Miracle-dz/UniFAR-FTUs huggingface dataset:
GARP dysfunction results in COPI displacement, depletion of Golgi v-SNAREs and calcium homeostasis proteins

Golgi-associated retrograde protein (GARP) is an evolutionary conserved heterotetrameric protein complex that tethers endosome-derived vesicles and is vital for Golgi glycosylation. Microscopy and proteomic approaches were employed to investigate defects in Golgi physiology in RPE1 cells depleted for the GARP complex. Both cis and trans-Golgi compartments were significantly enlarged in GARP-knock-out (KO) cells. Proteomic analysis of Golgi-enriched membranes revealed significant depletion of a subset of Golgi residents, including Ca2+ binding proteins, enzymes, and SNAREs. Validation of proteomics studies revealed that SDF4 and ATP2C1, related to Golgi calcium homeostasis, as well as intra-Golgi v-SNAREs GOSR1 and BET1L, were significantly depleted in GARP-KO cells. Finding that GARP-KO is more deleterious to Golgi physiology than deletion of GARP-sensitive v-SNAREs, prompted a detailed investigation of COPI trafficking machinery. We discovered that in GARP-KO cells COPI is significantly displaced from the Golgi and partially relocalized to the ER-Golgi intermediate compartment (ERGIC). Moreover, COPI accessory proteins GOLPH3, ARFGAP1, GBF1, and BIG1 are also relocated to off-Golgi compartments. We propose that the dysregulation of COPI machinery, along with the depletion of Golgi v-SNAREs and alteration of Golgi Ca2+ homeostasis, are the major driving factors for the depletion of Golgi resident proteins, structural alterations, and glycosylation defects in GARP deficient cells.
Cell cycle block by p53 activation reduces SARS-CoV-2 release in infected alveolar basal epithelial A549-hACE2 cells

SARS-CoV viruses have been shown to downregulate cellular events that control antiviral defenses. They adopt several strategies to silence p53, key molecule for cell homeostasis and immune control, indicating that p53 has a central role in controlling their proliferation in the host. Specific actions are the stabilization of its inhibitor, MDM2, and the interference with its transcriptional activity. The aim of our work was to evaluate a new approach against SARS-CoV-2 by using MDM2 inhibitors to raise p53 levels and activate p53-dependent pathways, therefore leading to cell cycle inhibition. Experimental setting was performed in the alveolar basal epithelial cell line A549-hACE2, expressing high level of ACE2 receptor, to allow virus entry, as well as p53 wild-type. Cells were treated with several concentrations of Nutlin-3 or RG-7112, two known MDM2 inhibitors, for the instauration of a cell cycle block steady-state condition before and during SARS-CoV-2 infection, and for the evaluation of p53 activation and impact on virus release and related innate immune events. The results indicated an efficient cell cycle block with inhibition of the virion release and a significant inhibition of IL-6, NF-kB and IFN-λ expression. These data suggest that p53 is an efficient target for new therapies against the virus and that MDM2 inhibitors deserve to be further investigated in this field.
Novel potential biomarkers for severe alcoholic liver disease

