Miracle-dz/UniFAR-FTUs huggingface dataset:
Visualizing Uncertainty for Non-Expert End Users: The Challenge of the Deterministic Construal Error

There is a growing body of evidence that numerical uncertainty expressions can be used by non-experts to improve decision quality. Moreover, there is some evidence that similar advantages extend to graphic expressions of uncertainty. However, visualizing uncertainty introduces challenges as well. Here, we discuss key misunderstandings that may arise from uncertainty visualizations, in particular the evidence that users sometimes fail to realize that the graphic depicts uncertainty. Instead they have a tendency to interpret the image as representing some deterministic quantity. We refer to this as the deterministic construal error. Although there is now growing evidence for the deterministic construal error, few studies are designed to detect it directly because they inform participants upfront that the visualization expresses uncertainty. In a natural setting such cues would be absent, perhaps making the deterministic assumption more likely. Here we discuss the psychological roots of this key but underappreciated misunderstanding as well as possible solutions. This is a critical question because it is now clear that members of the public understand that predictions involve uncertainty and have greater trust when uncertainty is included. Moreover, they can understand and use uncertainty predictions to tailor decisions to their own risk tolerance, as long as they are carefully expressed, taking into account the cognitive processes involved.
SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma

SARS-CoV-2 501Y.V2, a novel lineage of the coronavirus causing COVID-19, contains multiple mutations within two immunodominant domains of the spike protein. Here we show that this lineage exhibits complete escape from three classes of therapeutically relevant monoclonal antibodies. Furthermore 501Y.V2 shows substantial or complete escape from neutralizing antibodies in COVID-19 convalescent plasma. These data highlight the prospect of reinfection with antigenically distinct variants and may foreshadow reduced efficacy of current spike-based vaccines.
Mining metagenomes for natural product biosynthetic gene clusters: unlocking new potential with ultrafast techniques

Microorganisms produce an immense variety of natural products through the expression of Biosynthetic Gene Clusters (BGCs): physically clustered genes that encode the enzymes of a specialized metabolic pathway. These natural products cover a wide range of chemical classes (e.g., aminoglycosides, lantibiotics, nonribosomal peptides, oligosaccharides, polyketides, terpenes) that are highly valuable for industrial and medical applications1. Metagenomics, as a culture-independent approach, has greatly enhanced our ability to survey the functional potential of microorganisms and is growing in popularity for the mining of BGCs. However, to effectively exploit metagenomic data to this end, it will be crucial to more efficiently identify these genomic elements in highly complex and ever-increasing volumes of data2. Here, we address this challenge by developing the ultrafast Biosynthetic Gene cluster MEtagenomic eXploration toolbox (BiG-MEx). BiG-MEx rapidly identifies a broad range of BGC protein domains, assess their diversity and novelty, and predicts the abundance profile of natural product BGC classes in metagenomic data. We show the advantages of BiG-MEx compared to standard BGC-mining approaches, and use it to explore the BGC domain and class composition of samples in the TARA Oceans3 and Human Microbiome Project datasets4. In these analyses, we demonstrate BiG-MEx’s applicability to study the distribution, diversity, and ecological roles of BGCs in metagenomic data, and guide the exploration of natural products with clinical applications.
Recombination Facilitates Adaptive Evolution in Rhizobial Soil Bacteria

