Miracle-dz/UniFAR-FTUs huggingface dataset:
IslandCafe: Compositional Anomaly and Feature Enrichment Assessment for Delineation of Genomic Islands

One of the evolutionary forces driving bacterial genome evolution is the acquisition of clusters of genes through horizontal gene transfer (HGT). These genomic islands may confer adaptive advantages to the recipient bacteria, such as, the ability to thwart antibiotics, become virulent or hypervirulent, or acquire novel metabolic traits. Methods for detecting genomic islands either search for markers or features typical of islands or examine anomaly in oligonucleotide composition against the genome background. The former tends to underestimate, missing islands that have the markers either lost or degraded, while the latter tends to overestimate, due to their inability to discriminate compositional atypicality arising because of HGT from those that are a consequence of other biological factors. We propose here a framework that exploits the strengths of both these approaches while bypassing the pitfalls of either. Genomic islands lacking markers are identified by their association with genomic islands with markers. This was made possible by performing marker enrichment and phyletic pattern analyses within an integrated framework of recursive segmentation and clustering. The proposed method, IslandCafe, compared favorably with frequently used methods for genomic island detection on synthetic test datasets and on a test-set of known islands from 15 well-characterized bacterial species. Furthermore, IslandCafe identified novel islands with imprints of likely horizontal acquisition.
Non-alcoholic fatty liver disease (NAFLD) is associated with dynamic changes in DNA hydroxymethylation

ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is now the commonest cause of liver disease in developed countries affecting 25–33% of the general population and up to 75% of those with obesity. Recent data suggest that alterations in DNA methylation may be related to NAFLD pathogenesis and progression and we have previously shown that dynamic changes in the cell lineage identifier 5-hydroxymethylcytosine (5hmC) may be important in the pathogenesis of liver disease. We used a model of diet-induced obesity, maintaining male mice on a high-fat diet (HFD) to generate hepatic steatosis. We profiled hepatic gene expression, global and locus-specific 5hmC and additionally investigated the effects of weight loss on the phenotype. HFD led to increased weight gain, fasting hyperglycaemia, glucose intolerance, insulin resistance and hepatic periportal macrovesicular steatosis. Diet-induced hepatic steatosis associated with reversible 5hmC changes at a discrete number of functionally important genes. We propose that 5hmC profiles are a useful signature of gene transcription and a marker of cell state in NAFLD and suggest that 5hmC profiles hold potential as a biomarker of abnormal liver physiology.
Alzheimer’s Disease Research Using Human Microglia

Experimental studies of neuroinflammation in Alzheimer’s disease (AD) have mostly investigated microglia, the brain-resident macrophages. This review focused on human microglia obtained at rapid autopsies. Studies employing methods to isolate and culture human brain microglia in high purity for experimental studies were discussed. These methods were employed to isolate human microglia for investigation of a number of features of neuroinflammation, including activation phenotypes, neurotoxicity, responses to abnormal aggregated proteins such as amyloid beta, phagocytosis, and the effects of aging and disease on microglia cellular properties. In recent years, interest in human microglia and neuroinflammation has been renewed due to the identification of inflammation-related AD genetic risk factors, in particular the triggering receptor expressed on myeloid cells (TREM)-2. Because of the difficulties in developing effective treatments for AD, there has been a general need for greater understanding of the functions of microglia in normal and AD brains. While most experimental studies on neuroinflammation have employed rodent microglia, this review considered the role of human microglia in experimental studies. This review focused on the development of in vitro methodology for the culture of postmortem human microglia and the key findings obtained from experimental studies with these cells.
Dietary habits of newcomer children in Canada

