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Plant Biotechnology Journal Jun 2024Isoxaben is a pre-emergent herbicide used to control broadleaf weeds. While the phytotoxic mechanism is not completely understood, isoxaben interferes with cellulose...
Isoxaben is a pre-emergent herbicide used to control broadleaf weeds. While the phytotoxic mechanism is not completely understood, isoxaben interferes with cellulose synthesis. Certain mutations in cellulose synthase complex proteins can confer isoxaben tolerance; however, these mutations can cause compromised cellulose synthesis and perturbed plant growth, rendering them unsuitable as herbicide tolerance traits. We conducted a genetic screen to identify new genes associated with isoxaben tolerance by screening a selection of Arabidopsis thaliana T-DNA mutants. We found that mutations in a FERREDOXIN-NADP(+) OXIDOREDUCTASE-LIKE (FNRL) gene enhanced tolerance to isoxaben, exhibited as a reduction in primary root stunting, reactive oxygen species accumulation and ectopic lignification. The fnrl mutant did not exhibit a reduction in cellulose levels following exposure to isoxaben, indicating that FNRL operates upstream of isoxaben-induced cellulose inhibition. In line with these results, transcriptomic analysis revealed a highly reduced response to isoxaben treatment in fnrl mutant roots. The fnrl mutants displayed constitutively induced mitochondrial retrograde signalling, and the observed isoxaben tolerance is partially dependent on the transcription factor ANAC017, a key regulator of mitochondrial retrograde signalling. Moreover, FNRL is highly conserved across all plant lineages, implying conservation of its function. Notably, fnrl mutants did not show a growth penalty in shoots, making FNRL a promising target for biotechnological applications in breeding isoxaben tolerance in crops.
PubMed: 38935864
DOI: 10.1111/pbi.14421 -
Emerging Microbes & Infections Dec 2024Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral...
Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral therapy (ART). To address this gap, we developed an HLA-mismatched allogeneic adoptive immune therapy (AAIT) specifically targeting this patient population. The safety and efficacy of this novel therapeutic approach were preliminarily confirmed in our phase 1 trial. Subsequently, a multicenter, open-label, controlled, phase 2a trial was conducted to evaluate the efficacy of AAIT in combination with ART compared with the conventional ART-only regimen. No difference in the incidence of adverse events (AEs) was observed between the two groups at the 96-week follow-up. AAIT treatment improved CD4+ T cell recovery at weeks 72 (= 0.048) and 96 (= 0.024) compared to the Control Group. Additionally, stratified analysis of patients in the AAIT Group showed that donor/recipient sex mismatch was significantly associated with the likelihood of patients achieving an immunological response (OR = 8.667; 95% CI, 2.010-37.377; = 0.004). These findings suggest that AAIT serves as a promising adjunct therapy for improving the outcomes of patients with severely immunosuppressed AIDS. Further studies are needed to elucidate the immunological mechanisms underlying AAIT and identify the subpopulations that respond optimally to this therapeutic approach. This trial is registered at www.clinicaltrials.gov (NCT04098770). ClinicalTrials.gov identifier: NCT04098770. ClinicalTrials.gov identifier: NCT02651376.
Topics: Humans; Male; Female; Adult; Middle Aged; Immunotherapy, Adoptive; Immunocompromised Host; HLA Antigens; Acquired Immunodeficiency Syndrome; Treatment Outcome; AIDS-Related Opportunistic Infections; Transplantation, Homologous; CD4-Positive T-Lymphocytes; CD4 Lymphocyte Count
PubMed: 38935839
DOI: 10.1080/22221751.2024.2364744 -
PLoS Computational Biology Jun 2024Therapeutic interventions are designed to perturb the function of a biological system. However, there are many types of proteins that cannot be targeted with...
Therapeutic interventions are designed to perturb the function of a biological system. However, there are many types of proteins that cannot be targeted with conventional small molecule drugs. Accordingly, many identified gene-regulatory drivers and downstream effectors are currently undruggable. Drivers and effectors are often connected by druggable signaling and regulatory intermediates. Methods to identify druggable intermediates therefore have general value in expanding the set of targets available for hypothesis-driven validation. Here we identify and prioritize potential druggable intermediates by developing a network perturbation theory, termed NetPert, for response functions of biological networks. Dynamics are defined by a network structure in which vertices represent genes and proteins, and edges represent gene-regulatory interactions and protein-protein interactions. Perturbation theory for network dynamics prioritizes targets that interfere with signaling from driver to response genes. Applications to organoid models for metastatic breast cancer demonstrate the ability of this mathematical framework to identify and prioritize druggable intermediates. While the short-time limit of the perturbation theory resembles betweenness centrality, NetPert is superior in generating target rankings that correlate with previous wet-lab assays and are more robust to incomplete or noisy network data. NetPert also performs better than a related graph diffusion approach. Wet-lab assays demonstrate that drugs for targets identified by NetPert, including targets that are not themselves differentially expressed, are active in suppressing additional metastatic phenotypes.
