causes differential regulation of genes mediating actin binding, cytoskeleton organization, and potassium ion channel activity. Wnt signaling regulated expression ofKcnj13, Kcnd3, Kcnj8,andAbcc9as demonstrated by in vitro studies and in vivo analysis inWnt5aand β-catenindeficient tracheas. Pharmacological inhibition of potassium ion channels and Wnt signaling impaired contractility of developing trachealis smooth muscle and formation of cartilaginous mesenchymal condensation. Thus, in mice, epithelial-induced Wnt/β-catenin signaling mediates trachealis muscle and cartilage development via modulation of ion channel expression, promoting trachealis muscle architecture, contractility, and cartilaginous extracellular matrix. In turn, ion channel activity may influence tracheal morphogenesis underlying TBM and CTR.
Angiopoietin-like 4 shapes the intrahepatic T-cell landscape via eIF2α signaling during steatohepatitis in diet-induced NAFLD
Authors: Low Zun Siong , Chua Damien , Cheng Hong Sheng , Tee Rachel , Tan Wei Ren , Ball Christopher , Sahib Norliza Binte Esmail , Ng Ser Sue , Qu Jing , Liu Yingzi , Hong Haiyu , Cai Chaonong , Rao Nandini C. L. , Wee Aileen , Muthiah Mark D. , Bichler Zoë , Mickelson Barbara , Lee Jia Qi , Kong Mei Suen , Tay Vanessa S.Y. , Yan Zhuang , Chen Jiapeng , Ng Aik Seng , Yip Yun Sheng , Vos Marcus Ivan Gerard , Lim Debbie Xiu En , Chittezhath Manesh , Yaligar Jadegoud , Verma Sanjay Kumar , Poptani Harish , Guan Xue Li , Velan S. Sendhil , Ali Yusuf , Li Liang , Tan Nguan Soon , Wahli Walter
Published: January 2023

Adaptive T-cell immune response is essential in conferring protective immunity, a process requiring tight cellular homeostasis regulation. Pathological intrahepatic T-cell landscape has a role in NAFLD propagation; however, its activation remains unknown. To address this gap, we extensively characterized a novel diet-induced NAFLD murine model (LIDPAD) featuring key phenotypic and genetic attributes reflective of human NAFLD. Comparative transcriptomic-guided staging of human and murine NASH reinforced the robustness of LIDPAD in recapitulating critical transitory stages of human NAFLD. We found that angiopoietin-like 4 (Angptl4) shapes activation of the intrahepatic T-cell landscape through the modulation of eIF2α signaling during fibrosis. Single-immune cell analysis and hepatic transcriptomics during fibrosis, and kinase inhibitor screening confirmed that Angptl4 orchestrates the hyperactivation of intrahepatic adaptive immunity via eIF2α signaling. Consistently, immunoblocking of cAngplt4 reduces T-cell overactivation, delaying disease aggravation. Taken together, Angptl4 is a crucial determinant in shaping intrahepatic adaptive immunity during fibrosis in NAFLD.
Distinct representations of innate and learned threats within the thalamic-amygdala pathway
Authors: Khalil Valentina , Faress Islam , Mermet-Joret Noëmie , Kerwin Peter , Yonehara Keisuke , Nabavi Sadegh
Published: January 2023

Behavioral flexibility and timely reactions to salient stimuli are essential for survival. The subcortical thalamic-basolateral amygdala (BLA) pathway serves as a shortcut for salient stimuli ensuring rapid processing. Here, we show that BLA neuronal and thalamic axonal activity mirror the defensive behavior evoked by an innate visual threat as well as an auditory learned threat. Importantly, perturbing this pathway compromises defensive responses to both forms of threats, in that animals fail to switch from exploratory to defensive behavior. Despite the shared pathway between the two forms of threat processing, we observed noticeable differences. Blocking beta-adrenergic receptors impair the defensive response to the innate but not the learned threats. This reduced defensive response, surprisingly, is reflected in the suppression of the activity exclusively in the BLA, as the thalamic input response remains intact. Our side-by-side examination highlights the similarities and differences between innate and learned threat-processing, thus providing new fundamental insights.
MRBEE: A novel bias-corrected multivariable Mendelian Randomization method
Authors: Lorincz-Comi Noah , Yang Yihe , Li Gen , Zhu Xiaofeng
Published: January 2023