Abstract Objective: To explore the dietary habits, nutrient adequacies and dietary change experiences of immigrant and refugee children. Design: Mixed-methods cross-sectional design. Children completed three 24 h dietary recalls to determine nutrient inadequacies. Parents and service providers were interviewed to capture dietary practices. Setting: Healthy Immigrant Children study, Saskatchewan, Canada. Participants: Three hundred immigrant and refugee children aged 3–13 years and twenty-two parents who lived in Regina or Saskatoon for less than 5 years; twenty-four newcomer services providers. Results: Immigrant children had higher mean intakes of meat and alternatives, milk and alternatives, and whole grains; and consumed more vitamin B12, folate, Ca, vitamin D, Fe and Zn compared with refugee children. Refugee children were at higher risk of having inadequate intakes of folate (37 %) and Fe (18 %). Both immigrant and refugee children were at high risk of inadequate vitamin D (87 and 93 %, respectively) and Ca intakes (79 and 80 %), and a substantial portion were at risk for inadequate Zn intake (21 and 31 %). Participants mentioned challenges with maintaining a healthy traditional diet in the midst of a busy schedule, while responding to their children’s demands for foods high in fat and sugar. Conclusions: Newcomer children are at risk for inadequate intakes of vitamin D, Ca and Zn, while refugee children are at additional risk for inadequate folate and Fe intakes. Newcomers to Canada may experience subtle or drastic changes in their food environment leading to dietary acculturation that includes increased consumption of foods high in sugar, salt and fat.
Cellular and genetic determinants of the sensitivity of cancer to alpha-particle irradiation.

Targeted alpha-particle emitting radionuclides have great potential for the treatment of a broad range of cancers at different stages of progression. A platform that accurately measures cancer cellular sensitivity to alpha-particle irradiation could guide and accelerate clinical translation. Herein, we performed high-content profiling of cellular survival following exposure to alpha-particles emitted from radium-223 (223Ra) using 28 genetically diverse human tumor cell lines. Significant variation in cellular sensitivity across tumor cells was observed. 223Ra was significantly more potent than sparsely ionizing irradiation, with a median relative biologic effectiveness of 10.4 (IQR: 8.4-14.3). Cells that are the most resistant to alpha radiation, such as Nrf2 gain-of-function mutant cells, were sensitive to alpha-particles. Combining these profiling results with genetic features we identified several somatic copy number alterations, gene mutations, and the basal expression of gene sets that correlated with radiation survival. Activating mutations in PIK3CA, a frequent event in cancer, decreased sensitivity to 223Ra. The identification of cellular and genetic determinants of sensitivity to 223Ra may guide the clinical incorporation of targeted alpha-particle emitters in the treatment of several cancer types.
Epidermal Growth Factor Receptor (EGFR) Pathway, Yes-Associated Protein (YAP) and the Regulation of Programmed Death-Ligand 1 (PD-L1) in Non-Small Cell Lung Cancer (NSCLC)

The epidermal growth factor receptor (EGFR) pathway is a well-studied oncogenic pathway in human non-small cell lung cancer (NSCLC). A subset of advanced NSCLC patients (15–55%) have EGFR-driven mutations and benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). Immune checkpoint inhibitors (ICIs) targeting the PD-1/PDL-1 axis are a new anti-cancer therapy for metastatic NSCLC. The anti-PD-1/PDL-1 ICIs showed promising efficacy (~30% response rate) and improved the survival of patients with metastatic NSCLC, but the role of anti-PD-1/PDL-1 ICIs for EGFR mutant NSCLC is not clear. YAP (yes-associated protein) is the main mediator of the Hippo pathway and has been identified as promoting cancer progression, drug resistance, and metastasis in NSCLC. Here, we review recent studies that examined the correlation between the EGFR, YAP pathways, and PD-L1 and demonstrate the mechanism by which EGFR and YAP regulate PD-L1 expression in human NSCLC. About 50% of EGFR mutant NSCLC patients acquire resistance to EGFR-TKIs without known targetable secondary mutations. Targeting YAP therapy is suggested as a potential treatment for NSCLC with acquired resistance to EGFR-TKIs. Future work should focus on the efficacy of YAP inhibitors in combination with immune checkpoint PD-L1/PD-1 blockade in EGFR mutant NSCLC without targetable resistant mutations.
Alternatively spliced variants of the 5’-UTR of the ARPC2 mRNA regulate translation by an internal ribosome entry site (IRES) harboring a guanine-quadruplex motif

