Miracle-dz/UniFAR-FTUs huggingface dataset:
4-1BB Agonism Combined With PD-L1 Blockade Increases the Number of Tissue-Resident CD8+ T Cells and Facilitates Tumor Abrogation

Although the milestone discovery of immune checkpoint blockade (ICB) has been translated into clinical practice, only a fraction of patients can benefit from it with durable responses and subsequent long-term survival. Here, we tested the anti-tumor effect of combining PD-L1 blockade with 4-1BB costimulation in 3LL and 4T1.2 murine tumor models. Dual treatment induced further tumor regression and enhanced survival in tumor-bearing mice more so than PD-L1 and 4-1BB mAb alone. It was demonstrated that dual anti-PD-L1/anti-4-1BB immunotherapy increased the number of intratumoral CD103+CD8+ T cells and altered their distribution. Phenotypically, CD103+CD8+ T cells expressed a higher level of 4-1BB and PD-1 than their CD103− counterparts. Administration of PD-L1 mAb and 4-1BB mAb further increased the cytolytic capacity of CD103+CD8+ T cells. In vivo, CD103−CD8+ T cells could differentiate into CD103+CD8+ progeny cells. In a human setting, more CD8+ T cells differentiated into CD103+CD8+ T cells in the peripheral tumor region of lung cancer tissues than in the central tumor region. Collectively, infiltrated CD103+CD8+ T cells served as a potential effector T cell population. Combining 4-1BB agonism with PD-L1 blockade could increase tumor-infiltrated CD103+CD8+T cells, thereby facilitating tumor regression.
Speech-Induced Suppression for Delayed Auditory Feedback in Adults Who Do and Do Not Stutter

Speech-induced suppression is the normal, relative amplitude reduction of the auditory evoked potential for self-, compared to externally-generated, auditory stimulation. It remains controversial as to whether adults who stutter exhibit expected auditory modulation during speech; some studies have reported a significant difference between stuttering and fluent groups in speech-induced suppression during speech movement planning, while others have not. We compared auditory evoked potentials (N1 component) for auditory feedback arising from one’s own voice (Speaking condition) with passive listening to a recording of one’s own voice (Listening condition) in 24 normally-fluent speakers and 16 adults who stutter under various delayed auditory feedback (DAF) time conditions (100 ms, 200 ms, 500 ms, and 1,000 ms). We presented the participant’s own voice with a delay, immediately after presenting it without a delay. Our working hypothesis was that the shorter the delay time, the more likely the delayed sound is perceived as self-generated. Therefore, shorter delay time conditions are proposed to result in relatively enhanced suppression of the auditory system. Results showed that in fluent speakers, the shorter the delay time, the more the auditory evoked potential in the Speaking condition tended to be suppressed. In the Listening condition, there was a larger evoked potential with shorter delay times. As a result, speech-induced suppression was only significant at the short delay time conditions of 100 and 200 ms. Adults who stutter did not show the opposing changes in the Speaking and Listening conditions seen in the fluent group. Although the evoked potential in the Listening condition tended to decrease as the delay time increased, that in the Speaking condition did not show a distinct trend, and there was a significant suppression only at 200 ms delay. For the 200 ms delay condition, speakers with more severe stuttering showed significantly greater speech-induced suppression than those with less severe stuttering. This preliminary study suggests our methods for investigating evoked potentials by presenting own voice with a delay may provide a clue as to the nature of auditory modulation in stuttering.
Post-induction Measurable Residual Disease Using Multicolor Flow Cytometry Is Strongly Predictive of Inferior Clinical Outcome in the Real-Life Management of Childhood T-Cell Acute Lymphoblastic Leukemia: A Study of 256 Patients

