Miracle-dz/UniFAR-FTUs huggingface dataset:
Interactome and evolutionary conservation of Dictyostelid small GTPases and their direct regulators

ABSTRACT GTP binding proteins known as small GTPases make up one of the largest groups of regulatory proteins and control almost all functions of living cells. Their activity is under, respectively, positive and negative regulation by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), which together with their upstream regulators and the downstream targets of the small GTPases form formidable signalling networks. While genomics has revealed the large size of the GTPase, GEF and GAP repertoires, only a small fraction of their interactions and functions have yet been experimentally explored. Dictyostelid social amoebas have been particularly useful in unravelling the roles of many proteins in the Rac-Rho and Ras-Rap families of GTPases in directional cell migration and regulation of the actin cytoskeleton. Genomes and cell-type specific and developmental transcriptomes are available for Dictyostelium species that span the 0.5 billion years of evolution of the group from their unicellular ancestors. In this work, we identified all GTPases, GEFs and GAPs from genomes representative of the four major taxon groups and investigated their phylogenetic relationships and evolutionary conservation and changes in their functional domain architecture and in their developmental and cell-type specific expression. We performed a hierarchical cluster analysis of the expression profiles of the ~2000 analysed genes to identify putative interacting sets of GTPases, GEFs and GAPs, which highlight sets known to interact experimentally and many novel combinations. This work represents a valuable resource for research into all fields of cellular regulation.
Bi‐allelic mutations in MCIDAS and CCNO cause human infertility associated with abnormal gamete transport

Reduced generation of multiple motile cilia (RGMC) and the consequent primary ciliary dyskinesia (PCD) cause infertility due to a substantial reduction in the number of multiciliated cells (MCCs) in the efferent ducts (EDs)/oviducts. MCIDAS acts upstream of CCNO to regulate the biogenesis of basal bodies (BBs); therefore, both genes play a vital role in the multiciliogenesis of the reproductive tract epithelium. In this study, whole‐exome sequencing was performed to identify the causative genes in 10 unrelated infertile patients with PCD: seven males and three females. Notably, homozygous frameshift mutations in MCIDAS (c.186dupT, p.Pro63Serfs*22) and CCNO (c.262_263insGGCCC, p.Gln88Argfs*8) were identified in one male and one female participant from two unrelated consanguineous families. Haematoxylin–eosin staining/scanning electron microscopy revealed abnormal MCCs in the mutated EDs/oviducts. Furthermore, transmission electron microscopy revealed significantly reduced BBs. Immunofluorescence staining showed the absence of MCIDAS and CCNO signals in the affected tissues and confirmed that MCIDAS acts upstream of CCNO in the context of multiciliogenesis in the reproductive tract epithelium. In vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) was successful, with a positive pregnancy outcome in both MCIDAS‐ and CCNO‐mutated patients. Our results support the use of IVF/ICSI interventions to treat infertility due to RGMC in couples.
Optimization of Swelling Percentage of Poly(AAm-co-AA) in BaCl2 Salt Solution Using Response Surface Methodology (RSM)

: Unwanted water production from oil and gas reservoirs is a serious problem for producers. Preformed particle gel (PPG) treatment is a benefit approach to control excess water production. Swelling percentage of PPG samples in saline water is a key factor affecting the efficiency of the water conformance process. In this study, an efficient series of PPGs were synthesized and their swelling behaviors were studied. The design of experiments (DOE) software was used to design synthesis experiments and optimum swelling percentage of PPGs in BaCl2 salt solution. Results showed that the optimized range of the dominant factors including mole ratio of acrylamide (AAm) to acrylic acid (AA), the mole percentage of N,N'-methylenebisacrylamide (MBA) and time were found to be 6.8 to 7.4, 4.2 to 4.5 percent and 179.8 to 180 min, respectively. Additionally, PPGs had the maximum swelling percentage of 529% in the optimum conditions. In the end, for the first time, an empirical correlation was proposed by the software that predicts the swelling percentage of PPGs in BaCl2 salt solution, which had good compatibility with the laboratory data.
A Survey of Brain Tumor Segmentation and Classification Algorithms