Mendelian randomization (MR) is an instrumental variable approach used to infer causal relationships between exposures and outcomes and can apply to summary data from genome-wide association studies (GWAS). Since GWAS summary statistics are subject to estimation errors, most existing MR approaches suffer from measurement error bias, whose scale and direction are influenced by weak instrumental variables and GWAS sample overlap, respectively. We introduce MRBEE (MR using Bias-corrected Estimating Equation), a novel multivariable MR method capable of simultaneously removing measurement error bias and identifying horizontal pleiotropy. In simulations, we showed that MRBEE is capable of effectively removing measurement error bias in the presence of weak instrumental variables and sample overlap. In two independent real data analyses, we discovered that the causal effect of BMI on coronary artery disease risk is entirely mediated by blood pressure, and that existing MR methods may underestimate the causal effect of cannabis use disorder on schizophrenia risk compared to MRBEE. MRBEE possesses significant potential for advancing genetic research by providing a valuable tool to study causality between multiple risk factors and disease outcomes, particularly as a large number of GWAS summary statistics become publicly available.
Identification of Cell-Type Specific Alternative Transcripts in the MulticellularAlga Volvox carteri
Authors: Balasubramanian Ravi N. , Umen James
Published: January 2023

Cell type specialization is a hallmark of complex multicellular organisms and is usually established through implementation of cell-type-specific gene expression programs. The multicellular green algaVolvox carterihas just two cell types, germ and soma, that have previously been shown to have very different transcriptome compositions which reflect differences in their respective forms and functions. Here we interrogated another potential mechanism for differentiation inV. carteri, cell type specific alternative transcript isoforms (CTSAI). We used pre-existing predictions of alternative transcripts andde novotranscript assembly to compile a list of 1978 loci with two or more transcript isoforms, 67 of which also showed cell type isoform expression biases. Manual curation identified 15 strong candidates for CTSAI, three of which were experimentally verified and provide insight into potential functional differentiation of encoded protein isoforms. Alternative transcript isoforms are also found in a unicellular relative ofV. carteri,Chlamydomonas reinhardtii, but there was little overlap in orthologous gene pairs in the two species which both exhibited CTSAI, suggesting that CTSAI observed inV. carteriarose after the two lineages diverged. CTSAIs in metazoans are often generated through alternative pre-mRNA processing mediated by RNA binding proteins (RBPs). We interrogated cell type expression patterns of 126V. carteripredicted RBP encoding genes and found 40 that showed either somatic or germ cell expression bias. These RBPs are potential mediators of CTSAI inV. carteriand suggest possible pre-adaptation for cell type specific RNA processing and a potential path for generating CTSAI in the early ancestors of metazoans and plants.
Microfluidics-enabled fluorescence-activated cell sorting of single pathogen-specific antibody secreting cells for the rapid discovery of monoclonal antibodies
Authors: Fischer Katrin , Lulla Aleksei , So Tsz Y , Pereyra-Gerber Pehuén , Raybould Matthew I. J. , Kohler Timo N. , Kaminski Tomasz S. , Yam-Puc Juan Carlos , Hughes Robert , Leiß-Maier Florian , Brear Paul , Matheson Nicholas J. , Deane Charlotte M. , Hyvönen Marko , Thaventhiran James E. D. , Hollfelder Florian
Published: January 2023

