Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of Natural Inhibitors Against SARS-CoV-2 Drugable Targets Using Molecular Docking, Molecular Dynamics Simulation, and MM-PBSA Approach

The present study explores the SARS-CoV-2 drugable target inhibition efficacy of phytochemicals from Indian medicinal plants using molecular docking, molecular dynamics (MD) simulation, and MM-PBSA analysis. A total of 130 phytochemicals were screened against SARS-CoV-2 Spike (S)-protein, RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro). Result of molecular docking showed that Isoquercetin potentially binds with the active site/protein binding site of the Spike, RdRP, and Mpro targets with a docking score of -8.22, -6.86, and -9.73 kcal/mole, respectively. Further, MS 3, 7-Hydroxyaloin B, 10-Hydroxyaloin A, showed -9.57, -7.07, -8.57 kcal/mole docking score against Spike, RdRP, and Mpro targets respectively. The MD simulation was performed to study the favorable confirmation and energetically stable complex formation ability of Isoquercetin and 10-Hydroxyaloin A phytochemicals in Mpro-unbound/ligand bound/standard inhibitor bound system. The parameters such as RMSD, RMSF, Rg, SASA, Hydrogen-bond formation, energy landscape, principal component analysis showed that the lead phytochemicals form stable and energetically stabilized complex with the target protein. Further, MM-PBSA analysis was performed to compare the Gibbs free energy of the Mpro-ligand bound and standard inhibitor bound complexes. The analysis revealed that the His-41, Cys145, Met49, and Leu27 amino acid residues were majorly responsible for the lower free energy of the complex. Drug likeness and physiochemical properties of the test compounds showed satisfactory results. Taken together, the study concludes that that the Isoquercetin and 10-Hydroxyaloin A phytochemical possess significant efficacy to bind SARS-Cov-2 Mpro active site. The study necessitates further in vitro and in vivo experimental validation of these lead phytochemicals to assess their anti-SARS-CoV-2 potential.
Climate Change Induced Trends and Uncertainties in Phytoplankton Spring Bloom Dynamics

Spring phytoplankton blooms in the southern North Sea substantially contribute to annual primary production and largely influence food web dynamics. Studying long-term changes in spring bloom dynamics is therefore crucial for understanding future climate responses and predicting implications on the marine ecosystem. This paper aims to study long term changes in spring bloom dynamics in the Dutch coastal waters, using historical coastal in-situ data and satellite observations as well as projected future solar radiation and air temperature trajectories from regional climate models as driving forces covering the twenty-first century. The main objective is to derive long-term trends and quantify climate induced uncertainties in future coastal phytoplankton phenology. The three main methodological steps to achieve this goal include (1) developing a data fusion model to interlace coastal in-situ measurements and satellite chlorophyll-a observations into a single multi-decadal signal; (2) applying a Bayesian structural time series model to produce long-term projections of chlorophyll-a concentrations over the twenty-first century; and (3) developing a feature extraction method to derive the cardinal dates (beginning, peak, end) of the spring bloom to track the historical and the projected changes in its dynamics. The data fusion model produced an enhanced chlorophyll-a time series with improved accuracy by correcting the satellite observed signal with in-situ observations. The applied structural time series model proved to have sufficient goodness-of-fit to produce long term chlorophyll-a projections, and the feature extraction method was found to be robust in detecting cardinal dates when spring blooms were present. The main research findings indicate that at the study site location the spring bloom characteristics are impacted by the changing climatic conditions. Our results suggest that toward the end of the twenty-first century spring blooms will steadily shift earlier, resulting in longer spring bloom duration. Spring bloom magnitudes are also projected to increase with a 0.4% year−1 trend. Based on the ensemble simulation the largest uncertainty lies in the timing of the spring bloom beginning and -end timing, while the peak timing has less variation. Further studies would be required to link the findings of this paper and ecosystem behavior to better understand possible consequences to the ecosystem.
M2 Macrophage-Based Prognostic Nomogram for Gastric Cancer After Surgical Resection