PubMed: 38935814
DOI: 10.1371/journal.pcbi.1012195 -
PLoS Genetics Jun 2024Sperm heads contain not only the nucleus but also the acrosome which is a distinctive cap-like structure located anterior to the nucleus and is derived from the Golgi...
Sperm heads contain not only the nucleus but also the acrosome which is a distinctive cap-like structure located anterior to the nucleus and is derived from the Golgi apparatus. The Golgi Associated RAB2 Interactors (GARINs; also known as FAM71) protein family shows predominant expression in the testis and all possess a RAB2-binding domain which confers binding affinity to RAB2, a small GTPase that is responsible for membrane transport and vesicle trafficking. Our previous study showed that GARIN1A and GARIN1B are important for acrosome biogenesis and that GARIN1B is indispensable for male fertility in mice. Here, we generated KO mice of other Garins, namely Garin2, Garin3, Garin4, Garin5a, and Garin5b (Garin2-5b). Using computer-assisted morphological analysis, we found that the loss of each Garin2-5b resulted in aberrant sperm head morphogenesis. While the fertilities of Garin2-/- and Garin4-/- males are normal, Garin5a-/- and Garin5b-/- males are subfertile, and Garin3-/- males are infertile. Further analysis revealed that Garin3-/- males exhibited abnormal acrosomal morphology, but not as severely as Garin1b-/- males; instead, the amounts of membrane proteins, particularly ADAM family proteins, decreased in Garin3 KO spermatozoa. Moreover, only Garin4 KO mice exhibit vacuoles in the sperm head. These results indicate that GARINs assure correct head morphogenesis and some members of the GARIN family function distinctively in male fertility.
PubMed: 38935810
DOI: 10.1371/journal.pgen.1011337 -
PloS One 2024Highlighting minorities and crime survivors through public discourse is essential for their support and protection. However, advocating for minorities is challenging due...
Highlighting minorities and crime survivors through public discourse is essential for their support and protection. However, advocating for minorities is challenging due to the fear of potential isolation from one's social circles. This reluctance contributes to the societal phenomenon known as the "spiral of silence," significantly impeding efforts to support socially vulnerable individuals. This study centers on a pivotal instance where the silence surrounding sexual abuse in the Japanese entertainment industry was disrupted, in which the late company president had allegedly abused idol trainees of the company for decades. Utilizing extensive data from news media and social media, the study probes the engagement dynamics of public attention to this scandal. Results indicate that users on social media provided earlier and greater coverage for this scandal compared to news media outlets. Furthermore, television demonstrated a significant delay in addressing this issue compared to other news media, such as tabloids, magazines, and online news. Regarding social media engagement, idol fans exhibited a more subdued response to the issue compared to the general public. Notably, fans more loyal to the company tended to be slower to mention the issue, with a higher likelihood of standing in defense of the perpetrators. Moreover, conflicting attitudes were observed within the fan communities, culminating in an observable "echo chamber" phenomenon. This paper presents a novel examination of the process of disruption of social silence and offers critical insights for aiding vulnerable individuals in environments dominated by an unacknowledged spiral of silence. This study is novel in that it suggests a reinterpretation of the "spiral of silence theory" in the age of social media, through a comprehensive analysis of relevant social media data and news media data. This contributes to the body of research that has analyzed the spiral of silence theory online.
Topics: Humans; Social Media; Japan; Sex Offenses; Mass Media; Industry; Female; East Asian People
PubMed: 38935809
DOI: 10.1371/journal.pone.0306104 -
PLoS Pathogens Jun 2024The bloodstream form of Trypanosoma brucei expresses large poly-N-acetyllactosamine (pNAL) chains on complex N-glycans of a subset of glycoproteins. It has been...