Homologous recombination is expected to increase natural selection efficacy by decoupling the fate of beneficial and deleterious mutations and by readily creating new combinations of beneficial alleles. Here, we investigate how the proportion of amino acid substitutions fixed by adaptive evolution (α) depends on the recombination rate in bacteria. We analyze 3086 core protein-coding sequences from 196 genomes belonging to five closely-related species of the genus Rhizobium. These genes are found in all species and do not display any signs of introgression between species. We estimate α using the site frequency spectrum (SFS) and divergence data for all pairs of species. We evaluate the impact of recombination within each species by dividing genes into three equally sized recombination classes based on their average level of intragenic linkage disequilibrium. We find that α varies from 0.07 to 0.39 across species and is positively correlated with the level of recombination. This is both due to a higher estimated rate of adaptive evolution and a lower estimated rate of non-adaptive evolution, suggesting that recombination both increases the fixation probability of advantageous variants and decreases the probability of fixation of deleterious variants. Our results demonstrate that homologous recombination facilitates adaptive evolution measured by α in the core genome of prokaryote species in agreement with studies in eukaryotes. Significance statement Whether intraspecific homologous recombination has a net beneficial or detrimental effect on adaptive evolution is largely unexplored in natural bacterial populations. We address this question by evaluating polymorphism and divergence data across the core genomes of 196 bacterial sequences––belonging to five closely related species of the genus Rhizobium. We show that the proportion of amino acid changes fixed due to adaptive evolution (α) increases with an increased recombination rate. This correlation is observed both in the interspecies and intraspecific comparisons. By using a population genetics approach our results demonstrate that homologous recombination directly impacts the efficacy of natural selection in the core genome of prokaryotes, as previously reported in eukaryotes.
Splenic Denervation Attenuates Repeated Social Defeat Stress-Induced T Lymphocyte Inflammation

Background Post-traumatic stress disorder (PTSD) is a devastating psychological disorder that significantly increases the risk for inflammatory diseases. While the exact etiology of this predisposition remains unclear, PTSD canonically increases overall sympathetic tone resulting in increased norepinephrine (NE) outflow. Previously, we demonstrated that exogenous NE alters mitochondrial superoxide in T-lymphocytes to produce a pro-inflammatory T-helper 17 (TH17) phenotype. Therefore, we hypothesized sympathetic-driven neuroimmune interactions could mediate psychological trauma-induced T-lymphocyte inflammation. Methods Repeated social defeat stress (RSDS) is a preclinical murine model that recapitulates the behavioral, autonomic, and inflammatory aspects of PTSD. Targeted splenic denervation (Dnx) was performed to deduce the contribution of splenic sympathetic nerves to RSDS-induced inflammation. Eighty-five C57BL/6J mice underwent Dnx or sham-operation, followed by RSDS or control paradigms. Animals were assessed for behavioral, autonomic, inflammatory, and redox profiles. Results Dnx did not alter the antisocial or anxiety-like behavior induced by RSDS. In circulation, RSDS Dnx animals exhibited diminished levels of T-lymphocyte-specific cytokines (IL-2, IL-17A, and IL-22) compared to intact animals, whereas other non-specific inflammatory cytokines (e.g., IL-6, TNF-α, and IL-10) were unaffected by Dnx. Importantly, Dnx specifically ameliorated the increases in RSDS-induced T-lymphocyte mitochondrial superoxide, TH17 polarization, and pro-inflammatory gene expression with minimal impact to non-T-lymphocyte immune populations. Conclusions Overall, our data suggest that sympathetic nerves regulate RSDS-induced splenic T-lymphocyte inflammation, but play a minimal role in the behavioral and non-T-lymphocyte inflammatory phenotypes induced by this psychological trauma paradigm.
Spatial Connectivity and Drivers of Shark Habitat Use Within a Large Marine Protected Area in the Caribbean, The Bahamas Shark Sanctuary

Marine protected areas (MPAs) have emerged as potentially important conservation tools for the conservation of biodiversity and mitigation of climate impacts. Among MPAs, a large percentage has been created with the implicit goal of protecting shark populations, including 17 shark sanctuaries which fully protect sharks throughout their jurisdiction. The Commonwealth of the Bahamas represents a long-term MPA for sharks, following the banning of commercial longlining in 1993 and subsequent designation as a shark sanctuary in 2011. Little is known, however, about the long-term behavior and space use of sharks within this protected area, particularly among reef-associated sharks for which the sanctuary presumably offers the most benefit. We used acoustic telemetry to advance our understanding of the ecology of such sharks, namely Caribbean reef sharks (Carcharhinus perezi) and tiger sharks (Galeocerdo cuvier), over two discrete islands (New Providence and Great Exuma) varying in human activity level, over 2 years. We evaluated which factors influenced the likelihood of detection of individuals, analyzed patterns of movement and occurrence, and identified variability in habitat selection among species and regions, using a dataset of 23 Caribbean reef sharks and 15 tiger sharks which were passively monitored in two arrays with a combined total of 13 acoustic receivers. Caribbean reef sharks had lower detection probabilities than tiger sharks, and exhibited relatively low habitat connectivity and high residency, while tiger sharks demonstrated wider roaming behavior across much greater space. Tiger sharks were associated with shallow seagrass habitats where available, but frequently transited between and connected different habitat types. Our data support the notion that large MPAs afford greater degrees of protection for highly resident species such as Caribbean reef sharks, shark, acoustic telemetry, marine protected area, MPA, seagrass, coral reef, Bahamas, Caribbean
In Silico, In Vitro and In Vivo Pharmacodynamic Characterization of Novel Analgesic Drug Candidate Somatostatin SST4 Receptor Agonists