A good prediction model is useful to accurately predict patient prognosis. Tumor–node–metastasis (TNM) staging often cannot accurately predict prognosis when used alone. Some researchers have shown that the infiltration of M2 macrophages in many tumors indicates poor prognosis. This approach has the potential to predict prognosis more accurately when used in combination with TNM staging, but there is less research in gastric cancer. A multivariate analysis demonstrated that CD163 expression, TNM staging, age, and gender were independent risk factors for overall survival. Thus, these parameters were assessed to develop the nomogram in the training data set, which was tested in the validation and whole data sets. The model showed a high degree of discrimination, calibration, and good clinical benefit in the training, validation, and whole data sets. In conclusion, we combined CD163 expression in macrophages, TNM staging, age, and gender to develop a nomogram to predict 3- and 5-year overall survivals after curative resection for gastric cancer. This model has the potential to provide further diagnostic and prognostic value for patients with gastric cancer.
Breast-Conserving Therapy Has Better Prognosis for Tumors in the Central and Nipple Portion of Breast Cancer Compared with Mastectomy: A SEER Data-Based Study

Background and Objectives Currently, the location of primary tumor was an independent prognostic factor of breast cancer. Tumors in the central and nipple portion (TCNP) had poor prognosis compared to other peripheral quadrants. The breast-conserving therapy (BCT) is becoming increasingly common worldwide in breast cancer operations. However, whether the availability of BCT was performed for TCNP remained a matter of debate. We sought to investigate whether BCT was suitable for TCNP with respect to survival outcomes, compared with mastectomy therapy. Methods Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we obtained TCNP breast cancer patients diagnosed during the period of 2010–2015. One-to-one (1:1) propensity score matching (PSM) was applied to construct a matched sample consisting of pairs of BCT and mastectomy groups. Univariate and multivariate Cox proportional hazard models were applied to estimate the factors associated with breast cancer-specific survival (BCSS) and overall survival (OS). Survival analysis was performed with the Kaplan–Meier method. Results In the overall cohort, a total of 9,900 patients were enrolled. We found that patients with BCT showed significantly better BCSS (log-rank, p < 0.001) and OS (log-rank, p < 0.001) than the mastectomy group before PSM. The same finding was also shown in 5,820 patients after PSM. Additionally, none of the subgroups, including age, sex, race, histological grade, AJCC stage, and molecular subtype undergoing mastectomy therapy, had better BCSS than BCT. Conclusions Our study was the first research to show that BCT exhibited superior prognosis in the cohort of TCNP from SEER databases than mastectomy therapy. This finding could provide a cue for treatment strategies for suitable TCNP patients, especially those with a strong willingness to conserve their breasts.
Psychological Well-Being of Parents of Very Young Children With Type 1 Diabetes – Baseline Assessment

Background Type 1 diabetes in young children is a heavy parental burden. As part of pilot phase of the KIDSAP01 study, we conducted a baseline assessment in parents to study the association between hypoglycemia fear, parental well-being and child behavior. Methods All parents were invited to fill in baseline questionnaires: hypoglycemia fear survey (HFS), WHO-5, Epworth Sleepiness Scale and Strength and Difficulties Questionnaire (SDQ). Results 24 children (median age: 5-year, range 1-7 years, 63% male, mean diabetes duration: 3 ± 1.7 years) participated. 23/24 parents filled out the questionnaires. We found a higher score for the hypoglycemia fear behavior 33.9 ± 5.6 compared to hypoglycemia worry 34.6 ± 12.2. Median WHO-5 score was 16 (8 - 22) with poor well-being in two parents. Median daytime sleepiness score was high in five parents (>10). For six children a high total behavioral difficulty score (>16) was reported. Pro social behavior score was lower than normal in six children (<6). Parental well-being was negatively associated with HFS total (r = - 0.50, p <.05) and subscale scores (r = - 0.44, p <.05 for HFS-Worry and HFS-Behavior), child behavior (r = - 0.45, p = .05) and positively with child age and diabetes duration (r = 0.58, p <.01, r = 0.6, p <.01). HFS, parental well-being nor daytime sleepiness are associated with the HbA1c. Conclusion Regular screening of parental well-being, hypoglycemia fear and child behavior should be part of routine care to target early intervention.
Which Trauma Treatment Suits me? Identification of Patients' Treatment Preferences for Posttraumatic Stress Disorder (PTSD)