Background Alcoholic liver disease (ALD) is a leading cause of advanced liver disease; however, minor clinical symptoms in the early stage frequently result in delayed diagnosis and therapy. Invasive liver biopsy, the gold standard for diagnosing ALD, is unsuitable for repetitive analysis. This study aims to identify potential serum biomarkers that could contribute to non-invasive disease screening and monitoring. Methods Label-free LC-MS/MS quantitative proteomics analysis was performed to identify differentially expressed proteins in the discovery cohort, followed by bioinformatics analysis based on the KEGG, GO, and String databases. Prioritized proteins were validated subsequently by quantitative assays. The area under the receiver operating characteristic curve (AUROC) was used to assess the diagnosis performance of potential biomarkers. Results A total of 161 differentially expressed proteins were identified in the discovery cohort, of which 123 were up-regulated and 38 were down-regulated. B2M, IGFALS, and IGFBP3 were evaluated, and all demonstrated excellent diagnosis performance with AUROCs of over 0.9 when distinguishing patients with severe ALD from healthy controls. The AUROC values of B2M, IGFBP3, and IGFALS were 0.7131, 0.8877, and 0.9896 for differentiating severe ALD from non-severe ALD to indicate disease severity. B2M could distinguish patients with non-severe ALD and HC participants with an AUROC value of 0.8985. The efficiency of multiple combinations of these biomarkers was superior to that of the existing liver fibrosis evaluation indices used to monitor disease progression, with AUROC values of over 0.9. IGFALS showed a positive correlation with ALT/AST (r=0.4648, P=0.0009) and may be developed as a therapeutic target. Conclusion This proteomic study identified three novel candidate proteins as promising circulating biomarkers for clinical diagnosis and disease progression and also provided the proteomic atlas for ALD pathophysiological mechanisms.
Physio-biochemical and molecular stress regulators and their crosstalk for low-temperature stress responses in fruit crops: A review

Low-temperature stress (LTS) drastically affects vegetative and reproductive growth in fruit crops leading to a gross reduction in the yield and loss in product quality. Among the fruit crops, temperate fruits, during the period of evolution, have developed the mechanism of tolerance, i.e., adaptive capability to chilling and freezing when exposed to LTS. However, tropical and sub-tropical fruit crops are most vulnerable to LTS. As a result, fruit crops respond to LTS by inducing the expression of LTS related genes, which is for climatic acclimatization. The activation of the stress-responsive gene leads to changes in physiological and biochemical mechanisms such as photosynthesis, chlorophyll biosynthesis, respiration, membrane composition changes, alteration in protein synthesis, increased antioxidant activity, altered levels of metabolites, and signaling pathways that enhance their tolerance/resistance and alleviate the damage caused due to LTS and chilling injury. The gene induction mechanism has been investigated extensively in the model crop Arabidopsis and several winter kinds of cereal. The ICE1 (inducer of C-repeat binding factor expression 1) and the CBF (C-repeat binding factor) transcriptional cascade are involved in transcriptional control. The functions of various CBFs and aquaporin genes were well studied in crop plants and their role in multiple stresses including cold stresses is deciphered. In addition, tissue nutrients and plant growth regulators like ABA, ethylene, jasmonic acid etc., also play a significant role in alleviating the LTS and chilling injury in fruit crops. However, these physiological, biochemical and molecular understanding of LTS tolerance/resistance are restricted to few of the temperate and tropical fruit crops. Therefore, a better understanding of cold tolerance’s underlying physio-biochemical and molecular components in fruit crops is required under open and simulated LTS. The understanding of LTS tolerance/resistance mechanism will lay the foundation for tailoring the novel fruit genotypes for successful crop production under erratic weather conditions.
Host tree species effects on long-term persistence of epiphytic orchid populations

The destinies of epiphytic orchids (about 70% of all orchids) are linked to their host trees. However, there is little information on if differences in host trees characteristics can affect the long-term persistence of orchid populations, and how this might vary under different climatic conditions. We compared the population dynamics of two epiphytic orchid species, Alamania punicea and Oncidium brachyandrum growing on two host trees with contrasting leaf phenologies: the deciduous Quercus martinezii and the semideciduous Q. rugosa, over 3 years with varying levels of rainfall, in a montane tropical oak forest in Oaxaca, Mexico. Using data from > 500 individuals growing on 63 host trees, we applied linear mixed effects models, Integral Projection Models, and Life Table Response Experiments to identify the effects of host tree on orchid vital rates and population growth rates. For both orchid species, survival and growth did not differ between host species during wettest year. However, during the driest year both vital rates were higher on the semi-deciduous host Q. rugosa than on the deciduous Q. martinezii. Host species did not affect fecundity for A. punicea, but for O. brachyandrum fecundity was higher on the deciduous host. For A. punicea, λ values were similar between hosts during the wettest and intermediate years, but significantly lower (Δ λ = 0.28) on the deciduous than on the semi-deciduous host during the driest year. This was due primarily to lower survival on the deciduous host. For O. brachyandrum, λ was slightly higher (Δ λ = 0.03) on the deciduous than the semideciduous host during the wettest year, due to higher growth and reproduction. However, during the intermediate and driest years, λ values were significantly higher on the semi-deciduous than on the deciduous host (Δ λ = 0.13 and 0.15, respectively). This was due to higher survival and growth. A. punicea populations appear more vulnerable to dry conditions than O. brachyandrum, likely due to its smaller pseudobulbs, and hence lower water-storing capacity. Our results show that host tree species can both influence the vital rates and the long-term dynamics of orchid populations, and these effects vary across orchids species and over time. Our results highlight the importance of maintaining a diversity of host trees to ensure long-term population persistence.
Co-exposures to physical and psychosocial work factors increase the occurrence of workplace injuries among French care workers