Monoclonal antibodies are increasingly used to prevent and treat viral infections, playing a pivotal role in pandemic response efforts. Antibody secreting cells (ASCs, plasma cells and plasmablasts) are an excellent source of high-affinity antibodies with therapeutic potential. Current methodologies to study antigen-specific ASCs either have low throughput, require expensive and labour-intensive screening or are technically demanding and therefore not accessible to the wider research community. Here, we present a straightforward technology for the rapid discovery of monoclonal antibodies from ASCs: we combine microfluidic encapsulation of single cells into an antibody capture hydrogel with antigen bait sorting by conventional flow cytometry. With our technology, we screened millions of mouse and human ASCs and obtained anti-SARS-CoV-2 monoclonal antibodies with high affinity (pM) and neutralising capacity (<100 ng/mL) in two weeks with a high hit rate (>85%). By facilitating access into the underexplored ASC compartment, we enable fast and efficient antibody discovery as well as immunological studies into the generation of protective antibodies.
Brain signatures indexing variation in internal processing during perceptual decision-making
Authors: Nakuci Johan , Samaha Jason , Rahnev Dobromir
Published: January 2023

Brain activity is highly variable even while performing the same cognitive task with consequences for performance. Discovering, characterizing, and linking variability in brain activity to internal processes has primarily relied on experimentally inducing changes (e.g., via attention manipulation) to identify neuronal and behavioral consequences or studying spontaneous changes in ongoing brain dynamics. However, changes in internal processing could arise from many factors, such as variation in strategy or arousal, that are independent of experimental conditions. Here we utilize a data-driven clustering method based on modularity-maximation to identify consistent spatial-temporal EEG activity patterns across individual trials and relate this activity to behavioral performance. Subjects (N = 25) performed a motion direction discrimination task with six interleaved levels of motion coherence. Modularity-maximization based clustering identified two discrete spatial-temporal clusters, or subtypes, of trials with different patterns of brain activity. Surprisingly, even though Subtype 1 occurred more frequently with lower motion coherence, it was nonetheless associated with faster response times. Computational modeling suggests that Subtype 1 was characterized by a lower threshold for reaching a decision. These results highlight trial-to-trial variability in decision processes usually masked to experimenters and provide a method for identifying endogenous brain state variability relevant to cognition and behavior.

Highlights

⍰ Brain activity is highly variable.

⍰ We find multiple and distinct stimulus-driven patterns in EEG.

⍰ With changes in decision-making and drift-diffusion parameters.

⍰ These results suggest a new way to identify brain states relevant to behavior.

Graphical Abstract
A Network Pharmacology Approach to Elucidate the Anti-inflammatory Effects of Ellagic Acid
Authors: Hoang Skyler H. , Dao Hue , Lam Emerson My
Published: January 2023

Ellagic acid (EA) is a naturally occurring polyphenolic compound found in various fruits and vegetables like strawberries, raspberries, pomegranates, and nuts such as pecans and walnuts. With its antioxidant properties, EA has shown potential health benefits, although further research is necessary to fully comprehend its effects, mechanisms, and safe and effective application as a complementary medicine. Notably, there is accumulating evidence of EA’s anti-inflammatory effects; however, the precise underlying mechanism remains unclear. To investigate the anti-inflammatory properties of EA, a network pharmacology approach was employed. The study identified 52 inflammation-related targets of EA and revealed significant signaling pathways and relevant diseases associated with inflammation through GO and KEGG analysis. Furthermore, topological analysis identified 10 important targets, including AKT1, VEGFA, TNF, MAPK3, ALB, SELP, MMP9, MMP2, PTGS2, and ICAM1. Molecular docking and molecular dynamics simulations (integrated with were conducted molecular mechanics Poisson-Boltzmann), indicating that AKT1, PTGS2, VEGFA, and MAPK3 are the most likely targets of EA. In summary, this study not only confirmed the anti-inflammatory effects of EA observed in previous research but also identified the most probable targets of EA.
Anthracyclines inhibit SARS-CoV-2 infection
Authors: Wang Zhen , Pan Qinghua , Ma Ling , Zhao Jianyuan , McIntosh Fiona , Liu Zhenlong , Ding Shilei , Lin Rongtuan , Chen Shan , Finzi Andrés , Liang Chen
Published: January 2023