Background: Measurable/minimal residual disease (MRD) status is suggested as a powerful indicator of clinical-outcome in T-cell lymphoblastic leukemia/lymphoma (T-ALL). Contrary to B-cell ALL, reports on T-ALL MRD are limited and mostly based on molecular methods, mainly from developed countries. Multicolor flow cytometry (MFC)-based T-ALL studies are very few. Clinically relevant cut-off levels and ideal time-point for MRD assessment are still inconclusive. In view of lack of T-ALL MRD data from the developing world, we evaluated the prognostic value of MFC-based post-induction (PI)-MRD assessment in T-ALL in the context of standard practice. Methods: We included 256 childhood-T-ALL patients (age < 15 years) treated with a modified-MCP841 protocol, which uses high-dose cytarabine during consolidation, as a part of standard hospital practice. MRD was studied using 10-color 11-antibody MFC with any level of detectable disease being considered positive. Post-induction (PI)-MRD was available in all patients, and post-consolidation (PC) MRD was available mostly in PI-MRD-positive patients (n = 88). Results: Three years cumulative-incidence-of-relapse (3years-CIR) in PI-MRD-positive patients was inferior to negative patients (46.3% vs. 18.4%). The median relapse-free-survival (RFS), event-free-survival (EFS) and overall-survival (OS) with hazard ratio (HR) of PI-MRD-positive patients were 21.4 months vs not reached (p < 0.0001, HR-4.7), 21.6 months vs. not-reached (p = 0.0003, HR-2.01) and 37.3 months vs. not reached (p = 0.026, HR-1.64) respectively. RFS, EFS and OS of patients with PI-MRD<0.01% (n = 17) were as inferior as PI-MRD ≥ 0.01% in comparison with MRD-negative patients with HR of 4.7 (p < 0.0001), 2.45 (p = 0.0003), and 2.5 (p = 0.029), respectively. Three-years-CIR of patients with hyperleukocytosis (≥100 × 109/L) was also higher (50.5 vs. 27.6%) with inferior RFS, EFS, and OS. Among PI-MRD-positive patients, 3years-CIR, RFS, EFS, and OS of PC-MRD-positive were also inferior to that of negative patients. On multivariate analysis any-level detectable PI-MRD and hyperleukocytosis remained independently associated with inferior RFS, EFS, and OS. A combination of PI-MRD-positive status and hyperleukocytosis identified the patients with the worst clinical outcomes. Conclusion: Detectable PI-MRD using MFC was found to be the strong predictive factor of inferior clinical outcome in T-ALL patients. The combination of PI-MRD status and hyperleukocytosis provides the most influential tool for the management of T-ALL in resource constrained settings from developing world.
Identifying Candida albicans Gene Networks Involved in Pathogenicity

Candida albicans is a normal member of the human microbiome. It is also an opportunistic pathogen, which can cause life-threatening systemic infections in severely immunocompromized individuals. Despite the availability of antifungal drugs, mortality rates of systemic infections are high and new drugs are needed to overcome therapeutic challenges including the emergence of drug resistance. Targeting known disease pathways has been suggested as a promising avenue for the development of new antifungals. However, <30% of C. albicans genes are verified with experimental evidence of a gene product, and the full complement of genes involved in important disease processes is currently unknown. Tools to predict the function of partially or uncharacterized genes and generate testable hypotheses will, therefore, help to identify potential targets for new antifungal development. Here, we employ a network-extracted ontology to leverage publicly available transcriptomics data and identify potential candidate genes involved in disease processes. A subset of these genes has been phenotypically screened using available deletion strains and we present preliminary data that one candidate, PEP8, is involved in hyphal development and immune evasion. This work demonstrates the utility of network-extracted ontologies in predicting gene function to generate testable hypotheses that can be applied to pathogenic systems. This could represent a novel first step to identifying targets for new antifungal therapies.
Underlying Cryptococcal Diseases and the Correlation With Serum Cryptococcal Antigen Titers in Hospitalized HIV-Infected Patients Screened Positive for Cryptococcal Antigenemia