A brain Magnetic resonance imaging (MRI) scan of a single individual consists of several slices across the 3D anatomical view. Therefore, manual segmentation of brain tumors from magnetic resonance (MR) images is a challenging and time-consuming task. In addition, an automated brain tumor classification from an MRI scan is non-invasive so that it avoids biopsy and make the diagnosis process safer. Since the beginning of this millennia and late nineties, the effort of the research community to come-up with automatic brain tumor segmentation and classification method has been tremendous. As a result, there are ample literature on the area focusing on segmentation using region growing, traditional machine learning and deep learning methods. Similarly, a number of tasks have been performed in the area of brain tumor classification into their respective histological type, and an impressive performance results have been obtained. Considering state of-the-art methods and their performance, the purpose of this paper is to provide a comprehensive survey of three, recently proposed, major brain tumor segmentation and classification model techniques, namely, region growing, shallow machine learning and deep learning. The established works included in this survey also covers technical aspects such as the strengths and weaknesses of different approaches, pre- and post-processing techniques, feature extraction, datasets, and models’ performance evaluation metrics.
Processed pseudogenes: A substrate for evolutionary innovation

Processed pseudogenes may serve as a genetic reservoir for evolutionary innovation. Here, we argue that through the activity of long interspersed element‐1 retrotransposons, processed pseudogenes disperse coding and noncoding sequences rich with regulatory potential throughout the human genome. While these sequences may appear to be non‐functional, a lack of contemporary function does not prohibit future development of biological activity. Here, we discuss the dynamic evolution of certain processed pseudogenes into coding and noncoding genes and regulatory elements, and their implication in wide‐ranging biological and pathological processes. Also see the video abstract here: https://youtu.be/iUY_mteVoPI
Incidence and Demographics of Nasopharyngeal Carcinoma in Cheung Chau Island of Hong Kong—A Distinct Geographical Area With Minimal Residential Mobility and Restricted Public Healthcare Referral Network

Background Nasopharyngeal carcinoma (NPC) is endemic in Hong Kong with a skewed geographical and ethnic distribution. We performed an epidemiological study of NPC in Cheung Chau Island, a fishing village with very minimal residential mobility, and compared its demographics and survival with the rest of Hong Kong. Methods NPC data in Cheung Chau and non–Cheung Chau residents between 2006 and 2017 treated in our tertiary center were collected. The incidence, stage distribution, and mortality of Cheung Chau NPC residents were compared with those of their counterparts in the whole Hong Kong obtained from the Hong Kong Cancer Registry. Propensity score matching (PSM) was performed between Cheung Chau and non–Cheung Chau cases in a 1:4 ratio. Overall survival (OS), progression-free survival (PFS), and cancer-specific survival (CSS) were compared between these two cohorts by product limit estimation and log-rank tests. Results Sixty-one patients residing in Cheung Chau were identified between 2006 and 2017. There was a significantly higher NPC incidence (P < .001) but an insignificant difference in the mortality rate in Cheung Chau compared to the whole Hong Kong data. After PSM with 237 non–Cheung Chau patients, the Cheung Chau cohort revealed a stronger NPC family history (P < .001). However, there were no significant differences in OS (P = .170), PFS (P = .053), and CSS (P = .160) between these two cohorts. Conclusion Our results revealed that Cheung Chau had a higher NPC incidence but similar survival outcomes compared to the whole of Hong Kong. Further prospective studies are warranted to verify this finding and to explore the possible underlying mechanisms.
A mesocosm study on bacteria‐kelp interactions: Importance of nitrogen availability and kelp genetics