Vaccines and drugs are two effective medical interventions to mitigate SARS-CoV-2 infection. Three SARS-CoV-2 inhibitors, remdesivir, paxlovid, and molnupiravir, have been approved for treating COVID-19 patients, but more are needed, because each drug has its limitation of usage and SARS-CoV-2 constantly develops drug resistance mutations. In addition, SARS-CoV-2 drugs have the potential to be repurposed to inhibit new human coronaviruses, thus help to prepare for future coronavirus outbreaks. We have screened a library of microbial metabolites to discover new SARS-CoV-2 inhibitors. To facilitate this screening effort, we generated a recombinant SARS-CoV-2 Delta variant carrying the nano luciferase as a reporter for measuring viral infection. Six compounds were found to inhibit SARS-CoV-2 at the half maximal inhibitory concentration (IC50) below 1 μM, including the anthracycline drug aclarubicin that markedly reduced viral RNA-dependent RNA polymerase (RdRp)-mediated gene expression, whereas other anthracyclines inhibited SARS-CoV-2 by activating the expression of interferon and antiviral genes. As the most commonly prescribed anti-cancer drugs, anthracyclines hold the promise of becoming new SARS-CoV-2 inhibitors.

IMPORTANCE

Microbial metabolites are a rich source of bioactive molecules. The best examples are antibiotics and immunosuppressants that have transformed the practice of modern medicine and saved millions of lives. Recently, some microbial metabolites were reported to have antiviral activity, including the inhibition of Zika virus and Ebola virus. In this study, we discovered several microbial metabolites that effectively inhibit SARS-CoV-2 infection, including anthracyclines that have also been shown to inhibit other viruses including Ebola virus through enhancing interferon responses, which indicates potentially broad antiviral properties of these microbial metabolites and can lead to the discovery of pan-antiviral molecules.
Uncovering specific mechanisms across cell types in dynamical models
Authors: Hauber Adrian L. , Rosenblatt Marcus , Timmer Jens
Published: January 2023

Ordinary differential equations are frequently employed for mathematical modeling of biological systems. The identification of mechanisms that are specific to certain cell types is crucial for building useful models and to gain insights into the underlying biological processes. Regularization techniques have been proposed and applied to identify mechanisms specific to two cell types, e.g., healthy and cancer cells, including the LASSO (least absolute shrinkage and selection operator). However, when analyzing more than two cell types, these approaches are not consistent, and require the selection of a reference cell type, which can affect the results.

To make the regularization approach applicable to identifying cell-type specific mechanisms in any number of cell types, we propose to incorporate the clustered LASSO into the framework of ordinary differential equation modeling by penalizing the pairwise differences of the logarithmized fold-change parameters encoding a specific mechanism in different cell types. The symmetry introduced by this approach renders the results independent of the reference cell type. We discuss the necessary adaptations of state-of-the-art numerical optimization techniques and the process of model selection for this method. We assess the performance with realistic biological models and synthetic data, and demonstrate that it outperforms existing approaches. Finally, we also exemplify its application to published biological models including experimental data, and link the results to independent biological measurements.

Contact

adrian.hauber@fdm.uni-freiburg.de

Author Summary

Mathematical models enable insights into biological systems beyond what is possible in the wet lab alone. However, constructing useful models can be challenging, since they both need a certain amount of complexity to adequately describe real-world observations, and simultaneously enough simplicity to enable understanding of these observations and precise predictions. Regularization techniques were suggested to tackle this challenge, especially when building models that describe two different types of cells, such as healthy and cancer cells. Typically, both cell types have a large portion of biological mechanisms in common, and the task is to identify the relevant differences that need to be included into the model.

For more than two types of cells, the existing approaches are not readily applicable, because they require defining one of the cell types as reference, which potentially influences the results. In this work, we present a regularization method that is independent from the choice of a reference. We demonstrate its working principle and compare its performance to existing approaches. Since we implemented this method in a freely available software package, it is accessible to a broad range of researchers and will facilitate the construction of useful mathematical models for multiple types of cells.
Galectin-3 and Heart Failure with Preserved Ejection Fraction: Clarifying an Emerging Relationship
Authors: Baccouche Basil M. , Rhodenhiser Emmajane
Published: January 2023

Introduction

HFpEF is one of the leading causes of death whose burden is estimated to expand in the coming decades. This paper examines the relationship between circulating levels of galectin-3, an emerging risk factor for cardiovascular disease, and the clinical diagnosis of HFpEF.