ABSTRACT The 5ʹ-UTR of the actin-related protein 2/3 complex subunit 2 (ARPC2) mRNA exists in two variants. Using a bicistronic reporter construct, the present study demonstrates that the longer variant of the 5ʹ-UTR harbours an internal ribosome entry site (IRES) which is lacking in the shorter one. Multiple control assays confirmed that only this variant promotes cap-independent translation. Furthermore, it includes a guanine-rich region that is capable of forming a guanine-quadruplex (G-quadruplex) structure which was found to contribute to the IRES activity. To investigate the cellular function of the IRES element, we determined the expression level of ARPC2 at various cell densities. At high cell density, the relative ARPC2 protein level increases, supporting the presumed function of IRES elements in driving the expression of certain genes under stressful conditions that compromise cap-dependent translation. Based on chemical probing experiments and computer-based predictions, we propose a structural model of the IRES element, which includes the G-quadruplex motif exposed from the central stem-loop element. Taken together, our study describes the functional relevance of two alternative 5ʹ-UTR splice variants of the ARPC2 mRNA, one of which contains an IRES element with a G-quadruplex as a central motif, promoting translation under stressful cellular conditions Graphical abstract
Comparison of complication rates and incidences associated with different peripherally inserted central catheters (PICC) in patients with hematological malignancies: a retrospective cohort study

Abstract Patients with hematological malignancies (HM) or undergoing hematopoietic cell transplantation (HCT) require reliable vascular access. Peripherally inserted central catheters (PICC) meet this need, however, studies suggest these patients have higher rates of PICC-associated complications. This retrospective cohort study evaluates the influence of PICC type on the rates and incidences of complications. Four hundred and eighty-five dual lumen PICCs were inserted into 469 complex patients with HM or undergoing HCT: 161 Groshong®, 60 PowerPICC® Solo, 165 BioFlo®, and 99 Arrow®. The rates and incidences of complications differed significantly across the PICC types. The overall rate of complication ranged from 7.40 to 26.4/1000 catheter days (CDs). The rate of deep vein thrombosis (0.31–1.48/1000 CDs) and occlusion differed across the PICC types, while the rate of central line-associated bloodstream infection (0.53–0.74/1000 CDs) did not. Following multivariate adjustment, PICC type was associated with complication rate. This highlights that PICC type should be considered in clinical decisions.
The mediation role of companies’ dynamic capabilities for business performance excellence: insights from foreign direct investments. The case of transitional partnership

Abstract This study uses a combination of multinational enterprises and dynamic capabilities perspectives to illustrate how the involvement of foreign investors is able to contribute to a company’s corporate performance. Using Russian companies as an empirical sample and applying PLS-SEM, we test hypotheses regarding the impact of dynamic capabilities in terms of absorptive, adaptive, and communicative capabilities, on the relationship between foreign ownership and performance. Findings indicate that dynamic capabilities fully mediate the process of foreign direct investments transformation into firm’s results. Our findings contribute to the understanding of the mechanism by which dynamic capabilities enhance the positive effects of foreign direct investments on business performance, and advance the theoretical understanding of how a dynamic capabilities concept could be incorporated into multinational enterprises theory in the framework of relationships between companies from economies with different knowledge endowment.
Effect of Size on Solid Tumor Disposition of Protein Therapeutics

