Miracle-dz/UniFAR-FTUs huggingface dataset:
Evaluating the Clinical Utility of Genome Sequencing for Cytogenetically Balanced Chromosomal Abnormalities in Prenatal Diagnosis

Balanced chromosomal abnormalities (BCAs) are changes in the localization or orientation of a chromosomal segment without visible gain or loss of genetic material. BCAs occur at a frequency of 1 in 500 newborns and are associated with an increased risk of multiple congenital anomalies and/or neurodevelopmental disorders, especially if it is a de novo mutation. In this pilot project, we used short read genome sequencing (GS) to retrospectively re-sequence ten prenatal subjects with de novo BCAs and compared the performance of GS with the original karyotyping. GS characterized all BCAs found by conventional karyotyping with the added benefit of precise sub-band delineation. By identifying BCA breakpoints at the nucleotide level using GS, we found disruption of OMIM genes in three cases and identified cryptic gain/loss at the breakpoints in two cases. Of these five cases, four cases reached a definitive genetic diagnosis while the other one case had a BCA interpreted as unknown clinical significance. The additional information gained from GS can change the interpretation of the BCAs and has the potential to improve the genetic counseling and perinatal management by providing a more specific genetic diagnosis. This demonstrates the added clinical utility of using GS for the diagnosis of BCAs.
Beyond Passion and Perseverance: Review and Future Research Initiatives on the Science of Grit

Grit, which is originally conceptualized as passion and perseverance for long-term goals, has been associated with optimal performance. Although previous meta-analytic and systematic reviews summarized how grit relates to performance outcomes, they possess considerable shortcomings, such as (a) absence of summary on the association of grit with well-being outcomes; (b) absence of discussion on social, psychological, and emotional mechanisms linking grit to well-being; and (c) lack of elaboration on how alternative models can resolve fundamental problems in the grit construct. This integrative review provides a comprehensive summary on the link of grit to performance and well-being outcomes. Importantly, it elaborates how alternative models can potentially address flaws in the existing grit theory. Future research directions are discussed on how to move forward the science of grit.
Standard vs. Modified Antiplatelet Therapy Based on Thromboelastography With Platelet Mapping for Preventing Bleeding Events in Patients Undergoing Stent-Assisted Coil for a Ruptured Intracranial Aneurysm

Background and Purpose: Stent-assisted coiling (SAC) of intracranial aneurysms is usually treated with antiplatelet therapy to reduce the risk of postoperative ischemic events. However, using the same antiplatelet therapy for all patients may increase the risk of bleeding in patients with aneurysmal subarachnoid hemorrhage (aSAH). Thromboelastography-platelet mapping (TEG-PM) measures platelet function, which reflects the effect of antiplatelet drugs. This study aimed to evaluate the benefits of individualized antiplatelet regimens based on TEG-PM parameters for patients with aSAH who underwent SAC. Methods: We retrospectively included patients with aSAH who treated with SAC during the period from June 2012 to December 2019. Patients were divided into two groups: patients whose antiplatelet therapy adjusted by TEG-PM parameters after surgery (adjustment group) and patients who were treated with standard dual antiplatelet therapy without TEG-PM test (control group). The occurrence of major/minor bleeding events, major/minor thromboembolic events, and favorable outcome (modified Rankin scale <3) were compared in both groups during hospitalization. Results: Of 188 aSAH patients considered for this study, 145 met the criteria for inclusion and were included in the analysis (93 patients in the adjustment group and 52 patients in the control group). The risks of minor bleeding events (1.1 vs. 9.6%, p = 0.02) were significantly lower in patients in the adjustment group. However, there was no significant difference in the rate of major bleeding events at discharge between adjustment and control groups (p = 0.35). The rates of thromboembolic events and favorable outcome were similar in both groups (22.6 vs. 28.8%, p = 0.42, 95.7 vs. 96.2%, p = 1.00). Furthermore, the minor thromboembolic events rate was significantly lower in the patients treated with treatment plan C (p = 0.02 for treatment plan C vs. treatment A, p = 0.03 for treatment plan C vs. treatment plan B). However, there was no significant difference in the rate of other mentioned above complications and favorable outcomes among patients treated with different antiplatelet regimens. Conclusions: Individualized antiplatelet therapy based on TEG-PM parameters might positively impact the bleeding risk of aSAH patients, without increasing the risk for clinically relevant thromboembolic events.
Correlation of HPV16 Gene Status and Gene Expression With Antibody Seropositivity and TIL Status in OPSCC