Methods

The authors reviewed peer-reviewed literature and 18 studies met inclusion criteria. Study characteristics, study outcome definitions, assay characteristics, main findings, and measures of association were tabulated and summarized.

Results

Five (1–5) studies found significant associations between galectin-3 and HFpEF diagnosis compared to healthy controls, and one (6) did not. Five studies (7–11) found significant associations between galectin-3 concentration in circulation and severity of diastolic dysfunction. Three studies (12–14) found a statistically significant association between circulating galectin-3 and all-cause mortality or rehospitalization. Two studies (15,16) found levels of circulating galectin-3 to be a statistically significant predictor of later HFpEF onset. Finally, two studies examined whether galectin-3 was associated with incident HFpEF, one (17) found a significant association and the other (18) did not.

Conclusion

Given the paucity of effective therapeutics for HFpEF, galectin-3 shows promise as a possible HFpEF-linked biomarker that may, with further study, inform and predict treatment course to reduce morbidity and mortality.
Intron retention of an adhesion GPCR generates single transmembrane-helix isoforms to enable 7TM-adhesion GPCR function
Authors: Bormann Anne , Körner Marek B. , Dahse Anne-Kristin , Gläser Marie S. , Irmer Johanna , Lede Vera , Alenfelder Judith , Lehmann Joris , Hall Daniella C.N. , Thane Michael , Schleyer Michael , Kostenis Evi , Schöneberg Torsten , Bigl Marina , Langenhan Tobias , Ljaschenko Dmitrij , Scholz Nicole
Published: January 2023

Adhesion G protein-coupled receptors (aGPCR) function as metabotropic mechanosensors in the nervous system and other organs. aGPCR are heavily spliced forecasting an extraordinary molecular structural diversity. Many predicted isoforms lack the transmembrane (7TM) signaling subunit, but to what extent these non-GPCR isoforms are produced and what physiological purpose they serve is unknown. Alternative splicing through intron retention ofADGRL/Latrophilin/CirlmRNA inDrosophilagenerates transcripts encoding unconventional proteins with an extracellular domain anchored by a single transmembrane helix (Cirl1TM). Here, we show thatCirl1TMtranscripts are translatedin vivoand that Cirl1TMbinds Cirl7TMN-terminal fragment-dependently. This interaction enables mechanosensory neurons to distinguish input intensities through Gαo-dependent signaling. Similarly, a direct interaction was found for mammalian GPR126/ADGRG6 isoforms. Together, our findings define intron retention and isoform-specific heteromerization as extraordinary molecular strategies to adjustCirl-dependent mechanosensation and demonstrate physiological relevance of versatile aGPCR isoform repertoire to tune cellular responsiveness.
Pupil dilation scales with movement distance of real but not of imagined reaching movements
Authors: Voudouris Dimitris , Schuetz Immo , Schinke Tabea , Fiehler Katja
Published: January 2023

Pupillary responses have now been reliably identified for cognitive and motor tasks, but less is known about their relation to mentally simulating movements (known as motor imagery). Previous work found pupil dilations during the performance of simple finger movements, where peak pupillary dilation scaled with the complexity of the finger movement and force required. Recently, pupillary dilations were reported during imagery of grasping and piano playing. Here we examined whether pupillary responses are sensitive to the dynamics of the underlying motor task for both executed and imagined reach movements. Participants reached or imagined reaching to one of three targets placed at different distances from a start position. Both executed and imagined movement times scaled with target distance, and they were highly correlated, confirming previous work and suggesting that participants did imagine the respective movement. Increased pupillary dilation was evident during motor execution compared to rest, with stronger dilations for larger movements. Pupil dilations also occurred during motor imagery, however they were generally weaker than during motor execution and they were not influenced by imagined movement distance. Instead, dilations during motor imagery resembled pupil responses obtained during a non-motor imagery task (imagining a previously viewed painting). Our results demonstrate that pupillary responses can reliably capture the dynamics of an executed goal-directed reaching movement, but suggest that pupillary responses during imagined reaching movements reflect general cognitive rather than motor-specific components of the motor imagery process.