Several psychotherapy treatments exist for posttraumatic stress disorder. This study examines the treatment preferences of treatment-seeking traumatized adults in Germany and investigates the reasons for their treatment choices. Preferences for prolonged exposure, cognitive behavioral therapy (CBT), eye movement desensitization and reprocessing (EMDR), psychodynamic psychotherapy and stabilization were assessed via an online survey. Reasons for preferences were analyzed by means of thematic coding by two independent rates. 104 traumatized adults completed the survey. Prolonged exposure and CBT were each preferred by nearly 30%, and EMDR and psychodynamic psychotherapy were preferred by nearly 20%. Stabilization was significantly less preferred than all other options, by only 4%. Significantly higher proportions of patients were disinclined to choose EMDR and stabilization. Patients who preferred psychodynamic psychotherapy were significantly older than those who preferred CBT. Reasons underlying preferences included the perceived treatment mechanisms and treatment efficacy. Traumatized patients vary in their treatment preferences. Preference assessments may help clinicians comprehensively address patients' individual needs and thus improve therapy outcomes.
Identification of BRCA2 Cis Double Heterozygous Breast Cancer Cases Using Whole Exome Sequencing: Phenotypic Expression and Impact on Personalized Oncology

BRCA1 and BRCA2 are the most commonly mutated breast cancer susceptibility genes that convey a high risk of breast and ovarian cancer. Most BRCA1 or BRCA2 mutation carriers have inherited a single heterozygous mutation. In recent years, very rare cases with biallelic or trans double heterozygous mutations on BRCA1 and or BRCA2 have been identified and seem to be associated with distinctive phenotypes. Given that this genotype-phenotype correlation in cancer predisposing hereditary conditions is of relevance for oncological prevention and genetic testing, it is important to investigate these rare BRCA genotypes for better clinical management of BRCA mutation carriers. Here we present the first report on Cis double heterozygosity (Cis DH) on BRCA2 gene identified using Whole exome sequencing (WES) in a Tunisian family with two BRCA2 mutations namely: c.632-1G>A and c. 1310_1313DelAAGA that are both reported as pathogenic in ClinVar database. Subsequent analysis in 300 high-risk Tunisian breast cancer families detected this Cis double heterozygous genotype in 8 additional individuals belonging to 5 families from the same geographic origin suggesting a founder effect. Moreover, the observed Cis DH seems to be associated with an early age of onset (mean age = 35.33 years) and severe phenotype of the disease with high breast cancer grade and multiple cancer cases in the family. The identification of unusual BRCA genotypes in this Tunisian cohort highlights the importance of performing genetic studies in under-investigated populations. This will also potentially help avoiding erroneous classifications of genetic variants in African population and therefore avoiding clinical misdiagnosis of BRCA related cancers. Our findings will also have an impact on the genetic testing and the clinical management of North African breast cancer patients as well as patients from different other ethnic groups in regard to several emerging target therapies such as PARP inhibitors.
Late Quaternary Climate Reconstruction and Lead-Lag Relationships of Biotic and Sediment-Geochemical Indicators at Lake Bolshoe Toko, Siberia

