Miracle-dz/UniFAR-FTUs huggingface dataset:
CORDIC-Astrocyte: Tripartite Glutamate-IP3-Ca$^{2+}$ Interaction Dynamics on FPGA

Real-time, large-scale simulation of biological systems is challenging due to different types of nonlinear functions describing biochemical reactions in the cells. The promise of the high speed, cost effectiveness, and power efficiency in addition to parallel processing has made application-specific hardware an attractive simulation platform. This paper proposes high-speed and low-cost digital hardware to emulate a biological-plausible astrocyte and glutamate-release mechanism. The nonlinear terms of these models were calculated using a high-precision and cost-effective algorithm. Subsequently, the modified models were simulated to study and validate their functions. We developed several hardware versions by setting different constraints to investigate trade-offs and find the best possible design. FPGA implementation results confirmed the ability of the design to emulate biological cell behaviours in detail with high accuracy. As for performance, the proposed design turned out to be faster and more efficient than previously published works that targeted digital hardware for biological-plausible astrocytes.
Cultural Moderation of Unconscious Hedonic Responses to Food

Previous psychological studies have shown that images of food elicit hedonic responses, either consciously or unconsciously, and that participants’ cultural experiences moderate conscious hedonic ratings of food. However, whether cultural factors moderate unconscious hedonic responses to food remains unknown. We investigated this issue in Polish and Japanese participants using the subliminal affective priming paradigm. Images of international fast food and domestic Japanese food were presented subliminally as prime stimuli. Participants rated their preferences for the subsequently presented target ideographs. Participants also rated their preferences for supraliminally presented food images. In the subliminal rating task, Polish participants showed higher preference ratings for fast food primes than for Japanese food primes, whereas Japanese participants showed comparable preference ratings across these two conditions. In the supraliminal rating task, both Polish and Japanese participants reported comparable preferences for fast and Japanese food stimuli. These results suggest that cultural experiences moderate unconscious hedonic responses to food, which may not be detected based on explicit ratings.
Towards Understanding KSHV Fusion and Entry

How viruses enter cells is of critical importance to pathogenesis in the host and for treatment strategies. Over the last several years, the herpesvirus field has made numerous and thoroughly fascinating discoveries about the entry of alpha-, beta-, and gamma-herpesviruses, giving rise to knowledge of entry at the amino acid level and the realization that, in some cases, researchers had overlooked whole sets of molecules essential for entry into critical cell types. Herpesviruses come equipped with multiple envelope glycoproteins which have several roles in many aspects of infection. For herpesvirus entry, it is usual that a collective of glycoproteins is involved in attachment to the cell surface, specific interactions then take place between viral glycoproteins and host cell receptors, and then molecular interactions and triggers occur, ultimately leading to viral envelope fusion with the host cell membrane. The fact that there are multiple cell and virus molecules involved with the build-up to fusion enhances the diversity and specificity of target cell types, the cellular entry pathways the virus commandeers, and the final triggers of fusion. This review will examine discoveries relating to how Kaposi’s sarcoma-associated herpesvirus (KSHV) encounters and binds to critical cell types, how cells internalize the virus, and how the fusion may occur between the viral membrane and the host cell membrane. Particular focus is given to viral glycoproteins and what is known about their mechanisms of action.
The La-related proteins: structures and interactions of a versatile superfamily of RNA-binding proteins

ABSTRACT The La-related proteins (LaRPs) are an ancient superfamily of RNA-binding proteins orchestrating the major fates of RNA, from processing and maturation to regulation of mRNA translation. LaRPs are instrumental in modulating complex assemblies where the RNA is bound, folded, processed, escorted and presented to the functional effectors often through recruitment of protein partners. This intricate web of protein-RNA and protein–protein interactions is enabled by the modular nature of the LaRPs, comprising several structured domains connected by flexible linkers, and other sequences lacking recognizable folded motifs. Recent structures, together with biochemical and biophysical studies, have provided insights into how each LaRP family has evolved unique mechanisms of RNA recognition, not only through the conserved RNA-binding unit, the La-module, but also mediated by other family-specific motifs. Furthermore, in a series of unexpected twists and turns, they have revealed that the dynamic and conformational interplay of multi-structured domains and disordered regions operate in unison to achieve RNA substrate discrimination. This review proposes a perspective of our current knowledge of the structure–function relationship of the LaRP superfamily.
Prostaglandin E2 receptor EP4 regulates cell migration through Orai1