Objective The aim of this study was to analyze the effect of co-exposures to physical and psychosocial factors (PSF) regarding the incidence of workplace injuries (WI) among care workers. Additional objective was to identify the work factors associated with the co-exposure combinations leading to the highest rates of WI. Methods The study sample consisted of 4,418 care workers participating to the French Working Conditions Survey both in 2013 and 2016. WI were assessed during the 4-year follow-up by matching the databases of the National Health Insurance Funds' compensation system. We assessed exposure for physical factors and PSF using factorial analyses and hierarchical clustering. We implemented a Poisson regression model with the WI incidence as the outcome and the clusters as independent variables of interest. Logistic regression model allowed identifying the work factors that predicted co-exposure combinations with a WI rate > 40%. Results WI were highly related to both physical and psychosocial exposures. With low exposure to one or the other, there was no increased risk of WI. Physical factors and PSF potentiated each other and their co-exposure significantly increased the risk of WI, with model predicted rates per 1,000 persons-year for those most exposed to physical risk of 14.6 [4.5–24.8] with low PSF and 38.0 [29.8–46.3] with high PSF. Work factors that predicted co-exposure combinations with a rate > 40 WI% were: working as nursing assistant or hospital services officer, lack of predictability and flexibility of schedules, overtime, controlled schedules, work-family imbalance and insufficient preventive measures. Conclusions Our findings highlight the need to take into account psychosocial factors in addition of only considering physical factors when analyzing WI occurrence, as usually done. Prevention actions must be taken to reduce both physical and psychosocial exposure. These results provide keys points for the prevention of WI among care workers.
Toward a personalized closed-loop stimulation of the visual cortex: Advances and challenges

Current cortical visual prosthesis approaches are primarily unidirectional and do not consider the feed-back circuits that exist in just about every part of the nervous system. Herein, we provide a brief overview of some recent developments for better controlling brain stimulation and present preliminary human data indicating that closed-loop strategies could considerably enhance the effectiveness, safety, and long-term stability of visual cortex stimulation. We propose that the development of improved closed-loop strategies may help to enhance our capacity to communicate with the brain.
Synapse integrity and function: Dependence on protein synthesis and identification of potential failure points

Synaptic integrity and function depend on myriad proteins - labile molecules with finite lifetimes that need to be continually replaced with freshly synthesized copies. Here we describe experiments designed to expose synaptic (and neuronal) properties and functions that are particularly sensitive to disruptions in protein supply, identify proteins lost early upon such disruptions, and uncover potential, yet currently underappreciated failure points. We report here that acute suppressions of protein synthesis are followed within hours by reductions in spontaneous network activity levels, impaired oxidative phosphorylation and mitochondrial function, and, importantly, destabilization and loss of both excitatory and inhibitory postsynaptic specializations. Conversely, gross impairments in presynaptic vesicle recycling occur over longer time scales (days), as does overt cell death. Proteomic analysis identified groups of potentially essential ‘early-lost’ proteins including regulators of synapse stability, proteins related to bioenergetics, fatty acid and lipid metabolism, and, unexpectedly, numerous proteins involved in Alzheimer’s disease pathology and amyloid beta processing. Collectively, these findings point to neuronal excitability, energy supply and synaptic stability as early-occurring failure points under conditions of compromised supply of newly synthesized protein copies.
Evaluation of the non-auditory neurocognitive test MoCA-HI for hearing-impaired