The bloodstream form of Trypanosoma brucei expresses large poly-N-acetyllactosamine (pNAL) chains on complex N-glycans of a subset of glycoproteins. It has been hypothesised that pNAL may be required for receptor-mediated endocytosis. African trypanosomes contain a unique family of glycosyltransferases, the GT67 family. Two of these, TbGT10 and TbGT8, have been shown to be involved in pNAL biosynthesis in bloodstream form Trypanosoma brucei, raising the possibility that deleting both enzymes simultaneously might abolish pNAL biosynthesis and provide clues to pNAL function and/or essentiality. In this paper, we describe the creation of a TbGT10 null mutant containing a single TbGT8 allele that can be excised upon the addition of rapamycin and, from that, a TbGT10 and TbGT8 double null mutant. These mutants were analysed by lectin blotting, glycopeptide methylation linkage analysis and flow cytometry. The data show that the mutants are defective, but not abrogated, in pNAL synthesis, suggesting that other GT67 family members can compensate to some degree for loss of TbGT10 and TbGT8. Despite there being residual pNAL synthesis in these mutants, certain glycoproteins appear to be particularly affected. These include the lysosomal CBP1B serine carboxypeptidase, cell surface ESAG2 and the ESAG6 subunit of the essential parasite transferrin receptor (TfR). The pNAL deficient TfR in the mutants continued to function normally with respect to protein stability, transferrin binding, receptor mediated endocytosis of transferrin and subcellular localisation. Further the pNAL deficient mutants were as viable as wild type parasites in vitro and in in vivo mouse infection experiments. Although we were able to reproduce the inhibition of transferrin uptake with high concentrations of pNAL structural analogues (N-acetylchito-oligosaccharides), this effect disappeared at lower concentrations that still inhibited tomato lectin uptake, i.e., at concentrations able to outcompete lectin-pNAL binding. Based on these findings, we recommend revision of the pNAL-dependent receptor mediated endocytosis hypothesis.
PubMed: 38935804
DOI: 10.1371/journal.ppat.1012333 -
PLoS Computational Biology Jun 2024Spatial transcriptomics has gained popularity over the past decade due to its ability to evaluate transcriptome data while preserving spatial information. Cell...
Spatial transcriptomics has gained popularity over the past decade due to its ability to evaluate transcriptome data while preserving spatial information. Cell segmentation is a crucial step in spatial transcriptomic analysis, as it enables the avoidance of unpredictable tissue disentanglement steps. Although high-quality cell segmentation algorithms can aid in the extraction of valuable data, traditional methods are frequently non-spatial, do not account for spatial information efficiently, and perform poorly when confronted with the problem of spatial transcriptome cell segmentation with varying shapes. In this study, we propose ST-CellSeg, an image-based machine learning method for spatial transcriptomics that uses manifold for cell segmentation and is novel in its consideration of multi-scale information. We first construct a fully connected graph which acts as a spatial transcriptomic manifold. Using multi-scale data, we then determine the low-dimensional spatial probability distribution representation for cell segmentation. Using the adjusted Rand index (ARI), normalized mutual information (NMI), and Silhouette coefficient (SC) as model performance measures, the proposed algorithm significantly outperforms baseline models in selected datasets and is efficient in computational complexity.
PubMed: 38935799
DOI: 10.1371/journal.pcbi.1012254 -
PloS One 2024The elderly is commonly susceptible to depression, the symptoms for which may overlap with natural aging or other illnesses, and therefore miss being captured by routine...
BACKGROUND
The elderly is commonly susceptible to depression, the symptoms for which may overlap with natural aging or other illnesses, and therefore miss being captured by routine screening questionnaires. Passive sensing data have been promoted as a tool for depressive symptoms detection though there is still limited evidence on its usage in the elderly. Therefore, this study aims to review current knowledge on the use of passive sensing data via smartphones and smartwatches in depressive symptom screening for the elderly.
METHOD
The search of literature was performed in PubMed, IEEE Xplore digital library, and PsycINFO. Literature investigating the use of passive sensing data to screen, monitor, and/or predict depressive symptoms in the elderly (aged 60 and above) via smartphones and/or wrist-worn wearables was included for initial screening. Studies in English from international journals published between January 2012 to September 2022 were included. The reviewed studies were further analyzed by a narrative analysis.
RESULTS
The majority of 21 included studies were conducted in Western countries with a few in Asia and Australia. Most studies adopted a cohort study design (n = 12), followed by cross-sectional design (n = 7) and a case-control design (n = 2). The most popular passive sensing data was related to sleep and physical activity using an actigraphy. Sleep characteristics, such as prolonged wakefulness after sleep onset, along with lower levels of physical activity, exhibited a significant association with depression. However, cohort studies expressed concerns regarding data quality stemming from incomplete follow-up and potential confounding effects.
CONCLUSION
Passive sensing data, such as sleep, and physical activity parameters should be promoted for depressive symptoms detection. However, the validity, reliability, feasibility, and privacy concerns still need further exploration.
Topics: Humans; Smartphone; Depression; Aged; Mass Screening; Wearable Electronic Devices; Sleep; Middle Aged; Exercise; Female
PubMed: 38935797
DOI: 10.1371/journal.pone.0304845 -
PloS One 2024Chronic enteropathies are a common cause of morbidity in dogs and are associated with disruption of the normal gastrointestinal mucosal barrier. The objective of this...