Background: Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via its receptor subtype 4 (SST4) without influencing endocrine functions. Therefore, SST4 is considered to be a novel target for drug development in pain, especially chronic neuropathy which is a great unmet medical need. Purpose and Experimental Approach: Here, we examined the in silico binding, SST4-linked G protein activation and β-arrestin activation on stable SST4 expressing cells and the effects of our novel pyrrolo-pyrimidine molecules (20, 100, 500, 1,000, 2,000 µg·kg−1) on partial sciatic nerve ligation-induced traumatic mononeuropathic pain model in mice. Key Results: The novel compounds bind to the high affinity binding site of SST4 the receptor and activate the G protein. However, unlike the reference SST4 agonists NNC 26-9100 and J-2156, they do not induce β-arrestin activation responsible for receptor desensitization and internalization upon chronic use. They exert 65–80% maximal anti-hyperalgesic effects in the neuropathy model 1 h after a single oral administration of 100–500 µg·kg−1 doses. Conclusion and Implications: The novel orally active compounds show potent and effective SST4 receptor agonism in vitro and in vivo. All four novel ligands proved to be full agonists based on G protein activation, but failed to recruit β-arrestin. Based on their potent antinociceptive effect in the neuropathic pain model following a single oral administration, they are promising candidates for drug development.
Self-organization and information transfer in Antarctic krill swarms

Antarctic krill swarms are one of the largest known animal aggregations. However, despite being the keystone species of the Southern Ocean, little is known about how swarms are formed and maintained, and we lack a detailed understanding of the local interactions between individuals that provide the basis for these swarms. Here we analyzed the trajectories of captive, wild-caught krill in 3D to determine individual level interaction rules and quantify patterns of information flow. Our results suggest krill operate a novel form of collective organization, with measures of information flow and individual movement adjustments expressed most strongly in the vertical dimension, a finding not seen in other swarming species. In addition, local directional alignment with near neighbors, and strong regulation of both direction and speed relative to the positions of groupmates suggest social factors are vital to the formation and maintenance of swarms. This research represents a first step in understanding the fundamentally important swarming behavior of krill.
Retinal Microvascular Changes in Subtypes of Ischemic Stroke