Background Since hearing loss and cognitive decline often co-occur among older adults, a cognitive screening test suitable for hearing-impaired people is of high clinical relevance. We report the first evaluation of a German language version of the Montreal Cognitive Assessment—Hearing Impaired version (MoCA-HI). Objective The aim of the present study was to compare cognitively healthy participants with and without hearing loss, to examine the impact of age, sex, educational level and degree of hearing impairment on the German MoCA-HI performance, and to develop normative data. Material and methods The German MoCA-HI was tested in 94 participants with normal or mild hearing impairment (group 1: 4PTA ≤ 40 dB on the better hearing ear) and 81 participants with moderate to profound hearing loss (group 2: 4PTA > 40 dB on the better hearing ear). Additionally, all participants performed the standard MoCA (version 8.2). Results No significant group difference between group 1 and 2 was found in the MoCA-HI total score (p = 0.05). In contrast, group 1 performed significantly better than group 2 on the standard MoCA (p < 0.001). There was no difference between the MoCA and the MoCA-HI performance in group 1 (p = 0.12), whereas individuals of group 2 performed significantly better on the MoCA-HI than on the standard MoCA (p < 0.001). Test-retest reliability of the MoCA-HI was high (p < 0.001). Higher age (p < 0.001), male sex (p = 0.009) and lower education (p < 0.001) were associated with a lower overall MoCA-HI score. Based on the demographic data normative data were developed by a regression-based approach. Conclusion The MoCA-HI is a cognitive screening test which is suitable for people with hearing impairment.
Cancer organoid applications to investigate chemotherapy resistance

In clinical practice, a large proportion of cancer patients receive chemotherapy, yet tumors persist or acquire resistance; removing this obstacle could help to lower the number of cancer-related fatalities. All areas of cancer research are increasingly using organoid technology, a culture technique that simulates the in vivo environment in vitro, especially in the quickly developing fields of anticancer drug resistance, drug-tolerant persisters, and drug screening. This review provides an overview of organoid technology, the use of organoids in the field of anticancer drug resistance research, their relevance to clinical information and clinical trials, and approaches to automation and high throughput.
Frequency of Vitamin a Deficiency in Children Hospitalized for Pneumonia: An Integrative Review

Objective: To identify the frequency of vitamin A deficiency in children aged 6 months to 5 years hospitalized for pneumonia. Methods: An integrative literature review was carried out, where searches were made by two independent researchers, with no language limits or publication time in the databases PubMed, LILACS, Web of Science, Scopus and CINAHL, and in the gray literature—OpenGrey, Proquest and Google Scholar. In the eligibility phase, the screened studies were read in full and those that did not answer the research question were excluded. Methodological quality was assessed using the Downs & Black (1998) checklist. Results: 1642 articles were identified, after all stages of screening and selection, 10 studies were included, of which 5 were longitudinal, 4 were intervention and 1 transversal. All studies identified subclinical vitamin A deficiency in children hospitalized with pneumonia; the highest frequency of subclinical vitamin A deficiency was 93.2%. All studies evaluated showed frequencies of subclinical vitamin A deficiency >20%. Conclusion: There is a high frequency of subclinical vitamin A deficiency in children with pneumonia; these data need to be further explored in terms of their associations. For this reason, new studies that evaluate this topic are of fundamental importance.
Diversity and adaptation properties of actinobacteria associated with Tunisian stone ruins