The EP4 prostanoid receptors are one of four receptor subtypes for prostaglandin E2 (PGE2). Therefore, EP4 may play an important role in cancer progression. However, little information is available regarding their function per se, including migration and the cellular signaling pathway of EP4 in oral cancer. First, we found that mRNA and protein expression of EP4 was abundantly expressed in human‐derived tongue squamous cell carcinoma cell lines HSC‐3 and OSC‐19. The EP4 agonist (ONO‐AE1‐437) significantly promoted cell migration in HSC‐3 cells. In contrast, knockdown of EP4 reduced cell migration. Furthermore, we confirmed that knockdown of EP4 suppressed metastasis of oral cancer cells in the lungs of mice in vivo. Therefore, we focused on the mechanism of migration/metastasis in EP4 signaling. Interestingly, EP4 agonist significantly induced intracellular Ca2+ elevation not in only oral cancer cells but also in other cells, including normal cells. Furthermore, we found that EP4 activated PI3K and induced Ca2+ influx through Orai1 without activation of store depletion and stromal interaction molecule 1 (STIM1). Immunoprecipitation showed that EP4 formed complexes with Orai1 and TRPC1, but not with STIM. Moreover, the EP4 agonist ONO‐AE1‐437 phosphorylated ERK and activated MMP‐2 and MMP‐9. Knockdown of Orai1 negated EP4 agonist‐induced ERK phosphorylation. Taken together, our data suggested that EP4 activated PI3K and then induced Ca2+ influx from the extracellular space through Orai1, resulting in ERK phosphorylation and promoting cell migration. Migration is regulated by EP4/PI3K/Orai1 signaling in oral cancer.
Unexpected relationships between frequency of antimicrobial resistance, disease phenotype and emm type in group A Streptococcus

Despite universal susceptibility to β-lactams, resistance to second-line antimicrobials (e.g. erythromycin) is increasingly common among group A Streptococcus (GAS). To better understand the frequency of regional GAS antimicrobial resistance, we screened a previously described GAS strain collection from Houston, TX, USA, for resistance to commonly used antimicrobials. A total of 100/929 (10.8 %) showed resistance to at least one antimicrobial. Tetracycline resistance was identified in 52 (5.6 %) GAS strains. The cumulative frequency of erythromycin and clindamycin resistance [macrolide (M) and macrolide-lincosamide-streptogramin (MLS) phenotypes] was greatest among invasive GAS strains (9.9 %) compared to that of strains derived from any other infection type (5.9 %, P=0.045). We identified emm types 11, 75, 77 and 92 as the only emm types with high (e.g. >50 %) within-emm type resistance and contributing to the majority (24/26; 92 %) of erythromycin/clindamycin resistance in invasive GAS. High-frequency resistance emm types were also significantly overrepresented in invasive GAS strains as indicated by invasive index. We performed whole-genome sequencing to define genetic elements associated with resistance among emm types 11, 75, 77 and 92. Diverse mobile elements contributed to GAS resistance including transposons, integrative conjugative elements, prophage and a plasmid. Phylogenetic analysis suggests recent clonal emergence of emm92 GAS strains. Our findings indicate that less frequently encountered GAS emm types disproportionately contribute to resistance phenotypes, are defined by diverse mobile genetic elements and may favour invasive disease.
The cell stress response: extreme times call for post‐transcriptional measures