Macroalgal holobiont studies involve understanding interactions between the host, its microbiota, and the environment. We analyzed the effect of bacteria–kelp interactions on phenotypic responses of two genetically distinct populations of giant kelp, Macrocystis pyrifera (north and south), exposed to different nitrogen (N) concentrations. In co‐culture experiments with different N concentration treatments, we evaluated kelp growth responses and changes in three specific molecular markers associated with the N cycle, both in epiphytic bacteria (relative abundance of nrfA‐gene: cytochrome c nitrite reductase) and macroalgae (expression of NR‐gene: nitrate reductase; GluSyn‐gene: glutamate synthase). Both kelp populations responded differently to N limitation, with M. pyrifera‐south sporophytes having a lower specific growth rate (SGR) under N‐limiting conditions than the northern population; M. pyrifera‐north sporophytes showed no significant differences in SGR when exposed to low‐N and high‐N concentrations. This corresponded to a higher GluSyn‐gene expression in the M. pyrifera‐north sporophytes and the co‐occurrence of specific nrfA bacterial taxa. These bacteria may increase ammonium availability under low‐N concentrations, allowing M. pyrifera‐north to optimize nutrient assimilation by increasing the expression of GluSyn. We conclude that bacteria–kelp interactions are important in enhancing kelp growth rates under low N availability, although this effect may be regulated by the genetic background of kelp populations.
Mechanosensitive miR‐100 coordinates TGFβ and Wnt signaling in osteocytes during fluid shear stress

Organism scale mechanical forces elicit cellular scale changes through coordinated regulation of multiple signaling pathways. The mechanisms by which cells integrate signaling to generate a unified biological response remains a major question in mechanobiology. For example, the mechanosensitive response of bone and other tissues requires coordinated signaling by the transforming growth factor beta (TGFβ) and Wnt pathways through mechanisms that are not well‐defined. Here we report a new microRNA‐dependent mechanism that mediates mechanosensitive crosstalk between TGFβ and Wnt signaling in osteocytes exposed to fluid shear stress (FSS). From 60 mechanosensitive microRNA (miRs) identified by small‐RNAseq, miR100 expression is suppressed by in vivo hindlimb loading in the murine tibia and by cellular scale FSS in OCY454 cells. Though FSS activates both TGFβ and Wnt signaling in osteocytes, only TGFβ represses miR‐100 expression. miR‐100, in turn, antagonizes Wnt signaling by targeting and inhibiting expression of Frizzled receptors (FZD5/FZD8). Accordingly, miR‐100 inhibition blunts FSS‐ and TGFβ‐inducible Wnt signaling. Therefore, our results identify FSS‐responsive miRNAs in osteocytes, including one that integrates the mechanosensitive function of two essential signaling pathways in the osteoanabolic response of bone to mechanical load.
The Importance of the Epi-Transcriptome in Translation Fidelity

RNA modifications play an essential role in determining RNA fate. Recent studies have revealed the effects of such modifications on all steps of RNA metabolism. These modifications range from the addition of simple groups, such as methyl groups, to the addition of highly complex structures, such as sugars. Their consequences for translation fidelity are not always well documented. Unlike the well-known m6A modification, they are thought to have direct effects on either the folding of the molecule or the ability of tRNAs to bind their codons. Here we describe how modifications found in tRNAs anticodon-loop, rRNA, and mRNA can affect translation fidelity, and how approaches based on direct manipulations of the level of RNA modification could potentially be used to modulate translation for the treatment of human genetic diseases.
Physico-chemical and microbiological changes during the cabbage hybrid bravo heads fermentation: Salt, temperature and starter culture influence

The influence of temperatures (18, 22 and 26 °C), salt (60, 70 and 80 g/kg) and starter culture (0, 0.025 and 0.050 g/kg) on physico-chemical and microbiological changes during fermentation in cabbage heads were investigated. The experiment was set up in industrial conditions, samples were taken after 0, 5, 12, 27 and 62 days in order to determine the changes in color, texture, biogenic amines content, microbiological parameters, pH, aw, total sugar content, total acidity and salt content. Analysis of variance and Principal component analysis were applied to get a better overview of differences between samples and the similarities between different fermentation conditions. Significant color changes and softening of cabbage tissue did not occurred during the entire fermentation process. Cadaverine was not detected in samples containing starter culture, also the results were in range for maximum allowed putrescine and cadaverine doses for all cabbage samples. Total number of molds increased, contrary to number of yeasts on the last examined day in comparison with raw cabbage sample. Enterobacteriaceae were not detected after 5th fermentation day, while sharp increase of lactic acid bacteria number occurred until 12th day, and on the 12th fermentation day was in range of 7.82 to 9.84 log cfu/g. The fermentation process led to decrease in pH, aw and total sugar content, meanwhile total acidity 0.54%-0.89% and salt content 2.08%-3.19% in the cabbage heads increased, in comparison with raw sample where results for total acidity and salt content were 0.13% and 0.05%, respectively. Additionally, according Principal component analysis, temperature of fermentation had the greatest influence on the fermentation process, followed by the application of starter culture and then concentration of added salt.
In-hospital economic burden of anastomotic leakage after colorectal anastomosis surgery: a real-world cost analysis in Italy