Millennial-scale climate change history in eastern Siberia and relationships between diatom diversity, paleoclimate, and sediment-geochemical lake system trajectories are still poorly understood. This study investigates multi-proxy time series reaching back to the Late Pleistocene derived from radiocarbon dated Lake Bolshoe Toko sediment cores, southeastern Yakutia, Russia. We analyzed diatoms, elements (XRF), minerals (XRD), grain-size, organic carbon, and included chironomid analyses and published pollen-data for quantitative paleoclimate reconstruction. Changes in diatom species abundances reveal repeated episodes of thermal stratification indicated by shifts from euplanktonic Aulacoseira to Cyclotella species. Chironomid and pollen-inferred temperature reconstruction reveal that the main shift between these diatom species is related to the onset of Holocene Thermal Maximum (HTM) at 7.1 cal ka BP. Comparison to other paleoclimate records along a north-south transect through Yakutia shows that the HTM was delayed as far south as the Stanovoy mountains. Relationships between sediment-geochemistry, paleoclimate variability and diatom species richness (alpha diversity) was tested in a moving temporal offset approach to detect lead-lag relationships. Sediment-geochemical data, mainly uniform during the Holocene, revealed strongest positive or negative correlations ahead of species richness changes. Mean July air temperature (TJuly) reconstructions correlate with both Hill numbers and relative assemblage changes indicated by sample scores of multidimensional scaling analysis (MDS) over the entire time series. We found that sediment organic carbon revealed distinct positive correlations, i.e., centennial-scale delay to increases in diatom effective richness (Hill numbers N0 and N2). We conclude that a lag of deposited organic carbon concentrations behind changes in diatom alpha diversity reveals that species richness can augment the production and thus sequestration of organic matter in comparable lake systems.
Response to Immune Checkpoint Inhibitor Treatment in Advanced Cervical Cancer and Biomarker Study

Background: Checkpoint inhibitor immunotherapy or immuno-oncology (IO) treatment in refractory cervical cancer yielded an objective response rate (ORR) of 12% in tumors expressing the programmed cell death ligand-1 (PD-L1) in the KEYNOTE-158 phase II study. We hypothesized that the positive response might be associated with the level of PD-L1 expression and/or the tumor mutation burden (TMB). We also aimed to analyze if responses could be associated with platinum sensitivity. Methods: This is a retrospective study of all consecutive patients with cervical cancer who received pembrolizumab or nivolumab. Results: Ten patients were identified. Median age was 64.5 years old (range 48–80). The response rate was 70% and the median duration of response was 21.0 months (range 1.8–26.7) after 20.7 months of follow-up (range 2.0–31.0). The response rate was 80% in patients with PD-L1 combined positive score (CPS) ≥ 10, and 75% in patients with tumor mutation burden (TMB) ≥ 10 mut/Mb. The mean progression-free survival (PFS) for the entire cohort was 20.2 months (95% CI 12.0–28.5). Seven patients had treatment for >12 months (range 14.6–31.0). Five patients were platinum-sensitive and 5 patients were platinum-resistant at the time of immunotherapy, and the response rate was similar regardless of platinum sensitivity. Conclusions: The positive response to IO treatment in advanced cervical cancer in this study was higher than published, and a possible association with the level of PD-L1 expression and the TMB level was suggested. A PD-L1 CPS score ≥ 10 or TMB ≥ 10 may be biomarkers to correlate with response, which should be explored in large studies.
Current Understanding of Hearing Loss in Sporadic Vestibular Schwannomas: A Systematic Review

