Miracle-dz/UniFAR-FTUs huggingface dataset:
Fragment Library of Natural Products and Compound Databases for Drug Discovery †

Natural products and semi-synthetic compounds continue to be a significant source of drug candidates for a broad range of diseases, including coronavirus disease 2019 (COVID-19), which is causing the current pandemic. Besides being attractive sources of bioactive compounds for further development or optimization, natural products are excellent substrates of unique substructures for fragment-based drug discovery. To this end, fragment libraries should be incorporated into automated drug design pipelines. However, public fragment libraries based on extensive collections of natural products are still limited. Herein, we report the generation and analysis of a fragment library of natural products derived from a database with more than 400,000 compounds. We also report fragment libraries of a large food chemical database and other compound datasets of interest in drug discovery, including compound libraries relevant for COVID-19 drug discovery. The fragment libraries were characterized in terms of content and diversity.
Comorbidity patterns among people living with HIV: a hierarchical clustering approach through integrated electronic health records data in South Carolina

ABSTRACT Comorbidity among people living with HIV (PLWH) is understudied although identifying its patterns and socio-demographic predictors would be beneficial for comorbidity management. Using electronic health records (EHR) data, 8,490 PLWH diagnosed between January 2005 and December 2016 in South Carolina were included in the current study. An initial list of 86 individual diagnoses of chronic conditions was extracted in the EHR data. After grouping individual diagnoses with a pathophysiological similarity, 24 diagnosis groups were generated. Hierarchical cluster analysis was applied to these 24 diagnosis groups and yielded four comorbidity clusters: “substance use and mental disorder” (e.g., alcohol use, depression, and illicit drug use); “metabolic disorder” (e.g., hypothyroidism, diabetes, hypertension, and chronic kidney disease); “liver disease and cancer” (e.g., hepatitis B, chronic liver disease, and non-AIDS defining cancers); and “cerebrovascular disease” (e.g., stroke and dementia). Multivariable logistic regression was conducted to investigate the association between socio-demographic factors and multimorbidity (defined as concurrence of ≥ 2 comorbidity clusters). The multivariable logistic regression showed that age, gender, transmission risk, race, initial CD4 counts, and viral load were significant factors associated with multimorbidity. The results suggested the importance of integrated clinical care that addresses the complexities of multiple, and potentially interacting comorbidities among PLWH.
Immunogenic cell death pathway polymorphisms for predicting oxaliplatin efficacy in metastatic colorectal cancer

Background Immunogenic cell death (ICD) is a tumor cell death involving both innate and adaptive immune responses. Given published findings that oxaliplatin, but not irinotecan, drives ICD, we investigated whether single nucleotide polymorphisms (SNPs) in the ICD pathway are associated with the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer (mCRC). Methods Two randomized clinical trials data were analyzed: discovery cohort, FOLFOX/bevacizumab arm (MAVERICC); validation cohort, FOLFOXIRI/bevacizumab arm (TRIBE); and two control cohorts, FOLFIRI/bevacizumab arms (both trials). Genomic DNA extracted from blood samples was genotyped. Ten SNPs in the ICD pathway were tested for associations with clinical outcomes. Results In total, 648 patients were included. In the discovery cohort, three SNPs were significantly associated with clinical outcomes in univariate analysis: CALR rs1010222 with progression-free survival (G/G vs any A, HR=0.61, 95% CI 0.43–0.88), ANXA1 rs1050305 with overall survival (OS) (A/A vs any G, HR=1.87, 95% CI 1.04–3.35), and LRP1 rs1799986 with OS (C/C vs any T, HR=1.69, 95% CI 1.07–2.70). Multivariate analysis confirmed the trend, but statistical significance was not reached. In the validation cohort, ANXA1 rs1050305, and LRP1 rs1799986 were validated to have the significant associations with clinical outcome. No significant associations of these SNPs were observed in the two control cohorts. Treatment-by-SNP interaction test confirmed the predictive values. Conclusions The predictive utility of ICD-related SNPs for the efficacy of oxaliplatin-based chemotherapy was demonstrated, warranting further validation studies to be translated into personalized treatment strategies using conventional cytotoxic agents in mCRC.
Impact of the coronavirus disease 2019 (COVID-19) pandemic on the Italian congenital cardiac surgery system: a national survey