New and noteworthy

Pupil size is influenced by the performance of cognitive tasks. Here we demonstrate that pupil size increases during execution and mental simulation of goal-directed reaching movements compared to rest. Pupil dilations scale with movement amplitude only during motor execution, whereas they are similar during motor imagery and a non-motor imagery, cognitive task.
Floral presence and flower identity alter cereal aphid endosymbiont communities on adjacent crops
Authors: Zytynska Sharon E. , Sturm Sarah , Hawes Cathy , Weisser Wolfgang W , Karley Alison
Published: January 2023

Floral plantings adjacent to crops fields can recruit populations of natural enemies by providing flower nectar and non-crop prey to increase natural pest regulation. Observed variation in success rates might be due to changes in the unseen community of protective endosymbionts hosted by many herbivorous insects, which can confer resistance to various specialist natural enemies, e.g. parasitoid wasps. Reduced insect control may occur if highly protective symbiont combinations increase in frequency via selection effects, and this is expected to be stronger in lower diversity systems.

We used a large-scale field trial to analyse the bacterial endosymbiont communities hosted by cereal aphids (Sitobion avenae) collected along transects into strip plots of barley plants managed by either conventional or integrated (including floral field margins and reduced inputs) methods. In addition, we conducted an outdoor pot experiment to analyse endosymbionts inS. avenaeaphids collected on barley plants that were either grown alone or alongside one of three flowering plants, across three time points.

In the field, aphids hosted up to four symbionts. The abundance of aphids and parasitoid wasps was reduced towards the middle of all fields while aphid symbiont species richness and diversity decreased into the field in conventional, but not integrated, field-strips. The proportion of aphids hosting different symbiont combinations varied across cropping systems, with distances into the fields, and were correlated with parasitoid wasp abundances.

In the pot experiment, aphids hosted up to six symbionts. Flower presence increased natural enemy abundance and diversity, and decreased aphid abundance. The proportion of aphids hosting different symbiont combinations varied across the flower treatment and time, and were correlated with varying abundances of the different specialist parasitoid wasp species recruited by different flowers.

Synthesis and applications. Floral plantings and flower identity can have community-wide impacts on the combinations of bacterial endosymbionts hosted by herbivorous insects. Our work highlights the potential of within-season selection for symbiont-mediated pest resistance to natural enemies with biological control impacts. This could be mitigated through increased recruitment of diverse natural enemies by incorporating functional diversity of floral resources into the environment.
Novel reassortments of variation underlie repeated adaptation to whole genome duplication in two outcrossing Arabidopsis species
Authors: Bohutínská Magdalena , Petříková Eliška , Booker Tom R. , Cobo Cristina Vives , Vlček Jakub , Šrámková Gabriela , Poštulková Alžběta , Hojka Jakub , Marhold Karol , Yant Levi , Kolář Filip , Schmickl Roswitha
Published: January 2023

Polyploidy, the result of whole genome duplication (WGD), is widespread across the tree of life and is often associated with speciation or adaptability. It is thought that adaptation in autopolyploids (within-species polyploids) may be facilitated by increased access to genetic variation. This variation may be sourced from gene flow with sister diploids and new access to other tetraploid lineages, as well as from increased mutational targets provided by doubled DNA content. Here we deconstruct the origins of haplotype blocks displaying the strongest selection signals in established, successful autopolyploids,Arabidopsis lyrataandArabidopsis arenosa. We see strong signatures of selection in 17 genes implied in meiosis, cell cycle, and transcription across all four autotetraploid lineages present in our expanded sampling of 983 sequenced genomes. Most prominent in our results is the finding that the tetraploid-characteristic haplotype blocks with the most robust signals of selection were completely absent in diploid sisters. In contrast, the fine-scaled variant mosaics in the tetraploids originated from highly diverse evolutionary sources. These include novel reassortments of trans-specific polymorphism from diploids, new mutations, and tetraploid-specific inter-species hybridization. We speculate that this broad-scale allele acquisition and re-shuffling enabled the autotetraploids to rapidly adapt to the challenges inherent to WGD, and may further promote their adaptation to environmental challenges.