ABSTRACT Background Anastomotic leakage (AL) is a severe complication of colorectal surgery. We aimed to quantify inpatient costs and key cost contributors associated with AL in a single Italian center. Research design and methods Electronic records for adults who had undergone colorectal surgery with anastomosis (January 2015 – December 2016), were retrospectively reviewed. Patients with AL were identified using clinical signs and/or imaging findings and/or intraoperative findings. Available data included patient, clinical, and procedural characteristics, healthcare resource utilization, and inpatient costs. Multivariate models were used to adjust for potential confounders. Results AL occurred in 12.3% of patients (N = 317). Mean adjusted inpatient cost was 108% higher (p < 0.001) for patients with AL versus no AL (€14,711; 95% CI: 12,113; 17,866 versus €7,089; 95% CI: 6,623; 7,587). Key cost contributors were ward stay, disposables, operating room, and hospital consultations. Mean losses (reimbursement minus costs) were €2,041/patient with AL. AL extended mean length of stay by 9 days and increased odds of reoperation and ICU stay (all p < 0.001). Conclusions Patients with AL place considerable economic and resource burden on healthcare systems and hospital reimbursement rates do not cover treatment costs. This study highlights an unmet need for novel techniques to reduce the burden of AL.
Predicting post-stroke cognitive impairment using acute CT neuroimaging: A systematic review and meta-analysis

Background Identifying whether acute stroke patients are at risk of cognitive decline could improve prognostic discussions and management. Structural computed tomography neuroimaging is routine in acute stroke, and may identify those at risk of post-stroke dementia or post-stroke cognitive impairment (PSCI). Aim To systematically review the literature to identify which stroke or pre-stroke features on brain computed tomography scans, performed at the time of stroke, are associated with post-stroke dementia or PSCI. Summary of review We searched electronic databases to December 2020. We included studies reporting acute stroke brain computed tomography, and later diagnosis of a cognitive syndrome. We created summary estimates of size of unadjusted association between computed tomography features and cognition. Of 9536 citations, 28 studies (41 papers) were eligible (N = 7078, mean age 59.8–78.6 years). Cognitive outcomes were post-stroke dementia (10 studies), PSCI (17 studies), and one study analyzed both. Fifteen studies (N = 2952) reported data suitable for meta-analyses. White matter lesions (WML) (six studies, N = 1054, OR = 2.46, 95% CI = 1.25–4.84), cerebral atrophy (four studies, N = 558, OR = 2.80, 95% CI = 1.21–6.51), and pre-existing stroke lesions (three studies, N = 352, OR = 2.38, 95% CI = 1.06–5.32) were associated with post-stroke dementia. WML (four studies, N = 473, OR = 3.46, 95% CI = 2.17–5.52) were associated with PSCI. Other computed tomography features were either not associated with cognitive outcome, or there were insufficient data. Conclusions Cognitive impairment following stroke is of great concern to patients and carers. Features seen on visual assessment of acute stroke computed tomography brain scans are strongly associated with cognitive outcomes. Clinicians should consider when and how this information should be discussed with stroke survivors.
Wettability and contact angle affect precorneal retention and pharmacodynamic behavior of microspheres