Introduction Human papillomavirus 16 (HPV16) is the main cause of oropharyngeal squamous cell carcinoma (OPSCC). To date, the links between HPV16 gene expression and adaptive immune responses have not been investigated. We evaluated the correlation of HPV16 DNA, RNA transcripts and features of adaptive immune response by evaluating antibody isotypes against E2, E7 antigens and density of tumor-infiltrating lymphocytes (TIL). Material and Methods FFPE-tissue from 27/77 p16-positive OPSCC patients was available. DNA and RNA were extracted and quantified using qPCR for all HPV16 genes. The TIL status was assessed. Immune responses against E2 and E7 were quantified by ELISA (IgG, IgA, and IgM; 77 serum samples pre-treatment, 36 matched post-treatment). Results Amounts of HPV16 genes were highly correlated at DNA and RNA levels. RNA co-expression of all genes was detected in 37% (7/19). E7 qPCR results were correlated with higher anti-E7 antibody (IgG, IgA) level in the blood. Patients with high anti-E2 IgG antibody (>median) had better overall survival (p=0.0311); anti-E2 and anti-E7 IgA levels had no detectable effect. During the first 6 months after treatment, IgA but not IgG increased significantly, and >6 months both antibody classes declined over time. Patients with immune cell-rich tumors had higher levels of circulating antibodies against HPV antigens. Conclusion We describe an HPV16 qPCR assay to quantify genomic and transcriptomic expression and correlate this with serum antibody levels against HPV16 oncoproteins. Understanding DNA/RNA expression, relationship to the antibody response in patients regarding treatment and outcome offers an attractive tool to improve patient care.
The reintroduction of a dung-beetle associated primate increases the recruitment success of large seeds

The biased loss of large and medium frugivores alters seed dispersal and plant regeneration. Species reintroductions have been proposed as a strategy to reverse the consequences of species loss. However, reintroductions effects on ecological processes are seldom accessed, which hinders the comprehension of reintroductions’ potential to reestablish functioning ecosystems. In this study, we investigate the effect of howler monkey (Alouatta guariba) reintroduction in the plant regeneration of Tijuca National Park (TNP), a highly defaunated Atlantic Forest fragment. Howlers are medium sized folivore-frugivore primates, whose large clumped defecations attract dung beetles. Dung beetles bury seeds present in howlers’ feces, a process known as secondary seed dispersal. Thus, we expect that the fate of seeds dispersed by howlers will differ from those dispersed by the other frugivores present in the Park. We followed the fate of seeds between 3 and 14mm in diameter in three steps of the seed dispersal loop, each consisting of a different experiment. First, we estimated secondary seed dispersal and burial depth probabilities according to the frugivores’ defecation pattern; then, predation probability in different burial depths and defecation patterns; and, finally, recruitment probability in different burial depths. Considering the final result of the three experiments, the howlers’ reintroduction affected positively the regeneration of large seeds. 3mm seeds did not benefit as much because they weren’t frequently predated at shallower depths and couldn’t recruit when deeply buried. Seeds larger than 3mm reached more frequently the seedling stage when dispersed by howlers than when dispersed by other animals present in the Park. Thus, howler monkey reintroduction in defaunated areas, consisting mainly of smaller frugivores, whose defecation pattern doesn’t attract dung beetles as frequently, improves the regeneration of large seeds. We hope that this study will stimulate the resuming of howler reintroduction in TNP, as well as new howler reintroductions in defaunated areas.
A SH3_5 Cell Anchoring Domain for Non-recombinant Surface Display on Lactic Acid Bacteria

Lactic acid bacteria (LAB) are a group of gut commensals increasingly recognized for their potential to deliver bioactive molecules in vivo. The delivery of therapeutic proteins, in particular, can be achieved by anchoring them to the bacterial surface, and various anchoring domains have been described for this application. Here, we investigated a new cell anchoring domain (CAD4a) isolated from a Lactobacillus protein, containing repeats of a SH3_5 motif that binds non-covalently to peptidoglycan in the LAB cell wall. Using a fluorescent reporter, we showed that C-terminal CAD4a bound Lactobacillus fermentum selectively out of a panel of LAB strains, and cell anchoring was uniform across the cell surface. Conditions affecting CAD4a anchoring were studied, including temperature, pH, salt concentration, and bacterial growth phase. Quantitative analysis showed that CAD4a allowed display of 105 molecules of monomeric protein per cell. We demonstrated the surface display of a functional protein with superoxide dismutase (SOD), an antioxidant enzyme potentially useful for treating gut inflammation. SOD displayed on cells could be protected from gastric digestion using a polymer matrix. Taken together, our results show the feasibility of using CAD4a as a novel cell anchor for protein surface display on LAB.
Insights Into the Delivery of Personalized Nutrition: Evidence From Face-To-Face and Web-Based Dietary Interventions