Background: The prevalence of different underlying cryptococcal diseases in human immunodeficiency virus (HIV)-infected patients screened positive for cryptococcal antigenemia and the association between cryptococcal diseases and serum cryptococcal antigen (CrAg) titers were understudied. Methods: HIV-infected patients with CD4 < 200 cells/ul, admitted to the second hospital of Nanjing, Nanjing, China, from January 2016 to September 2019, were retrospectively analyzed. Integrated into routine HIV care, all these patients were screened for cryptococcal antigenemia with CrAg lateral flow assay. Positive patients received extensive laboratory and radiological studies to evaluate underlying cryptococcal diseases. Results: A total of 872 HIV inpatients were screened for serum CrAg. The prevalence of cryptococcal antigenemia in the study population was 10.3% (95% CI, 8.3–12.3%), 87.6% of which with cryptococcal antigenemia had clinically cryptococcal diseases. The prevalence of cryptococcal meningitis (CM), cryptococcemia and pulmonary cryptococcosis (PC) in patients with cryptococcal antigenemia were 58.4% (95% CI, 48.0–68.9%), 50.7% (95% CI, 39.1–62.2%), and 68.5% (95% CI, 58.7–78.4%), respectively. The median (range) serum CrAg titers in severe cryptococcal diseases (CM or cryptococcemia), localized PC (without co-existing CM or cryptococcemia) and isolated cryptococcal antigenemia were 1:2560 (1:10–1:2560), 1:20 (1:2–1:320), and 1:5 (1:2–1:320), respectively. Serum CrAg titers ≥1:320 were independently associated with CM (adjusted OR 26.88; 95%CI, 8.36–86.42). Severe cryptococcal diseases were found in all patients with serum CrAg titers ≥1:640. None of the patients with serum CrAg titers ≤ 1:5 had CM. Conclusion: The prevalence of cryptococcal antigenemia was high in HIV inpatients, supporting routine CrAg screening. Clinical cryptococcal diseases, most commonly the PC, existed in the majority of the patients with cryptococcal antigenemia. Since serum CrAg titer is correlated with cryptococcal disease severity, it may possibly guide anti-fungal treatment.
Direct Measurement of Plant Cellulose Microfibril and Bundles in Native Cell Walls

Plants use rigid cellulose together with non-cellulosic matrix polymers to build cell walls. Cellulose microfibrils comprise linear β(1,4)-glucan chains packed through inter- and intra-chain hydrogen-bonding networks and van der Waals forces. Due to its small size, the number of glucan chains and their arrangement in a microfibril remains elusive. Here we used atomic force microscopy (AFM) to directly image primary cell walls (PCWs) and secondary cell walls (SCWs) from fresh tissues of maize (Zea mays) under near-native conditions. By analyzing cellulose structure in different types of cell walls, we were able to measure the individual microfibrils in elongated PCWs at the sub-nanometer scale. The dimension of the microfibril was measured at 3.68 ± 0.13 nm in width and 2.25 ± 0.10 nm in height. By superimposing multiple AFM height profiles of these microfibrils, the overlay area representing the cross-section was estimated at 5.6 ± 0.4 nm2, which fitted well to an 18-chain model packed as six sheets with 234432 conformation. Interestingly we found in PCW, all these individual microfibrils could be traced back to a bundle in larger imaging area, suggesting cellulose are synthesized as large bundles in PCWs, and then split during cell expansion or elongation. In SCWs where cell growth has ceased we observed nearly-parallel twined or individual microfibrils that appeared to be embedded separately in the matrix polymers without the splitting effect, indicating different mechanisms of cellulose biosynthesis in PCW and SCW. The sub-nanometer structure of the microfibril presented here was measured exclusively from elongated PCWs, further study is required to verify if it represents the inherent structure synthesized by the cellulose synthase complex in PCWs and SCWs.
Plastome Evolution in Saxifragaceae and Multiple Plastid Capture Events Involving Heuchera and Tiarella