Chronic enteropathies are a common cause of morbidity in dogs and are associated with disruption of the normal gastrointestinal mucosal barrier. The objective of this prospective study was to determine the association between measures of gastrointestinal dysbiosis and plasma concentrations of glucagon-like peptide-2, a hormone responsible for normal mucosal structure, in dogs with chronic enteropathies. Fecal 16S V4 rRNA gene sequencing and quantitative PCR via the dysbiosis index was performed on 16 healthy controls and 18 dogs with chronic enteropathy prior to and 1 month after initiation of individualized therapy. Fasting and post-prandial plasma GLP-2 concentrations were measured via ELISA in healthy dogs and chronic enteropathy dogs at both time points. Alpha and beta diversity indices, as well as bacterial population abundances were compared between groups and time-points. Principal component analysis combined with least squares regression was used to identify taxa contributing to glucagon-like peptide-2 variance among groups. While the dysbiosis index did not differ between healthy dogs and dogs with chronic enteropathy, 16S V4 genomic sequencing identified 47 operational taxonomic units that differed between the groups, all but 2 of which resolved following chronic enteropathy treatment. Principal component analysis identified 6 families and 19 genera that contributed to differences in glucagon-like peptide-2 concentrations between groups. Dysbiosis associated with chronic enteropathies in dogs may contribute to the observed lower plasma glucagon-like peptide-2 concentrations. Further research into mechanisms of microbiota impact on the enteroendocrine system is needed. Association between glucagon-like peptide-2 secretion and microbiome indices may help to guide research into future treatment strategies for dogs with chronic enteropathy.
Topics: Dogs; Animals; Glucagon-Like Peptide 2; Dysbiosis; Dog Diseases; Female; Male; Gastrointestinal Microbiome; Chronic Disease; Prospective Studies; Feces; RNA, Ribosomal, 16S; Intestinal Diseases
PubMed: 38935795
DOI: 10.1371/journal.pone.0305711 -
PloS One 2024Health technology assessment uses a multidisciplinary approach to support health benefits package design towards universal health coverage. The evidence-informed... (Review)
Review
Health technology assessment for sexual reproductive health and rights benefits package design in sub-Saharan Africa: A scoping review of evidence-informed deliberative processes.
BACKGROUND
Health technology assessment uses a multidisciplinary approach to support health benefits package design towards universal health coverage. The evidence-informed deliberative process framework has been used alongside Health technology assessment to enhance stakeholder participation and deliberations in health benefits package design. Applying the evidence-informed deliberative framework for Health assessment could support the morally diverse sexual reproductive health and rights (SRHR) benefits package design process. However, evidence on participation and deliberations for stakeholders in health technology assessment for SRHR benefits package design has not been curated in sub-Saharan Africa. This study synthesises literature to fill this gap.
METHODS
This scoping review applies the preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews, and deductive analysis following the evidence-informed deliberative processes framework. The search strategy uses the Guttmacher-Lancet Commission-proposed comprehensive definition of SRHR and the World Health Organisation's universal health coverage compendium of SRHR interventions to generate search terms. Six databases and biographical hand searches were used to identify studies in Sub-Saharan Africa from 1994.
RESULTS
A total of 14 studies met the inclusion criteria. Evidence for yearly public budgets and explicit SRHR health technology assessment processes was not found. In 12 of the studies reviewed, new advisory committees were set up specifically for health technology assessment for SRHR priority-setting and benefits package design. In all decision-making processes reviewed, the committee member roles, participation and deliberations processes, and stakeholder veto powers were not clearly defined. Patients, the public, and producers of health technology were often excluded in the health technology assessment for the SRHR benefits package design. Most health technology assessment processes identified at least one decision-making criterion but failed to use this in their selection and appraisal stages for SRHR benefits design. The identification, selection, and scoping stages in health technology assessment for SRHR were non-existent in most studies. In 11 of the 14 processes of the included studies, stakeholders were dissatisfied with the health policy recommendation from the appraisal process in health technology assessment. Perceived benefits for evidence-informed deliberative processes included increased stakeholder engagement and fairness in decision-making.
CONCLUSION
To support the integration of diverse social values in health technology assessment for fairer SRHR benefits package design, evidence from this review suggests the need to institutionalise health technology assessment, establish prioritisation decision criteria, involve all relevant stakeholders, and standardise the process and assessment methodological approaches.
Topics: Africa South of the Sahara; Humans; Technology Assessment, Biomedical; Reproductive Health; Sexual Health
PubMed: 38935794
DOI: 10.1371/journal.pone.0306042