Abstract OBJECTIVES Italy has been one of the countries most severely affected by the coronavirus disease 2019 (COVID-19). The Italian government was forced to introduce quarantine measures quickly, and all elective health services were stopped or postponed. This emergency has dramatically changed the management of paediatric and adult patients with congenital heart disease. We analysed data from 14 Italian congenital cardiac surgery centres during lockdown, focusing on the impact of the pandemic on surgical activity, patients and healthcare providers and resource allocation. METHODS Fourteen centres participated in this study. The period analysed was from 9 March to 4 May. We collected data on the involvement of the hospitals in the treatment of patients with COVID-19 and on limitations on regular activity and on the contagion among patients and healthcare providers. RESULTS Four hospitals (29%) remained COVID-19 free, whereas 10 had a 39% reduction in the number of beds for surgical patients, especially in the northern area. Two hundred sixty-three surgical procedures were performed: 20% elective, 62% urgent, 10% emergency and 3% life-saving. Hospital mortality was 0.4%. Compared to 2019, the reduction in surgical activity was 52%. No patients operated on had positive test results before surgery for severe acute respiratory syndrome coronavirus 2, the virus responsible for COVID-19. Three patients were infected during the postoperative period. Twenty-nine nurses and 12 doctors were infected. Overall, 80% of our infected healthcare providers were in northern centres. CONCLUSIONS Our study shows that the pandemic had a different impact on the various Italian congenital cardiac surgery centres based on the different patterns of spread of the virus across the country. During the lockdown, the system was able to satisfy all emergency clinical needs with excellent results.
The Presence of Human Herpesvirus 6 in the Brain in Health and Disease

The human herpesvirus 6 (HHV-6) -A and -B are two dsDNA beta-herpesviruses infecting almost the entire worldwide population. These viruses have been implicated in multiple neurological conditions in individuals of various ages and immunological status, including encephalitis, epilepsy, and febrile seizures. HHV-6s have also been suggested as playing a role in the etiology of neurodegenerative diseases such as multiple sclerosis and Alzheimer’s disease. The apparent robustness of these suggested associations is contingent on the accuracy of HHV-6 detection in the nervous system. The effort of more than three decades of researching HHV-6 in the brain has yielded numerous observations, albeit using variable technical approaches in terms of tissue preservation, detection techniques, sample sizes, brain regions, and comorbidities. In this review, we aimed to summarize current knowledge about the entry routes and direct presence of HHV-6 in the brain parenchyma at the level of DNA, RNA, proteins, and specific cell types, in healthy subjects and in those with neurological conditions. We also discuss recent findings related to the presence of HHV-6 in the brains of patients with Alzheimer’s disease in light of available evidence.
Long-term maintenance of virologic suppression in native and migrant HIV-1 naïve patients: an Italian cohort study

ABSTRACT Little is known about long-term maintenance of virologic suppression in HIV migrants in Italy. The study aims to compare virologic failure rates and associated factors among antiretroviral therapy (ART)-naïve migrants and natives enrolled in the ARCA database since 2007 who achieved virologic suppression within 18 months from the beginning of the ART. Kaplan-Meier method assessed the probability of virologic suppression and failure. Cox regression model was used for multivariate analysis. Of 2515 patients, 2020 (80.3%) were Italian, 286 (10.6%) migrants from low-income countries, of whom 201 (75.0%) from Africa, and 227 (9.0%) from high-income-countries. The median follow-up was 4.5 years (IQR 2.5–7). No difference was observed in the time of achievement of virological suppression in the three groups (log-rank: p = 0.5687). Higher probability of virologic failure was observed in Africans compared to Italians, to patients from high-income-countries and from low-income-countries other than Africans (Log-rank = p < 0.001). In the adjusted analysis, a higher virologic failure risk was found in Africans only compared to Italians. [HR 4.01; 95% CI 2.44–6.56, p < 0.001]. In Italy, African migrants are less likely to maintain virologic suppression compared to natives and other migrants. Targeted interventions could be needed for foreigners, especially for Africans.
Layer- and Cell Type-Specific Response Properties of Gustatory Cortex Neurons in Awake Mice