Following cell stress, a wide range of molecular pathways are initiated to orchestrate the stress response and enable adaptation to an environmental or intracellular perturbation. The post‐transcriptional regulation strategies adopted during the stress response result in a substantial reorganization of gene expression, designed to prepare the cell for either acclimatization or programmed death, depending on the nature and intensity of the stress. Fundamental to the stress response is a rapid repression of global protein synthesis, commonly mediated by phosphorylation of translation initiation factor eIF2α. Recent structural and biochemical information have added unprecedented detail to our understanding of the molecular mechanisms underlying this regulation. During protein synthesis inhibition, the translation of stress‐specific mRNAs is nonetheless enhanced, often through the interaction between RNA‐binding proteins and specific RNA regulatory elements. Recent studies investigating the unfolded protein response (UPR) provide some important insights into how posttranscriptional events are spatially and temporally fine‐tuned in order to elicit the most appropriate response and to coordinate the transition from an early, acute stage into the chronic state of adaptation. Importantly, cancer cells are known to hi‐jack adaptive stress response pathways, particularly the UPR, to survive and proliferate in the unfavorable tumor environment. In this review, we consider the implications of recent research into stress‐dependent post‐transcriptional regulation and make the case for the exploration of the stress response as a strategy to identify novel targets in the development of cancer therapies.
Effects of a heat and moisture exchanger on respiratory function and symptoms post–cold air exercise

Exercise at temperatures below −15°C induces drying and cooling of lung airways which causes exercise‐induced bronchoconstriction (EIB) and respiratory symptoms, especially in winter sport athletes. The objective of this study was to evaluate whether a heat and moisture exchanger (HME) worn during intense cold air exercise improves lung function and reduces respiratory symptoms in healthy winter sport athletes.
Natural CLA-Enriched Lamb Meat Fat Modifies Tissue Fatty Acid Profile and Increases n-3 HUFA Score in Obese Zucker Rats

Ruminant fats are characterized by different levels of conjugated linoleic acid (CLA) and α-linolenic acid (18:3n-3, ALA), according to animal diet. Tissue fatty acids and their N-acylethanolamides were analyzed in male obese Zucker rats fed diets containing lamb meat fat with different fatty acid profiles: (A) enriched in CLA; (B) enriched in ALA and low in CLA; (C) low in ALA and CLA; and one containing a mixture of olive and corn oils: (D) high in linoleic acid (18:2n-6, LA) and ALA, in order to evaluate early lipid metabolism markers. No changes in body and liver weights were observed. CLA and ALA were incorporated into most tissues, mirroring the dietary content; eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) increased according to dietary ALA, which was strongly influenced by CLA. The n-3 highly-unsaturated fatty acid (HUFA) score, biomarker of the n-3/n-6 fatty acid ratio, was increased in tissues of rats fed animal fats high in CLA and/or ALA compared to those fed vegetable fat. DHA and CLA were associated with a significant increase in oleoylethanolamide and decrease in anandamide in subcutaneous fat. The results showed that meat fat nutritional values are strongly influenced by their CLA and ALA contents, modulating the tissue n-3 HUFA score.
Natural infection of a variant pseudorabies virus leads to bovine death in China.

Pseudorabies virus (PRV) infects numerous species of domestic and wild animals leading to severe diseases especially in swine and cattle. Since 2011, the variant PRVs were identified in pigs, which were genetically different from classic strains. Although variant PRV infection is widely observed in pigs, there is still no report of variant PRV infection in cattle. Here we reported a natural infection of variant PRV leading to acute bovine death in Eastern China. Our study suggests that the new variant PRV strains could be a potential threat to cattle industry and possibly to the public health of human.
The Patient‐Centered Future of Clinical Pharmacology