Stone surface is a unique biological niche that may host a rich microbial diversity. The exploration of the biodiversity of the stone microbiome represents a major challenge and an opportunity to characterize new strains equipped with valuable biological activity. Here, we explored the diversity and adaptation strategies of total bacterial communities associated with Roman stone ruins in Tunisia by considering the effects of geo-climatic regions and stone geochemistry. Environmental 16S rRNA gene amplicon was performed on DNA extracted from stones samples collected in three different sampling sites in Tunisia, along an almost 400km aridity transect, encompassing Mediterranean, semiarid and arid climates. The library was sequenced on an Illumina MiSeq sequencing platform. The cultivable Actinobacteria were isolated from stones samples using the dilution plate technique. A total of 71 strains were isolated and identified based on 16S rRNA gene sequences. Cultivable actinobacteria were further investigated to evaluate the adaptative strategies adopted to survive in/on stones. Amplicon sequencing showed that stone ruins bacterial communities were consistently dominated by Cyanobacteria, followed by Proteobacteria and Actinobacteria along the aridity gradient. However, the relative abundance of the bacterial community components changed according to the geo-climatic origin. Stone geochemistry, particularly the availability of magnesium, chromium, and copper, also influenced the bacterial communities’ diversity. Cultivable actinobacteria were further investigated to evaluate the adaptative strategies adopted to survive in/on stones. All the cultivated bacteria belonged to the Actinobacteria class, and the most abundant genera were Streptomyces, Kocuria and Arthrobacter. They were able to tolerate high temperatures (up to 45°C) and salt accumulation, and they produced enzymes involved in nutrients’ solubilization, such as phosphatase, amylase, protease, chitinase, and cellulase. Actinobacteria members also had an important role in the co-occurrence interactions among bacteria, favoring the community interactome and stabilization. Our findings provide new insights into actinobacteria’s diversity, adaptation, and role within the microbiome associated with stone ruins.
Bayesian latent class models to determine diagnostic sensitivities and specificities of two point of care rapid tests (Selma plus, Dipslide) for the detection of Streptococcus uberis associated with mastitis in dairy cows

Introduction Development and validations of accurate mastitis diagnostics are crucial to make timely and evidence-based decisions on mastitis therapy in order to reduce its impact on productivity, animal welfare and practicing the prudent use of antimicrobials on dairy farms. Methods The objectives of this study were to assess the agreement between test results from reference laboratory and two point of care tests (Selma plus, Dipslide) and to estimate the test accuracies with Bayesian latent class models (BLCMs). In total of 509 single quarter milk samples from cows with mastitis were included in the study. Results Among all analyzed mastitis pathogens, Streptococcus spp. was detected in up to one third of all analyzed samples and for Selma all Streptococcus samples were considered as Streptococcus uberis. The agreement (κ) when comparing two tests varied greatly depending on the bacteria, ranging from no agreement to good agreement (κ = negative to 0.86) depending on the prevalence of identified pathogens. Based on BLCMs to assess diagnostic test accuracies for the pathogen Streptococcus uberis, posterior sensitivities of 76, 71, and 64% for Selma plus, Dipslide and laboratory standard culture and specificities of 93%, 98% for Selma and Dipslide, respectively, were obtained. Discussion The two point of care rapid culture systems Dipslide and Selma plus plate can provide important preliminary pathogen identification for targeted mastitis therapy, especially when general information about growth and a rough classification of the bacteria into groups have an impact on treatment strategy. The two evaluated rapid culture systems, Dipslide and Selma plus plate, show good test accuracies for Streptococcus uberis at least at genus level. Therefore, using these tests may contribute to prudent use of antibiotics.
The dynamic properties of tubular DEAP actuators

Tubular actuators (push InLastor) fabricated from dielectric electro-active polymers (DEAP) have been developed and optimized with focus on high volume roll to roll automated manufacturing techniques and processes by Danfoss PolyPower®. This paper reports the dynamic mechanical behaviour from varying electrical stimulus of a PolyPower push InLastor. A simplified harmonic motion model of a spring load mass is shown to accurately predict the resonant frequency of push InLastors when working as displacement devices. The steady state frequency response results are presented for varying mechanical loads and drive voltage stimuli. The step function transient results are also present for different loading conditions. Methodology to extract parameters for the classic mass-spring-damper is also presented. Similarly, results are presented for the use of push Inlastors as force elements. The electrical to mechanical efficiency of PolyPower push InLastor is estimated.