Studies in visual, auditory, and somatosensory cortices have revealed that different cell types as well as neurons located in different laminae display distinct stimulus response profiles. The extent to which these layer and cell type-specific distinctions generalize to gustatory cortex (GC) remains unknown. In this study, we performed extracellular recordings in adult female mice to monitor the activity of putative pyramidal and inhibitory neurons located in deep and superficial layers of GC. Awake, head-restrained mice were trained to lick different tastants (sucrose, salt, citric acid, quinine, and water) from a lick spout. We found that deep layer neurons show higher baseline firing rates (FRs) in GC with deep-layer inhibitory neurons displaying highest FRs at baseline and following the stimulus. GC's activity shows robust modulations before animals' contact with tastants, and this phenomenon is most prevalent in deep-layer inhibitory neurons. Furthermore, we show that licking activity strongly shapes the spiking pattern of GC pyramidal neurons, eliciting phase-locked spiking across trials and tastants. We demonstrate that there is a greater percentage of taste-coding neurons in deep versus superficial layers with chemosensitive neurons across all categories showing similar breadth of tuning, but different decoding performance. Lastly, we provide evidence for functional convergence in GC, with neurons that can show prestimulus activity, licking-related rhythmicity and taste responses. Overall, our results demonstrate that baseline and stimulus-evoked firing profiles of GC neurons and their processing schemes change as a function of cortical layer and cell type in awake mice. SIGNIFICANCE STATEMENT Sensory cortical areas show a laminar structure, with each layer composed of distinct cell types embedded in different circuits. While studies in other primary sensory areas have elucidated that pyramidal and inhibitory neurons belonging to distinct layers show distinct response properties, whether and how response properties of gustatory cortex (GC) neurons change as a function of their laminar position and cell type remains uninvestigated. Here, we show that there are several notable differences in baseline, prestimulus, and stimulus-evoked response profiles of pyramidal and inhibitory neurons belonging to deep and superficial layers of GC.
miR-29 Modulates CD40 Signaling in Chronic Lymphocytic Leukemia by Targeting TRAF4: an Axis Affected by BCR inhibitors.

B cell receptor (BCR) signaling and T cell interactions play a pivotal role in chronic lymphocytic leukemia (CLL) pathogenesis and disease aggressiveness. CLL cells can utilize microRNAs (miRNAs) and their targets to modulate microenvironmental interactions in the lymph node niches. To identify miRNA expression changes in the CLL microenvironment, we performed complex profiling of short non-coding RNAs in this context by comparing CXCR4/CD5 intraclonal cell subpopulations (CXCR4dimCD5bright vs. CXCR4brightCD5dim cells). This identified dozens of differentially expressed miRNAs including several that have previously been shown to modulate BCR signaling (miR-155, miR-150, and miR-22), but also other candidates for a role in microenvironmental interactions. Notably, all three miR-29 family members (miR-29a, miR-29b, miR-29c) were consistently down-modulated in the immune niches, and lower miR-29(a/b/c) levels associated with an increased relative responsiveness of CLL cells to BCR ligation, and significantly shorter overall survival of CLL patients. We identified Tumor-Necrosis Factor Receptor-Associated Factor 4 (TRAF4) as a novel direct target of miR-29s and revealed that higher TRAF4 levels increase CLL responsiveness to CD40 activation and downstream NFkB signaling. In CLL, BCR-represses miR-29 expression via MYC, allowing for concurrent TRAF4 upregulation and stronger CD40-NFkB signaling. This regulatory loop is disrupted by "BCR inhibitors" (BTK inhibitor ibrutinib or PI3K inhibitor idelalisib). In summary, we showed for the first time that a miRNA-dependent mechanism acts to activate CD40 signaling/T-cell interactions in a CLL microenvironment and described a novel miR-29-TRAF4-CD40 signaling axis modulated by the BCR activity.
Insights into a Protein-Nanoparticle System by Paramagnetic Perturbation NMR Spectroscopy