Objective Hearing loss is the most common initial symptom in patients with sporadic vestibular schwannomas (SVS). Hearing preservation is an important goal of both conservative and surgical therapy. However, the mechanism of SVS-associated hearing loss remains unclear. Thus, we performed this systematic review to summarize the current understanding of hearing loss in the SVS and distill a testable hypothesis to further illuminate its underlying mechanism. Methods A systematic review querying four databases (PubMed, Medline, Embase, and Web of Science) was performed to identify studies evaluating hearing loss in patients with SVS and exploring the potential mechanisms of hearing impairment. Results A total of 50 articles were eligible and included in this review. After analysis, the retrieved studies could be categorized into four types: (1) 29 studies explore the relationship between hearing loss and the growth pattern of the tumor (e.g., tumor size/volume, growth rate, tumor location, etc.); (2) ten studies investigate the potential role of cochlear dysfunction in hearing deterioration, including structural abnormality, protein elevation in perilymph, and cochlear malfunctioning; (3) two studies looked into SVS-induced impairment of auditory pathway and cortex; (4) in the rest nine studies, researchers explored the molecular mechanism underlying hearing loss in SVS, which involves molecular and genetic alterations, inflammatory response, growth factors, and other tumor-associated secretions. Conclusions Multiple factors may contribute to the hearing impairment in SVS, including the growth pattern of tumor, cochlear dysfunction, impairment of auditory pathway and cortex, genetic and molecular changes. However, our current understanding is still limited, and future studies are needed to explore this multifactorial hypothesis and dig deeper into its underlying mechanism.
Development and Validation of a Nomogram for Predicting Prognosis to Immune Checkpoint Inhibitors Plus Chemotherapy in Patients With Non-Small Cell Lung Cancer

Background Immune checkpoint inhibitors (ICIs) plus chemotherapy improved the prognosis of patients with non-small cell lung cancer (NSCLC); however, reliable prognostic biomarkers are lacking. We explored factors associated with prognosis and developed a predictive model. Methods We retrospectively analyzed 130 consecutive stage IIIA–IVB NSCLC patients treated with ICIs combined with chemotherapy. Cox univariate and multivariate proportional hazards regression analyses were used to identify prognostic factors associated with progression-free survival (PFS). A nomogram was developed based on key factors in the training cohort (n = 86) and evaluated in the validation cohort (n = 44). According to the nomogram-based total point scores, we divided patients into low- and high-risk groups. Results In the training cohort, bone metastases (p = 0.017) and an increased derived neutrophil-to-lymphocyte ratio (p = 0.018) were significantly associated with poor PFS, while smoking (p = 0.007) and programmed death-ligand 1 (PD-L1) ≥50% (p = 0.001) were associated with improved PFS. A nomogram based on these factors was developed to predict PFS at 3, 6, and 12 months. The C-index of the nomogram to predict PFS was 0.725 (95% CI: 0.711–0.739) in the training cohort and 0.688 (95% CI: 0.665–0.711) in the validation cohort. The area under the curve (AUC) exhibited an acceptable discriminative ability, and calibration curves demonstrated a consistency between the actual results and predictions. In the training cohort, the median PFS (mPFS) was 12.3 and 5.7 months in the low- and high-risk groups, respectively (p < 0.001). In the validation cohort, the mPFS was 12.6 and 6.2 months in the low- and high-risk groups, respectively (p = 0.021). Conclusions A predictive nomogram was developed to help clinicians assess prognosis early for advanced NSCLC patients who received ICI plus chemotherapy.
The Emergence of Shared Leadership in Innovation Labs

Implementing innovation laboratories to leverage intrapreneurship are an increasingly popular organizational practice. A typical feature in these creative environments are semi-autonomous teams in which multiple members collectively exert leadership influence, thereby challenging traditional command-and-control conceptions of leadership. An extensive body of research on the team-centric concept of shared leadership has recognized the potential for pluralized leadership structures in enhancing team effectiveness; however, little empirical work has been conducted in organizational contexts in which creativity is key. This study set out to explore antecedents of shared leadership and its influence on team creativity in an innovation lab. Building on extant shared leadership and innovation research, we propose antecedents customary to creative teamwork, that is, experimental culture, task reflexivity, and voice. Multisource data were collected from 104 team members and 49 evaluations of 29 coaches nested in 21 teams working in a prototypical innovation lab. We identify factors specific to creative teamwork that facilitate the emergence of shared leadership by providing room for experimentation, encouraging team members to speak up in the creative process, and cultivating a reflective application of entrepreneurial thinking. We provide specific exemplary activities for innovation lab teams to increase levels of shared leadership.