In this study, we evaluated the effect of size on tumor disposition of protein therapeutics, including the plasma and tumor pharmacokinetics (PK) of trastuzumab (∼150 kDa), FcRn-nonbinding trastuzumab (∼150 kDa), F(ab)2 fragment of trastuzumab (∼100 kDa), Fab fragment of trastuzumab (∼50 kDa), and trastuzumab scFv (∼27 kDa) in both antigen (i.e., HER2)-overexpressing (N87) and antigen-nonexpressing (MDA-MB-468) tumor-bearing mice. The observed data were used to develop the maximum tumor uptake versus molecular weight and tumor-to-plasma area under the curve (AUC) ratio versus molecular weight relationships. Comparison of the PK of different sizes of FcRn nonbinding molecules in target-expressing tumor showed that ∼100 kDa is an optimal size to achieve maximum tumor uptake and ∼50 kDa is an optimal size to achieve maximum tumor-to-plasma exposure ratio of protein therapeutics. The PK data were also used to validate a systems PK model for tumor disposition of different-sized protein therapeutics. The PK model was able to predict a priori the PK of all five molecules in both tumor types reasonably well (within 2- to 3-fold). In addition, the model captured the bell-shaped relationships observed between maximum tumor uptake and molecular weight and between tumor-to-plasma AUC ratio and molecular weight. Our results provide an unprecedented insight into the effect of size and target engagement on the tumor PK of protein therapeutics. Our results also provide further validation of the tumor disposition model, which can be used to support discovery, development, and preclinical-to-clinical translation of different sizes of protein therapeutics. SIGNIFICANCE STATEMENT This article highlights the importance of molecular size and target engagement on the tumor disposition of protein therapeutics. Our results suggest that ∼100 kDa is an optimal size to achieve maximum tumor uptake and ∼50 kDa is an optimal size to achieve maximum tumor-to-plasma exposure ratio for non-FcRn-binding targeted protein therapeutics. We also demonstrate that a systems pharmacokinetics model developed to characterize tumor disposition of protein therapeutics can predict a priori the disposition of different-sized protein therapeutics in target-expressing and target-nonexpressing solid tumors.
Assessment of relationship between extracranial and intracranial carotid calcifications - Retrospective Cone Beam Computed Tomography study.

OBJECTIVES Cone Beam CT (CBCT) scans in current day dental practice are highly collimated yet involve areas along the course of the extracranial carotid artery. Detecting an extracranial carotid calcification on small volume scans leaves the dentist with two questions: whether the patient is likely to have intracranial carotid calcifications and whether the patient warrants further medical attention. This study aimed to assess the presence of intracranial carotid artery calcifications (ICAC) in the presence of extracranial carotid artery calcifications (ECAC). METHODS AND MATERIALS 450 CBCT scans were retrospectively evaluated for ECAC and ICAC. Erby et. al's classification was modified to classify calcifications as mild, moderate, and severe. The presence of ICAC when ECAC were present was evaluated in all three planes. The risk of ICAC in the presence of ECAC was calculated as odds ratio and the association between the two was calculated using a chi-square test. RESULTS The odds ratio for bilateral ICAC in the presence of bilateral ECAC was 15.09. The odds ratio for left ICAC/right ICAC in the presence of left/ right ECAC was 0.833 and 2.564, respectively. The number and severity of calcifications increased with age. The Chi-square test showed that there was a strong association (p < 0.001) between bilateral ECAC with bilateral ICAC. CONCLUSIONS The results of this group of patients showed that there is an increased presence of ICAC in the presence of ECAC.
Absolute Abstinence as a Treatment Outcome in Servicemen with Alcohol Dependence: A Retrospective Cohort Study

Abstract Background: Within India’s military medical framework, alcohol dependence syndrome (ADS) is deemed a treatable medical illness incompatible with military service, and complete abstinence is the only acceptable successful treatment outcome. Objective: This study was designed to identify factors which were able to differentiate treatment outcomes of abstinence and relapse among ADS patients in a military framework. Method: Recognizing personal incentives to misrepresent alcohol consumption, abstinence, and relapse outcomes were established using official reports from a patient’s parent unit, in combination with biochemical parameters and clinical examination. Patients serially admitted for ADS treatment or follow-up review were surveyed, and their socio-demographic and alcohol consumption profiles, coping styles, life events and specific relapse precipitants were recorded and compared as contributory variables in a cognitive-behavioral model of ADS. From this survey of 140 patients, membership to abstainer or relapser groups was then predicted using a discriminant analysis. Results: 34% of patients achieved early absolute abstinence. No baseline socio-demographic or drinking profile distinctions existed between abstainers and relapsers. Differences were forthcoming on coping styles, life-event, and relapse-precipitant exposure measures. Stepwise discriminant analysis produced a final equation comprising 10 independent variables (including two positive life event measures), which predicted an abstinence/relapse outcome with an 86% and 79% hit-rate (original and cross-validated). Conclusion: Using prevailing cognitive-behavioral constructs, early absolute abstinence emerged as an actionable objective and an achievable goal without any contributory socio-demographic predilections. This preliminary evaluation suggests it is a tenable and realistic target of current ADS treatment programs.
On the Horizon: Targeting Next-Generation Immune Checkpoints for Cancer Treatment