Background: The interaction between proteins and nanoparticles is a very relevant subject because of the potential applications in medicine and material science in general. Further interest derives from the amyloidogenic character of the considered protein, β2-microglobulin (β2m), which may be regarded as a paradigmatic system for possible therapeutic strategies. Previous evidence showed in fact that gold nanoparticles (AuNPs) are able to inhibit β2m fibril formation in vitro. Methods: NMR (Nuclear Magnetic Resonance) and ESR (Electron Spin Resonance) spectroscopy are employed to characterize the paramagnetic perturbation of the extrinsic nitroxide probe Tempol on β2m in the absence and presence of AuNPs to determine the surface accessibility properties and the occurrence of chemical or conformational exchange, based on measurements conducted under magnetization equilibrium and non-equilibrium conditions. Results: The nitroxide perturbation analysis successfully identifies the protein regions where protein-protein or protein-AuNPs interactions hinder accessibility or/and establish exchange contacts. These information give interesting clues to recognize the fibrillation interface of β2m and hypothesize a mechanism for AuNPs fibrillogenesis inhibition. Conclusions: The presented approach can be advantageously applied to the characterization of the interface in protein-protein and protein-nanoparticles interactions.
Studies of the Relative Biological Effectiveness and Biological Dose in Proton and Carbon Ion Therapy

Protons and heavier ions have an increased relative biological effectiveness (RBE) compared to photons. While variable RBE models are applied clinically in carbon ion therapy, the RBE in proton therapy is accounted for clinically by applying a constant RBE of 1.1. However, an increasing amount of experimental and clinical data show that also the proton RBE varies spatially within the patient. In addition, the existing carbon ion RBE models give substantially different RBE-weighted dose (often referred to as biological dose) distributions for the same irradiation scenarios. Improving the current RBE calculations is therefore crucial for the treatment received by patients. In this thesis, variables affecting the RBE and biological dose models were studied using the FLUKA Monte Carlo code. In the first part of the thesis, a low-energy proton beam cell irradiation experiment at the Oslo Cyclotron Laboratory (OCL) was implemented in FLUKA (Paper I). Applying the FLUKA implementation, the dose and linear energy transfer (LET) (both the dose-averaged LET (LETd) and LET spectra) were estimated in potential cell irradiation positions. The LETd values increased along the beam path, up to approximately 40 keV/μm in the distal dose-fall off. The LET spectra became narrower with depth in water. Comparisons with a simulated 80 MeV proton beam showed that the OCL beam had significantly higher LETd values and much narrower LET spectra for the same LETd values. The FLUKA implementation of the OCL beam demonstrated the importance of having proper proton beam characteristics to achieve accurate RBE versus LET data. In the second part of the thesis, the RBE model applied clinically in carbon ion therapy in Japan (the microdosimetric kinetic model, MKM) was implemented in FLUKA (Paper II). For the implementation, tables connecting the saturationcorrected dose-mean specific energy (  ) to particle type and particle kinetic energy were generated. The FLUKA implementation was then used to study the sensitivity of the MKM to variations in the model parameters (Paper III). The created  tables agreed well with the tables applied clinically in Japan. The
Workforce diversity and organizational performance of Kenya Tea Development Agency in Nairobi County, Kenya