Prevention strategies for non-communicable diseases (NCDs) are a global priority as it has been estimated that NCDs will account for around 73% of worldwide mortality by the year 2020. The adoption of diets that are low in saturated fat, free sugars, and red and processed meats and higher in unsaturated fats, wholegrains, fruit, and vegetables have been shown to reduce the risk of NCDs. With increasing internet use, several nutrition interventions are now being conducted online as well as face-to-face, however it is unclear which delivery method is most effective. Although a consumer preference toward face-to-face dietary advice delivery has been identified previously, interest in delivering web-based dietary advice, and in particular personalized nutrition (PN), has been rising, as internet delivery may be less costly and more scalable. This review compares published face-to-face and web-based dietary interventions to give insight into which dietary method might be more effective for PN. In total, 19 peer-reviewed randomized controlled trials were identified for inclusion in the review. The majority of face-to-face nutrition interventions were successful at facilitating dietary change. Results from web-based nutrition interventions suggested that personalized web-based nutrition interventions may be successful at inducing short-term dietary change compared to standardized dietary interventions, however, minimal evidence of long-term impact has been found across both delivery methods. Results of a trial that compared face-to-face with web-based diet intervention found significantly greater dietary changes in the face-to-face group compared to web-based and control groups. Further controlled comparative studies and cost-benefit analysis are needed to assess whether web-based methods can be used in place of face-to-face interventions for achieving dietary change.
Microscope-Cockpit: Python-based bespoke microscopy for bio-medical science

We have developed “Microscope-Cockpit” (Cockpit), a highly adaptable open source user-friendly Python-based GUI environment for precision control of both simple and elaborate bespoke microscope systems. The user environment allows next-generation near-instantaneous navigation of the entire slide landscape for efficient selection of specimens of interest and automated acquisition without the use of eyepieces. Cockpit uses “Python-Microscope” (Microscope) for high-performance coordinated control of a wide range of hardware devices using open source software. Microscope also controls complex hardware devices such as deformable mirrors for aberration correction and spatial light modulators for structured illumination via abstracted device models. We demonstrate the advantages of the Cockpit platform using several bespoke microscopes, including a simple widefield system and a complex system with adaptive optics and structured illumination. A key strength of Cockpit is its use of Python, which means that any microscope built with Cockpit is ready for future customisation by simply adding new libraries, for example machine learning algorithms to enable automated microscopy decision making while imaging. Highlights User-friendly setup and use for simple to complex bespoke microscopes. Facilitates collaborations between biomedical scientists and microscope technologists. Touchscreen for near-instantaneous navigation of specimen landscape. Uses Python-Microscope, for abstracted open source hardware device control. Well-suited for user training of AI-algorithms for automated microscopy.
Young domestic chicks spontaneously represent the absence of objects

Absence is a notion that is usually captured by language-related concepts like zero or negation. Whether non-linguistic creatures encode similar thoughts is an open question, as everyday behavior marked by absence (of food, of social partners) can be explained solely by expecting presence somewhere else. We investigated 8-day-old chicks’ looking behavior in response to events violating expectations about the presence or absence of an object. We found different behavioral responses to violations of presence and absence, suggesting distinct underlying mechanisms. Importantly, chicks displayed an avian signature of novelty detection to violations of absence, namely a sex-dependent left-eye-bias. Follow-up experiments excluded accounts that would explain this bias by perceptual mismatch or by representing the object at different locations. These results suggest that the ability to spontaneously form thoughts about the absence of objects likely belongs to the initial cognitive repertoire of vertebrate species.
Rapid Degradation Pathways of Host Proteins During HCMV Infection Revealed by Quantitative Proteomics

Human cytomegalovirus (HCMV) is an important pathogen in immunocompromised individuals and neonates, and a paradigm for viral immune evasion. We previously developed a quantitative proteomic approach that identified 133 proteins degraded during the early phase of HCMV infection, including known and novel antiviral factors. The majority were rescued from degradation by MG132, which is known to inhibit lysosomal cathepsins in addition to the proteasome. Global definition of the precise mechanisms of host protein degradation is important both to improve our understanding of viral biology, and to inform novel antiviral therapeutic strategies. We therefore developed and optimized a multiplexed comparative proteomic analysis using the selective proteasome inhibitor bortezomib in addition to MG132, to provide a global mechanistic view of protein degradation. Of proteins rescued from degradation by MG132, 34–47 proteins were also rescued by bortezomib, suggesting both that the predominant mechanism of protein degradation employed by HCMV is via the proteasome, and that alternative pathways for degradation are nevertheless important. Our approach and data will enable improved mechanistic understanding of HCMV and other viruses, and provide a shortlist of candidate restriction factors for further analysis.
A trans-complementation system for SARS-CoV-2