Abstract In the present study, we describe the development of betaxolol hydrochloride and montmorillonite with ion exchange in a single formulation to create a novel micro-interactive dual-functioning sustained-release delivery system (MIDFDS) for the treatment of glaucoma. Betaxolol hydrochloride molecule was loaded onto the montmorillonite by ion exchange and MIDFDS formation was confirmed by XPS data. MIDFDS showed similar physicochemical properties to those of Betoptic, such as particle size, pH, osmotic pressure, and rheological properties. Nevertheless, the microdialysis and intraocular pressure test revealed better in vivo performance of MIDFDS, such as pharmacokinetics and pharmacodynamics. With regards to wettability, MIDFDS had a larger contact angle (54.66 ± 5.35°) than Betoptic (36.68 ± 1.77°), enabling the MIDFDS (2.93 s) to spread slower on the cornea than Betoptic (2.50 s). Moderate spreading behavior and oppositely charged electrostatic micro-interactions had a comprehensive influence on micro-interactions with the tear film residue, resulting in a longer precorneal retention time. Furthermore, MIDFDS had a significant sustained-release effect, with complete release near the cornea. The dual-functioning sustained-release carrier together with prolonged pre-corneal retention time (80 min) provided sufficiently high drug concentrations in the aqueous humor to achieve a more stable and long-term IOP reduction for 10 h. In addition, cytotoxicity and hemolysis tests showed that MIDFDS had better biocompatibility than Betoptic. The dual-functioning microspheres presented in this study provide the possibility for improved compliance due to low cytotoxicity and hemolysis, which suggests promising clinical implications.
Mice Treated Subcutaneously with Mouse LPS-Converted PrPres or LPS Alone Showed Brain Gene Expression Profiles Characteristic of Prion Disease

Previously, we showed that bacterial lipopolysaccharide (LPS) converts mouse PrPC protein to a beta-rich isoform (moPrPres) resistant to proteinase K. In this study, we aimed to test if the LPS-converted PrPres is infectious and alters the expression of genes related to prion pathology in brains of terminally sick mice. Ninety female FVB/N mice at 5 weeks of age were randomly assigned to 6 groups treated subcutaneously (sc) for 6 weeks either with: (1) Saline (CTR); (2) LPS from Escherichia coli 0111:B4 (LPS), (3) one-time sc administration of de novo generated mouse recombinant prion protein (moPrP; 29-232) rich in beta-sheet by incubation with LPS (moPrPres), (4) LPS plus one-time sc injection of moPrPres, (5) one-time sc injection of brain homogenate from Rocky Mountain Lab (RLM) scrapie strain, and (6) LPS plus one-time sc injection of RML. Results showed that all treatments altered the expression of various genes related to prion disease and neuroinflammation starting at 11 weeks post-infection and more profoundly at the terminal stage. In conclusion, sc administration of de novo generated moPrPres, LPS, and a combination of moPrPres with LPS were able to alter the expression of multiple genes typical of prion pathology and inflammation.
Structure-based identification of novel scaffolds as potential HIV-1 entry inhibitors involving CCR5

Abstract C-C chemokine receptor 5 (CCR5), which is part of the chemokine receptor family, is a member of the G protein-coupled receptor superfamily. The interactions of CCR5 with HIV-1 during viral entry position it as an effective therapeutic target for designing potent antiviral therapies. The small-molecule Maraviroc was approved by the FDA as a CCR5 drug in 2007, while clinical trials failure has characterised many of the other CCR5 inhibitors. Thus, the continual identification of potential CCR5 inhibitors is, therefore, warranted. In this study, a structure-based discovery approach has been utilised to screen and retrieved novel potential CCR5 inhibitors from the Asinex antiviral compound (∼ 8,722) database. Explicit lipid-bilayer molecular dynamics simulation, in silico physicochemical and pharmacokinetic analyses, were further performed for the top compounds. A total of 23 structurally diverse compounds with binding scores higher than Maraviroc were selected. Subsequent molecular dynamics (MD) simulations analysis of the top four compounds LAS 51495192, BDB 26405401, BDB 26419079, and LAS 34154543, maintained stability at the CCR5 binding site. Furthermore, these compounds made pertinent interactions with CCR5 residues critical for the HIV-1 gp120-V3 loop binding such as Trp86, Tyr89, Phe109, Tyr108, Glu283 and Tyr251. Additionally, the predicted in silico physicochemical and pharmacokinetic descriptors of the selected compounds were within the acceptable range for drug-likeness. The results suggest positive indications that the identified molecules may represent promising CCR5 entry inhibitors. Further structural optimisations and biochemical testing of the proposed compounds may assist in the discovery of effective HIV-1 therapy. Communicated by Ramaswamy H. Sarma