Saxifragaceae, a family of over 600 species and approximately 30 genera of herbaceous perennials, is well-known for intergeneric hybridization. Of the main lineages in this family, the Heuchera group represents a valuable model for the analysis of plastid capture and its impact on phylogeny reconstruction. In this study, we investigated plastome evolution across the family, reconstructed the phylogeny of the Heuchera group and examined putative plastid capture between Heuchera and Tiarella. Seven species (11 individuals) representing Tiarella, as well as Mitella and Heuchera, were selected for genome skimming. We assembled the plastomes, and then compared these to six others published for Saxifragaceae; the plastomes were found to be highly similar in overall size, structure, gene order and content. Moreover, ycf15 was lost due to pseudogenization and rpl2 lost its only intron for all the analyzed plastomes. Comparative plastome analysis revealed that size variations of the plastomes are purely ascribed to the length differences of LSC, SSC, and IRs regions. Using nuclear ITS + ETS and the complete plastome, we fully resolved the species relationships of Tiarella, finding that the genus is monophyletic and the Asian species is most closely related to the western North American species. However, the position of the Heuchera species was highly incongruent between nuclear and plastid data. Comparisons of nuclear and plastid phylogenies revealed that multiple plastid capture events have occurred between Heuchera and Tiarella, through putative ancient hybridization. Moreover, we developed numerous molecular markers for Tiarella (e.g., plastid hotspot and polymorphic nuclear SSRs), which will be useful for future studies on the population genetics and phylogeography of this disjunct genus.
The Current and Future State of Vaccines, Antivirals and Gene Therapies Against Emerging Coronaviruses

Emerging coronaviruses (CoV) are constant global public health threats to society. Multiple ongoing clinical trials for vaccines and antivirals against CoVs showcase the availability of medical interventions to both prevent and treat the future emergence of highly pathogenic CoVs in human. However, given the diverse nature of CoVs and our close interactions with wild, domestic and companion animals, the next epidemic zoonotic CoV could resist the existing vaccines and antivirals developed, which are primarily focused on Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS CoV). In late 2019, the novel CoV (SARS-CoV-2) emerged in Wuhan, China, causing global public health concern. In this review, we will summarize the key advancements of current vaccines and antivirals against SARS-CoV and MERS-CoV as well as discuss the challenge and opportunity in the current SARS-CoV-2 crisis. At the end, we advocate the development of a “plug-and-play” platform technologies that could allow quick manufacturing and administration of broad-spectrum countermeasures in an outbreak setting. We will discuss the potential of AAV-based gene therapy technology for in vivo therapeutic antibody delivery to combat SARS-CoV-2 outbreak and the future emergence of severe CoVs.
Role of the Eye in Transmitting Human Coronavirus: What We Know and What We Do Not Know

The outbreak of the current 2019 novel coronavirus (2019-nCoV, now named SARS-CoV-2) infection has become a worldwide health threat. Currently, more information is needed so as to further understand the transmission and clinical characteristics of 2019-nCoV infection and the infection control procedures required. Recently, the role of the eye in transmitting 2019-nCoV has been intensively discussed. Previous investigations of other highly infectious human CoVs, that is, severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), may provide useful information. In this review, we describe the genomics and morphology of human CoVs, the epidemiology, systemic and ophthalmic manifestations, and mechanisms of human CoV infection, and recommendations for infection control procedures. The role of the eye in the transmission of 2019-nCoV is discussed in detail. Although the conjunctiva is directly exposed to extraocular pathogens, and the mucosa of the ocular surface and upper respiratory tract are connected by the nasolacrimal duct and share the same entry receptors for some respiratory viruses, the eye is rarely involved in human CoV infection, conjunctivitis is quite rare in patients with 2019-nCoV infection, and the CoV RNA positive rate by RT-PCR test in tears and conjunctival secretions from patients with 2019-nCoV and SARS-CoV infection is also extremely low. This suggests that the eye is neither a preferred organ of human CoV infection nor a preferred gateway of entry for human CoVs for infecting the respiratory tract. However, pathogens that the ocular surface is exposed to might be transported to nasal and nasopharyngeal mucosa by constant tear rinsing through the lacrimal duct system and then cause respiratory tract infection. Considering that close doctor-patient contact is quite common in ophthalmic practice and is apt to transmit human CoVs by droplets and fomites, strict hand hygiene and proper personal protection are highly recommended for health care workers to avoid hospital-related viral transmission during ophthalmic practice.
Organizational Citizenship Behavior Predicts Quality, Creativity, and Efficiency Performance: The Roles of Occupational and Collective Efficacies