The biosafety level-3 (BSL-3) requirement to culture severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a bottleneck for research and countermeasure development. Here we report a trans-complementation system that produces single-round infectious SARS-CoV-2 that recapitulates authentic viral replication. We demonstrate that the single-round infectious SARS-CoV-2 can be used at BSL-2 laboratories for high-throughput neutralization and antiviral testing. The trans-complementation system consists of two components: a genomic viral RNA containing a deletion of ORF3 and envelope gene, and a producer cell line expressing the two deleted genes. Trans-complementation of the two components generates virions that can infect naive cells for only one round, but does not produce wild-type SARS-CoV-2. Hamsters and K18-hACE2 transgenic mice inoculated with the complementation-derived virions exhibited no detectable disease, even after intracranial inoculation with the highest possible dose. The results suggest that the trans-complementation platform can be safely used at BSL-2 laboratories for research and countermeasure development.
Analgesic Effects of Lipid Raft Disruption by Sphingomyelinase and Myriocin via Transient Receptor Potential Vanilloid 1 and Transient Receptor Potential Ankyrin 1 Ion Channel Modulation

Transient Receptor Potential (TRP) Vanilloid 1 and Ankyrin 1 (TRPV1, TRPA1) cation channels are expressed in nociceptive primary sensory neurons, and integratively regulate nociceptor and inflammatory functions. Lipid rafts are liquid-ordered plasma membrane microdomains rich in cholesterol, sphingomyelin and gangliosides. We earlier showed that lipid raft disruption inhibits TRPV1 and TRPA1 functions in primary sensory neuronal cultures. Here we investigated the effects of sphingomyelinase (SMase) cleaving membrane sphingomyelin and myriocin (Myr) prohibiting sphingolipid synthesis in mouse pain models of different mechanisms. SMase (50 mU) or Myr (1 mM) pretreatment significantly decreased TRPV1 activation (capsaicin)-induced nocifensive eye-wiping movements by 37 and 41%, respectively. Intraplantar pretreatment by both compounds significantly diminished TRPV1 stimulation (resiniferatoxin)-evoked thermal allodynia developing mainly by peripheral sensitization. SMase (50 mU) also decreased mechanical hyperalgesia related to both peripheral and central sensitizations. SMase (50 mU) significantly reduced TRPA1 activation (formalin)-induced acute nocifensive behaviors by 64% in the second, neurogenic inflammatory phase. Myr, but not SMase altered the plasma membrane polarity related to the cholesterol composition as shown by fluorescence spectroscopy. These are the first in vivo results showing that sphingolipids play a key role in lipid raft integrity around nociceptive TRP channels, their activation and pain sensation. It is concluded that local SMase administration might open novel perspective for analgesic therapy.
Genome Recombination-Mediated tRNA Up-Regulation Conducts General Antibiotic Resistance of Bacteria at Early Stage

Bacterial antibiotic resistance sets a great challenge to human health. It seems that the bacteria can spontaneously evolve resistance against any antibiotic within short time without the horizontal transfer of heterologous genes and before accumulating drug-resistant mutations. We have shown that the tRNA-mediated translational regulation counteracts the reactive oxygen species in bacteria. In this study, we demonstrated that isolated and subcultured Escherichia coli elevated its tRNAs under antibiotic stress to rapidly provide antibiotic resistance, especially at the early stage, before upregulating the efflux pump and evolving resistance mutations. The DNA recombination system repaired the antibiotic-induced DNA breakage in the genome, causing numerous structural variations. These structural variations are overrepresented near the tRNA genes, which indicated the cause of tRNA up-regulation. The strains knocking out the recombination system could not up-regulate tRNAs, and coincidently, they could hardly evolve antibiotic resistance in multiple antibiotics, respectively. With these results, we proposed a multi-stage model of bacterial antibiotic resistance in an isolated scenario: the early stage (recombination – tRNA up-regulation – translational regulation); the medium stage (up-regulation of efflux pump); the late stage (resistance mutations). These results also indicated that the bacterial DNA recombination system and tRNA could be targeted to retard the bacterial spontaneous drug resistance.
Evolving Insights from SARS-CoV-2 Genome from 200K COVID-19 Patients

We present an updated version of our automated computational pipeline, Infection Pathogen Detector IPD 2.0 with a SARS-CoV-2 module, to perform genomic analysis to understand the pathogenesis and virulence of the virus. Analysing the currently available 208911 SARS-CoV2 genome sequences (as accessed on 28 Dec 2020), we generate an extensive database of sample- wise variants and clade annotation, which forms the core of the SARS-CoV-2 analysis module of the analysis pipeline. A comparative account of lineage-specific mutations in the newer SARS-CoV-2 strains emerging in the UK, South Africa and Brazil along with data reported from India identify overlapping and lineages specific acquired mutations suggesting a repetitive convergent and adaptive evolution. Thus, the persistence of pandemic may lead to the emergence of newer regional strains with improved fitness. IPD 2.0 also adopts the recent dynamic clade nomenclature and shows improvement in accuracy of clade assignment, processing time and portability, to its predecessor and thus could be a vital tool to help facilitate genomic surveillance in a population to identify variants involved in breakthrough infections.