The current changes in the business environment have exposed several challenges such as workforce diversity, which is a natural phenomenon that has both negative and positive impacts on the performance of the organization depending on how well it is managed. Failure to effectively manage diversity in the workforce can lead to poor performance of the organization. Consequently, this study sought to establish the influence of workforce diversity and the organizational performance of Kenya Tea Development Agency (KTDA) in Nairobi County, Kenya. The major purpose of the study was be guided by two specific objectives. The first specific objective was to establish the influence of age diversity on the organizational performance of KTDA in Nairobi County, Kenya. The second specific objective was to establish the influence of gender diversity on the organizational performance of KTDA in Nairobi County, Kenya. The study was guided by resource based view theory and social identity theory. Census method was used to study all the 68 senior managers drawn from 5 subsidiaries and the head office of KTDA in Nairobi County, Kenya. Structured questionnaires were used to collect data and the data was generalized by using descriptive statistics. Multiple Linear regression analysis to establish the association between the variables.The descriptive analysis results revealed that KTDA promotes age diversity and gender diversity. The multiple regression analysis results observed that age and gender diversities significantly boost the organizational performance of KTDA in terms of quality production of services, operational efficiency, profitability and effective service delivery. The government and the management of KTDA to formulate policies that would ensure that KTDA’s workforce contains both the old and young employees. Moreover, the government and the management of KTDA should formulate policies that ensure equal mix of both men and women in not only the managerial positions of the firm but also the junior roles across all of its departments. Since women have outstanding attributes that positively affects the strategic decisions of an organization.
Master Thesis: Estimation of a Simple New-Keynesian Model for Japan

In this paper, a simple version of the New-Keynesian DSGE model is described and then estimated for the Japanese economy using a Bayesian approach. Estimates for the parameters are obtained and the model’s statistical and economic properties are explained. A brief review of the main events of the late economic history of Japan is provided at a first stake, as well as a description of the Bayesian estimation techniques applied. Special focus is given to the fit of the standard Taylor monetary rule considered. Finally, a counterfactual exercise is done in order to explore the source of the reduction in volatility experienced.
GRAPHIC STYLES APPEARANCE IN EDUCATIONAL GAMES TO ENHANCE MALAYSIAN STUDENTS LEARNING: A Preliminary Study

Research on educational games has resulted to the increase in understanding of visual design elements in game development. The effectiveness of the graphic styles presentation in an educational game also benefited students in their learning process. This paper is intended to make an initial survey and discuss how graphic styles, learning and student involvement are inexorably linked. Interviews and questionnaires were conducted to identify the importance of graphic elements needed to conduct in the development of educational games. 39 respondents were selected to participate in this preliminary study ranging from an expert in games from Universiti Malaysia Sabah (UMS), two game developers, a teacher with ICT background, two high schools teachers and 30 Form one students. Preliminary study have shown that the educational games research in Malaysia is still less pressing in visual design aspect especially in terms of graphic styles which can be implicated in educational games and to enhance Malaysian students learning.
The Dilemma of Transplanting Wiskott-Aldrich Syndrome Patients or not to Transplant

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency disorder, It represents almost 3-5% of all our Primary Immune Deficiency Disease (PIDD) patients while Severe Combined Immune Deficiency (SCID) represents over 60% of all PIDD since the autosomal recessive takes the lead due to high rate of consanguinity in marriages. In this study we report 29 patients presented to our center and recorded in our database. Two families were excluded because of suspected Wiskott-Aldrich Interacting Protein (WIP) rather than WAS mutation. Twenty confirmed WAS patients have stem cell transplant, 14 patients received transplant from HLA-identical matched related donors while 6 patients received HLAmatched unrelated cord blood stem cells. We did not perform any MUDD or T-cell depleted haploidentical stem cell transplant in our center on any of our WAS patients. The overall survival of the transplanted patients was 89.5%, with 100% survival in the HLA-matched related stem cell recipients and 66.6 % survival in the matched –unrelated Cord blood stem cell recipients. Survival among non-transplanted patients was only 60% till the end of the study with very poor quality of life. According to our findings we highly recommend Hematopoietic stem cell transplantation in patients with WAS as early as possible if a fullmatched related donor available, for those with no such donor, Cord blood hematopoietic stem cell represent a good alterative in these patients especially those with severe disease.