Although numerous studies have shown that prosocial behavior impacts performance within organizations, the mechanisms that encourage or discourage these effects have rarely been explored. Two studies were conducted to shed light on the role of psychological beliefs on prosocial dynamics in predicting organizational performance. In Study 1, employees’ beliefs in their inner job-related resources (Occupational Efficacy – OE) were examined as a predictor of OCB. It was posited that OE, which is an inner resource, should positively predict OCB. Study 2 examined whether Collective Efficacy (CE), which is an external resource over which employees have less control, would moderate the OCB-performance prediction. Overall, performance and three core dimensions of performance (quality, creativity and efficiency) were assessed to better capture the specific influence of OCB effects on performance. In Study 1, employees completed inventories measuring their OE, OCB and performance. In Study 2, employees completed inventories measuring their CE and OCB. In addition, their managers completed inventories measuring the CE of their employees’ teams and their employees’ performance. The results of Study 1 revealed that OE emerged as an antecedent of OCB in predicting performance. In Study 2, OCB positively predicted employee performance above and beyond and the effects of their managers’ tenure in position, and CEs. In addition, both employees’ and managers’ CEs moderated the effects of OCB on performance: the performance effects of OCB increased as employees’ and managers’ CE increased, and specifically performance efficiency and performance creativity. These findings contribute to a better theoretical and practical understanding of the core factors that affect the organizational dynamics of prosocial behaviors that can lead to higher performance, and the ways in which OCB positively predicts performance in organizational settings.
The Use of Sheep Movement Data to Inform Design and Interpretation of Slaughterhouse-Based Surveillance Activities

The design of surveillance strategies is often a compromise between science, feasibility, and available resources, especially when sampling is based at fixed locations, such as slaughter-houses. Advances in animal identification, movement recording and traceability should provide data that can facilitate the development, design and interpretation of surveillance activities. Here, for the first time since the introduction of electronic identification of sheep, the utility of a statutory sheep movement database to inform the design and interpretation of slaughter-house based surveillance activities has been investigated. Scottish sheep movement records for 2015–2018 were analyzed in combination with several other data sources. Patterns of off-farm movements of Scottish sheep to slaughter were described and the spatial distribution of several distinct slaughter populations, throughputs and catchment areas for Scottish slaughterhouses were determined. These were used to evaluate the coverage of a convenience-sample slaughter-house based survey for antimicrobial resistance (AMR). In addition, non-slaughter sheep movements within and between Scottish regions were described and inter-and intra-regional movement matrices were produced. There is potential at a number of levels for bias in spatially-associated factors for ovine surveillance activities based at Scottish slaughterhouses. The first is intrinsic because the slaughtered in Scotland population differs from the overall Scottish sheep slaughter population. Other levels will be survey-dependent and occur when the catchment area differs from the slaughtered in Scotland population and when the sampled sheep differ from the catchment area. These are both observed in the AMR survey. Furthermore, the Scottish non-slaughter sheep population is dynamic. Inter-regional movements vary seasonally, driven by the sheep calendar year, structure of the Scottish sheep industry and management practices. These sheep movement data provide a valuable resource for surveillance purposes, despite a number of challenges and limitations that were encountered. They can be used to identify and characterize the spatial origin of relevant populations and so inform the interpretation of existing slaughterhouse-based surveillance activities. They can be used to improve future design by exploring the feasibility and cost:benefit of alternative sampling strategies. Further development could also contribute to other surveillance activities, such as situational awareness and resource allocation, for the benefit of stakeholders.
“I Invest by Following Lead Investors!” The Role of Lead Investors in Fundraising Performance of Equity Crowdfunding

Psychological factors play a critical role in affecting investor decisions. This study explores how lead investors influence following investors psychologically, thus affecting fundraising performance of equity crowdfunding. We draw upon the signaling theory and observational learning theory to argue that following investors could be induced to invest in a project if they observe the proportion of funding by lead investors in the funding target to be high, that the lead investors have rich investment experience, and that the lead investors can offer help to the projects. To test our hypotheses, we analyze a sample of 215 projects from a Chinese equity crowdfunding platform. The results reveal that the proportion of lead investor investment in the funding target and their investment experience are positively related to fundraising performance. However, the help offered by lead investors toward the projects has no impact on funding performance. Theoretical and practical implications are discussed.