Aims: Retinal microvasculature shares prominent similarities with the brain vasculature. We aimed to assess the association between retinal microvasculature and subtypes of ischemic stroke. Method: We consecutively enrolled ischemic stroke patients within 7 days of onset, who met the criteria of subtype of atherothrombosis (AT), small artery disease (SAD), or cardioembolism (CE) according to a modified version of the Trial of Org 10172 in Acute Stroke Treatment (NEW-TOAST). Digital fundus photographs were taken within 72 h of hospital admission using a digital camera (Topcon TRC-50DX), and fundus photographs were semi-automatically measured by software (Canvus 14 and NeuroLucida) for retinal vasculature parameters. Results: A total of 141 patients were enrolled, including 72 with AT, 54 with SAD, and 15 with CE. AT subtype patients had the widest mean venular diameter within 0.5–1.0 disk diameter (MVD0.5−1.0DD) followed by SAD and CE subtypes (86.37 ± 13.49 vs. 83.55 ± 11.54 vs. 77.90 ± 8.50, respectively, P = 0.047); CE subtype patients had the highest mean arteriovenous ratio within 0.5–1.0 disk diameter (MAVR0.5−1.0DD) followed by the AT and SAD subtype groups (0.97 ± 0.03 vs. 0.89 ± 0.99 vs. 0.89 ± 0.11, respectively, P = 0.010); SAD subtype patients were found with the highest mean venular tortuosity within 0.0–2.0 disk diameter (MVT0.0−2.0DD) followed by the AT and CE subtypes (1.0294 ± 0.0081 vs. 1.0259 ± 0.0084 vs. 1.0243 ± 0.0066, respectively, P = 0.024). After adjusting for clinic characteristics, MVD0.5−1.0DD was significantly different among AT, SAD, and CE subtypes (P = 0.033). By receiver operating characteristic curve analysis, MVD0.5−1.0DD predicted the AT subtype (area 0.690, 95% confidence interval, 0.566–0.815), with a cutoff value of 82.23 μm (sensitivity 61.1%, specificity 73.3%). Conclusion: Retinal MVD0.5−1.0DD (>82.23 μm) might be associated with the AT stroke subtype; however, we need large-scale prospective studies in future to explore the underlying mechanism and causal explanation for this finding.
Immunologic “Cold” Squamous Cell Carcinomas of the Head and Neck Are Associated With an Unfavorable Prognosis

Background: Head and neck squamous cell carcinoma (HNSCC) represents a common cancer worldwide. Past therapeutic advances have not significantly improved HNSCC prognosis. Therefore, it is necessary to further stratify HNSCC, especially with recent advances in tumor immunology. Methods: Tissue microarrays were assembled from tumor tissue samples and were complemented with comprehensive clinicopathological data of n = 419 patients. H&E whole slides from resection specimen (n = 289) were categorized according to their immune cell infiltrate as “hot,” “cold,” or “excluded. ” Results: Investigating tumor immune cell patterns, we found significant differences in survival rates. Immunologic “hot” and “excluded” HNSCCs are associated with better overall survival than “cold” HNSCC patients (p < 0.05). Interestingly, the percentage of all three patterns is nearly identical in p16 positive and negative HNSCCs. Conclusions: Using a plain histological H&E approach to categorize HNSCC as being immunologic “hot,” “cold,” or “excluded” can offer a forecast of patients' prognosis and may thus aid as a potential prognostic tool in routine pathology reports. This “hot-cold-excluded” scheme needs to be applied to more HNSCC cohorts and possibly to other cancer types to determine prognostic meaning, e.g., regarding OS or DFS. Furthermore, our cohort reflects epidemiological data in the national, European, and international context. It may, therefore, be of use for future HNSCC characterization.
Challenges of Psychiatry Drug Development and the Role of Human Pharmacology Models in Early Development—A Drug Developer's Perspective

Psychiatric diseases have the lowest probability of success in clinical drug development. This presents not only an issue to address the unmet medical needs of patients, but also a hurdle for pharmaceutical and biotech industry to continue R&D in this disease area. Fundamental pharmacokinetic and pharmacodynamic principles provide an understanding of the drug exposure, target binding and pharmacological activity at the target site of action for a new drug candidate. Collectively, these principles determine the likelihood of testing the mechanism of action and enhancing the likelihood of candidate survival in Phase 2 clinical development, therefore, they are termed as the “three pillars of survival. ” Human Phase 1 pharmacokinetic and pharmacodynamic studies provide evidence of the three pillars. Electroencephalogram (EEG) assessments and cognitive function tests in schizophrenia patients can provide proof of pharmacology and ensure that a pharmacological active regimen will be tested in Phase 2 proof of concept (POC) studies for the treatment of cognitive impairment associated with schizophrenia (CIAS).
Thromboembolism in Older Adults

Arterial and venous thromboembolism are both more common in older adults. The use of anticoagulants, the mainstay to prevent thromboembolism, requires consideration of the balance between risk and benefit. Such consideration is even more important in the very elderly in whom the risk of anticoagulant-related bleeding and thrombosis are higher. This review will focus on the challenges of implementing and managing anticoagulant therapy in older patients in an era when the options for anticoagulants include not only vitamin K antagonists (VKAs), but also direct-acting oral anticoagulants (DOACs).
POSTMORTEM BIOCHEMICAL AND TEXTURAL CHANGES IN THE ADDUCTOR MUSCLE OF CATARINA SCALLOP STORED AT 0C