Over the past decade, we have witnessed remarkable technological progress, advances in drug discovery, development, and regulation, as well as changes toward value-based and personalized health care. These changes provide unprecedented opportunities for innovation and focusing on patients in ways that have not happened before. Herein, we share our views about the future of clinical pharmacology and the opportunities and challenges of moving the field toward patient-centric clinical pharmacology and personalized medicine.
Successful venetoclax salvage in the setting of refractory, dialysis-dependent multiple myeloma with t(11;14)

A 53 year-old man presented in October 2017 with back pain on a background of an 8-year history of monoclonal gammopathy of uncertain significance (MGUS). Subsequent imaging revealed lytic lesions at the level of L1 on whole spine Magnetic Resonance Imaging (MRI) and an X-ray skeletal survey showed lytic lesions in the skull. Laboratory investigations revealed mild anemia with hemoglobin of 12 g/dL, but normal renal and bone profiles. Serum protein electrophoresis showed an IgG kappa paraprotein of 62 g/L. A bone marrow aspirate and biopsy demonstrated the presence of over 90% kappa-restricted clonal plasma cells, consistent with multiple myeloma. Albumin was 33 g/L, beta-2microglobulin 6.25mg/L, and lactate dehydrogenase was within normal limits. Cytogenetic testing revealed a IgH-CCND1/ t(11;14) translocation with hyperdiploidy (three copies of 5p15.2 and CEPI5). Gene expression profiling (GEP) using SKY92 identified a high risk expression profile. The patient was therefore Multiple Myeloma International Staging System (ISS) stage III (R-ISS stage II) at diagnosis, but with the presence of high risk GEP. He was enrolled on a phase Ib trial evaluating the combination of weekly cyclophosphamide, bortezomib, dexamethasone (CyBorD) in combination with daratumumab (DARA) as the initial therapy for symptomatic myeloma in patients eligible for an autologous stem cell transplant (ASCT) (NCT02955810). Following three cycles of induction his M-band had fallen from 62 g/L to 42 g/L. During cycle 4 in the setting of rising serum kappa light chains, he developed acute non-oliguric renal failure, with features consistent with light chain nephropathy on renal biopsy. He subsequently commenced thrice weekly dialysis. Treatment was changed to lenalidomide and dexamethasone, which was discontinued after one cycle due to lack of response/progression, and plasma exchange was performed, bringing the M-band down from 47 g/L to 16 g/L. The choice of lenalidomide and dexamethasone was made given the lack of an immunomodulatory agent in the first line regimen, in line with current guidelines, and reflecting the lack of availability of carfilzomib at the time in Ireland. He was switched to third-line treatment with pomalidomide, bortezomib and dexamethasone (PVD), which was commenced due to evidence of efficacy in patients with lenalidomide-refractory disease, but this failed to achieve rapid control with his paraprotein rising back to 27 g/L. Given the presence of t(11;14) we felt there was a strong rationale to consider the addition of the BCL2inhibitor venetoclax and the patient now met criteria for compassionate access (progression on both a proteasome inhibitor and an immunomodulatory drug). Venetoclax was provided by AbbVie on compassionate access and administered at 400 mg once daily for the first week, then escalated to 800 mg daily. Nausea prevented further dose-escalation. Within three cycles of adding venetoclax to PVD, the paraprotein had fallen to 5 g/L and a bone marrow examination revealed less than 5% clonal plas-
Next-generation sequencing and its application in diagnosis of retinitis pigmentosa