Lay summary

Polyploidy, the result of whole genome duplication, is associated with speciation and adaptation. To fuel their often remarkable adaptations, polyploids may access and maintain adaptive alleles more readily than diploids. Here we identify repeated signals of selection on genes that are thought to mediate adaptation to whole genome duplication in twoArabidopsisspecies. We found that the tetraploid-characteristic haplotype blocks, found in genes exhibiting the most robust signals of selection, were never present in their diploid relatives. Instead, these blocks were made of mosaics forged from multiple allelic sources. We hypothesize that this increased variation helped polyploids to adapt to the process that caused this increase – genome duplication – and may also help them adapt to novel environments.
Microtubule decay is a driver of neuronal ageing and a promising target for intervention
Authors: Okenve-Ramos Pilar , Gosling Rory , Chojnowska-Monga Monika , Gupta Kriti , Shields Samuel , Sanchez-Soriano Natalia
Published: January 2023

Natural ageing is accompanied by a decline in motor, sensory and cognitive functions, all impacting life quality. Ageing is the predominant risk factor for many neurodegenerative diseases, including Parkinson’s and Alzheimer’s disease. We need therefore to gain a better understanding of the cellular and physiological processes underlying age-related neuronal decay. However, gaining this understanding is a slow process due to the long time required to age mammalian or vertebrate model animals.

Here we introduce a new cellular model within theDrosophilabrain where neurons show typical ageing hallmarks known from the primate brain, including axonal swellings, cytoskeletal decay, a reduction in axonal calibre and morphological changes arising at synaptic terminals. In the fly brain, these changes occur within just a few weeks, ideal to study the underlying mechanisms. We observe that decay of the neuronal microtubule cytoskeleton clearly precedes other ageing hallmarks. We show that the microtubule-binding factors Tau, EB1 and Shot, are necessary for microtubule maintenance in axons and synapses. Their functional loss during ageing triggers microtubule bundle decay followed by the decline in axons and synapses. Genetic manipulations that improve microtubule networks, slow down other neuronal ageing hallmarks and confer aged specimens with the ability to outperform age-matched controls. Our work suggests therefore that microtubule networks are a key lesion site in ageing neurons and offer promising opportunities to improve neuronal decay in advanced age.
Inferring membrane properties during clathrin-mediated endocytosis using machine learning
Authors: Lin Zhiwei , Mao Zhiping , Ma Rui
Published: January 2023

Endocytosis is a fundamental cellular process for eukaryotic cells to transport molecules into the cell. To understand the molecular mechanisms behind the process, researchers have obtained abundant biochemical information about the protein dynamics involved in endocytosis via fluorescence microscopy and geometric information about membrane shapes via electron tomography. However, measuring the biophysical information, such as the osmotic pressure and the membrane tension, remains a problem due to the small dimension of the endocytic invagination. In this work, we combine Machine Learning and Helfrich model of the membrane, as well as the dataset of membrane shapes extracted from the electron tomography to infer biophysical information about endocytosis. Our results show that Machine Learning is able to find solutions that both match the experimental profile and fulfill the membrane shape equations. Furthermore, we show that at the early stage of endocytosis, the inferred membrane tension is negative, which implies strong compressive forces acting at the boundary of the endocytic invagination. This method provides a generic framework to extract membrane information from the super-resolution imaging.

SIGNIFICANCE

Endocytosis is a fundamental cellular process that has been extensively studied with the help of fluorescence microscopy and electron microscopy. A large amount of data has been accumulated about the protein dynamics and the membrane shapes. In this work, we combine the widely used Helfrich model and experimental data of membrane shapes to infer the physical information about endocytosis, including the membrane tension and the osmotic pressure. Our work not only proves Machine Learning as a power tool is able to solve the complicated membrane shape equations, but also provides novel biological insights about the initiation of endocytosis in yeast cells.