Postmortem characteristics of the adductor muscle of the Catarina scallop were evaluated for biochemical, chemical and textural changes during a 15-day storage period in ice (0C). K-value, pH, nitrogen of trimethylamine (TMA-N), nitrogen of total volatile bases (TVB-N), water-holding capacity (WHC), color and texture changes were monitored. K value increased linearly from an initial value of 20.5 to 68.5% at day 15. Spoilage indicators TVB-N and TMA-N (mg/100 g) increased from 13.5 and 2.6 to 21.4 and 3.4, respectively. However, they remained below critical limits, suggesting low microbial activity. In contrast, texture, pH, WHC, and color were not affected. Overall results indicated that the quality of iced Catarina scallop adductor muscle packed in ice was maintained over a period of 15 days.
Novel Combination Therapies for the Treatment of Bladder Cancer

Bladder cancer is the ninth most frequently diagnosed cancer world-wide and ranks 13th in cancer-related deaths. Two tremendous breakthroughs in bladder cancer therapy over the last decades are the approval of immune checkpoint inhibitors(ICIs)and the fibroblast growth factor receptor tyrosine kinase inhibitor (FGFR-TKI) erdafitinib for treating this deadly disease. Despite the beneficial effects of these approaches, the low response rate and the potential resistance of the cancer are major concerns. Hence, novel combination therapies to overcome these limitations have been investigated. In this context, combining immunotherapy with targeted drugs is an appealing therapeutic option to improve response and reduce the emergence of resistance in the management of bladder cancer. In this review, the rationale of using different therapeutic combinations is discussed according to the mechanistic differences, emphasizing the efficacy and safety based on evidence collected from preclinical and clinical studies. Finally, we highlight the limitations of these combinations and provide suggestions for further efforts in this challenging field.
In vitro infection of human lung tissue with SARS-CoV-2: Heterogeneity in host defense and therapeutic response

Cell lines are the mainstay in understanding the biology of COVID-19 infection, but do not recapitulate many of the complexities of human infection. The use of human lung tissue is one solution for the study of such novel respiratory pathogens. We hypothesized that a cryopreserved bank of human lung tissue allows for the in vitro study of the inter-individual heterogeneity of host response to SARS-CoV-2 infection, thus providing a bridge between studies with cell lines and studies in animal models. We generated a cryobank of tissues from 16 donors, most of whom had risk factors for severe illness from COVID-19. Cryopreserved tissues preserved 90% of cell viability and contained heterogeneous populations of metabolically active epithelial, endothelial, and immune cell subsets of the human lung. Samples were readily infectible with HCoV-OC43 and SARS-CoV-2 coronavirus strains, and demonstrated comparable susceptibility to infection. In contrast, we observed a marked donor-dependent heterogeneity in the expression of IL-6, CXCL8 and IFNβ in response to SARS-CoV-2 infection. Treatment of tissues with dexamethasone and the experimental drug, N-hydroxycytidine, suppressed viral growth in all samples, whereas chloroquine and remdesivir had no detectable effect. Metformin and sirolimus, molecules with predicted antiviral activity, suppressed viral replication in tissues from a subset of donors. In summary, we developed a novel system for the in vitro study of human SARS-CoV-2 infection using primary human lung tissue from a library of donor tissues. This model may be useful for drug screening and for understanding basic mechanisms of COVID-19 pathogenesis. Importance The current biological systems for the study of COVID-19 are in vitro systems that differ from the human lung in many respects, and animal hosts to which the virus is not adapted. We developed another alternative for studying pathogenesis and drug susceptibility of SARS-CoV-2 in a cryopreserved bank of human lung tissues. We consider the importance of this work to relate to the practical use of this culture system as a repeatable and scalable approach that allows for the study of an important infection in relevant tissues. The tissue bank highlights the heterogeneous response to SARS-CoV-2 infection and treatment, which allows researchers to investigate why treatments work in some donors but not others.