ABSTRACT Retinitis Pigmentosa (RP) is a major cause of heritable human blindness with a high genetic heterogeneity. It is characterized by the initial degeneration of rod photoreceptors followed by cone photoreceptors. RP is also a prominent reason of visual impairment, by a global prevalence of 1:4000. RP is usually specified with nyctalopia in puberty, followed by concentric visual ﬁeld loss, that reﬂects the main impairment of rod photoreceptors; later in the life, as disease progresses, because of cone dysfunction, central vision loss also occurs. A precise molecular diagnosis is crucial for disease characterization and clinical prognosis. DNA sequencing is a powerful tool for deciphering various causes of different human diseases. The arrival of next-generation sequencing (NGS) technologies has diminished sequencing cost and considerably augmented the throughput, making whole-genome sequencing (WGS) a conceivable way for obtaining comprehensive genomic data and a more precise clinical decision. Nevertheless, the advantages gained from NGS technologies are among a number of challenges that must be sufficiently addressed before this technique can be altered from an investigation tools to a helpful method in routine clinical practices. This article aims to provide an overview about NGS technology and its related platforms. The challenges in the analysis and choosing an appropriate NGS method likewise their potential applications in clinical diagnosis are also discussed. The merit of such technique has been reflected in some recent studies where it is shown that using NGS and molecular information could help with clinical diagnosis, providing potential treatment options or changes, up-to-date family counseling and management.
I’ve been robbed! – Can changes in floral traits discourage bee pollination?

Some floral visitors collect nectar by piercing flower external whorls, acting as nectar robbers. They leave robbery vestiges, which can cause changes in floral characteristics, including physical and chemical signals that may influence flower recognition by pollinators. If pollinating bees associate these changes with absence or reduction in nectar volume, they can avoid these flowers, negatively affecting pollination. We aimed to investigate the effect of robbery on primary and secondary attractants. Additionally, we experimentally investigated if the visual signs present in robbed flowers affect the bee pollination of this plant species by discouraging pollinator visits. This study was performed in a very common pollinator-plant-cheaters system comprised by a bee-pollinated Bignoniaceae species and a nectar-robber bee that lands on the corolla tube and makes slits at its base during the nectar robbery. We experimentally isolated the effect of nectar consumption by this nectar-robber and investigated if the slits caused by the nectar-robbers affected the floral scent emission. In addition, we experimentally evaluated the effect of visual signs (slits) associated to the nectar robbery and the effect of nectar depletion on the pollination of Jacaranda caroba (Bignoniaceae). The robbers visited around 75% of the flowers throughout the day and removed significant amounts of nectar from them. However, the damages the robbers cause did not affect floral scent emission and we did not verify significant differences on pollen deposition neither when comparing flowers with slits and control nor when comparing flowers with and without nectar. We showed that even though nectar-robbers visually honestly signal the robbery and deplete high amounts of nectar, they did not affect pollinator visitation. These results showed that presumably antagonistic interactions might in fact not be so.
Level III dissection in locally advanced breast cancer following neoadjuvant chemotherapy: a retrospective study.

INTRODUCTION Breast cancer is the most common female cancer in India, and 30-60% of patients present with locally advanced breast cancer. Level III clearance is routinely performed in India in locally advanced breast cancer following neoadjuvant chemotherapy, even in clinical complete response. We analysed our data of patients with locally advanced breast cancer post-neoadjuvant chemotherapy who have undergone level III clearance to identify any subgroup in which level III dissection can be avoided. MATERIAL AND METHODS This is a retrospective study of female patients with locally advanced breast cancer who received neoadjuvant chemotherapy and underwent breast surgery including level III nodal clearance between June 2016 and May 2018. Data collected included age, menopausal status, TNM stage at presentation, grade, estrogen, progesterone, human epidermal growth factor receptor 2 status, response to treatment, post-chemotherapy stage and final histopathology. Uni- and multivariate analysis was undertaken. RESULTS Data from 200 patients was analysed. The level III positivity rate was 15.5%. The clinical complete response rate was 43%, of which 41% had pathological complete response. A significant association was present between level III node positivity and pathological T stage (p=0.03). No association was seen between level III positivity and any other studied variables. In the subset of patients with cT3N1 and cT2N2, level III positivity was seen in only 3/49 (6.1%) and 1/31 (3%), respectively. CONCLUSION Level III positivity rate is high and so cannot be avoided in locally advanced breast cancer following neoadjuvant chemotherapy. None of the preoperative factors predict for level III positivity. Level III positivity in cT3N1 and cT2N2 is low and these subgroups require further studies.