Background: Immune checkpoints are critical regulatory pathways of the immune system which finely tune the response to biological threats. Among them, the CD-28/CTLA-4 and PD-1/PD-L1 axes play a key role in tumour immune escape and are well-established targets of cancer immunotherapy. Summary: The clinical experience accumulated to date provides unequivocal evidence that anti-CTLA-4, PD-1, or PD-L1 monoclonal antibodies, used as monotherapy or in combination regimes, are effective in a variety of advanced/metastatic types of cancer, with improved clinical outcomes compared to conventional chemotherapy. However, the therapeutic success is currently restricted to a limited subset of patients and reliable predictive biomarkers are still lacking. Key Message: The identification and characterization of additional co-inhibitory pathways as novel pharmacological targets to improve the clinical response in refractory patients has led to the development of different immune checkpoint inhibitors, the activities of which are currently under investigation. In this review, we discuss recent literature data concerning the mechanisms of action of next-generation monoclonal antibodies targeting LAG-3, TIM-3, and TIGIT co-inhibitory molecules that are being explored in clinical trials, as single agents or in combination with other immune-stimulating agents.
Precipitation amount and event size interact to reduce ecosystem functioning during dry years in a mesic grassland

Ongoing intensification of the hydrological cycle is altering rainfall regimes by increasing the frequency of extreme wet and dry years and the size of individual rainfall events. Despite long‐standing recognition of the importance of precipitation amount and variability for most terrestrial ecosystem processes, we lack understanding of their interactive effects on ecosystem functioning. We quantified this interaction in native grassland by experimentally eliminating temporal variability in growing season rainfall over a wide range of precipitation amounts, from extreme wet to dry conditions. We contrasted the rain use efficiency (RUE) of above‐ground net primary productivity (ANPP) under conditions of experimentally reduced versus naturally high rainfall variability using a 32‐year precipitation–ANPP dataset from the same site as our experiment. We found that increased growing season rainfall variability can reduce RUE and thus ecosystem functioning by as much as 42% during dry years, but that such impacts weaken as years become wetter. During low precipitation years, RUE is lowest when rainfall event sizes are relatively large, and when a larger proportion of total rainfall is derived from large events. Thus, a shift towards precipitation regimes dominated by fewer but larger rainfall events, already documented over much of the globe, can be expected to reduce the functioning of mesic ecosystems primarily during drought, when ecosystem processes are already compromised by low water availability.
Identification of coding and long non-coding RNAs differentially expressed in tumors and preferentially expressed in healthy tissues.

The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets allow unprecedented gene expression analyses. Here, using these datasets we performed pan-cancer and pan-tissue identification of coding and long non-coding RNA (lncRNAs) transcripts differentially expressed in tumors and preferentially expressed in healthy tissues and/or tumors. Pan-cancer comparison of mRNAs and lncRNAs showed that lncRNAs were deregulated in a more tumor-specific manner. Given that lncRNAs are more tissue-specific than mRNAs, we identified healthy tissues that preferentially express lncRNAs upregulated in tumors and found that testis, brain, the digestive tract and blood/spleen were the most prevalent. In addition, specific tumors also upregulate lncRNAs preferentially expressed in other tissues, generating a unique signature for each tumor type. Most tumors studied downregulated lncRNAs preferentially expressed in their tissue of origin, probably as a result of de-differentiation. However, the same lncRNAs could be upregulated in other tumors resulting in "bimorphic" transcripts. In hepatocellular carcinoma (HCC), the upregulated genes identified were expressed at higher levels in patients with worse prognosis. Some lncRNAs upregulated in HCC and preferentially expressed in healthy testis or brain were predicted to function as oncogenes and were significantly associated with higher tumor burden, and poor prognosis, suggesting their relevance in hepatocarcinogenesis and/or tumor evolution. Taken together, therapies targeting oncogenic lncRNAs should take into consideration the healthy tissue where the lncRNAs are preferentially expressed, to predict and decrease unwanted secondary effects and increase potency.