Miracle-dz/UniFAR-FTUs huggingface dataset:
Asymmetric requirement for α-tubulin over β-tubulin

How cells regulate the supply of α- and β-tubulin monomers to meet the demand for αβ- heterodimers while avoiding consequences of monomer imbalance is not understood. We investigate the role of gene copy number in tubulin regulation and how shifting the expression of α- or β-tubulin genes impacts tubulin proteostasis and microtubule function. We find that α- tubulin gene copy number is important for maintaining an excess α-tubulin protein compared to β-tubulin protein and preventing accumulation of super-stoichiometric β-tubulin. Super- stoichiometric β-tubulin is toxic to cells, leading to loss of microtubules, formation of non- microtubule assemblies of tubulin, and disrupted cell proliferation. In contrast, decreased β- tubulin or increased α-tubulin has minor effects. We provide evidence that cells rapidly equilibrate the concentration of α-tubulin protein during shifts in α-tubulin isotype expression to maintain a ratio in excess of β-tubulin. We propose an asymmetric relationship between α- and β-tubulins, where α-tubulins are maintained in excess to supply αβ-heterodimers and limit the accumulation of β-tubulin monomers.
Shiftless Restricts Viral Gene Expression and Influences RNA Granule Formation during KSHV lytic replication

Herpesviral infection reflects thousands of years of co-evolution and the constant struggle between virus and host for control of cellular gene expression. During Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic replication, the virus rapidly seizes control of host gene expression machinery by triggering a massive RNA decay event via a virally-encoded endoribonuclease, SOX. This virus takeover strategy decimates close to 80% of cellular transcripts, reallocating host resources toward viral replication. The host cell, however, is not entirely passive in this assault on RNA stability. A small pool of host transcripts that actively evade SOX cleavage has been identified over the years. One such “escapee”, C19ORF66 (herein referred to as Shiftless - SHFL) encodes a potent anti-viral protein capable of restricting the replication of multiple DNA, RNA, and retroviruses including KSHV. Here, we show that SHFL restricts KSHV replication by targeting the expression of critical viral early genes, including the master transactivator protein, KSHV ORF50, and thus subsequently the entire lytic gene cascade. Consistent with previous reports, we found the SHFL interactome throughout KSHV infection is dominated by RNA-binding proteins that influence both translation and protein stability, including the viral protein ORF57, a crucial regulator of viral RNA fate. We next show that SHFL affects cytoplasmic RNA granule formation, triggering the disassembly of processing bodies. Taken together, our findings provide insights into the complex relationship between RNA stability, RNA granule formation, and the anti-viral response to KSHV infection. Significance In the past five years, SHFL has emerged as a novel and integral piece of the innate immune response to viral infection. SHFL has been reported to restrict the replication of multiple viruses including several flaviviruses and the retrovirus HIV-1. However, to date, the mechanism(s) by which SHFL restricts DNA virus infection remains largely unknown. We have previously shown that following its escape from KSHV-induced RNA decay, SHFL acts as a potent anti-viral factor, restricting nearly every stage of KSHV lytic replication. In this study, we set out to determine the mechanism by which SHFL restricts KSHV infection. We demonstrate that SHFL impacts all classes of KSHV genes and found that SHFL restricts the expression of several key early genes, including KSHV ORF50 and ORF57. We then mapped the interactome of SHFL during KSHV infection and found several host and viral RNA-binding proteins that all play crucial roles in regulating RNA stability and translation. Lastly, we found that SHFL expression influences RNA granule formation both outside of and within the context of KSHV infection, highlighting its broader impact on global gene expression. Collectively, our findings highlight a novel relationship between a critical piece of the anti-viral response to KSHV infection and the regulation of RNA-protein dynamics.
Spectrum of BDNF expression changes and reactive glial phenotypes across brain regions precede neuronal loss and predict therapeutic effects of BDNF in early stages of SCA1 Abbreviated title: Brain wide SCA1 pathology and effects of BDNF

319 words) Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by an abnormal expansion of CAG repeats in the gene Ataxin1 (ATXN1) and characterized by motor deficits, cognitive decline, and premature lethality. Due to the severe cerebellar degeneration seen in SCA1, the pathogenesis of Purkinje cells has been the main focus of previous studies. However, mutant ATXN1 is expressed throughout the brain, and pathology in brain regions beyond the cerebellar cortex likely contributes to the symptoms of SCA1. Here, using immunohistochemistry and gene expression analysis we investigated early-stage SCA1 alterations in neurons, astrocytes, and microglia in clinically relevant SCA1 brain regions including the cerebellum, medulla oblongata, hippocampus, and motor cortex of Atxn1 mice, a knock-in mouse model of SCA1 expressing mutant ATXN1 broadly. Our results indicate a spectrum of astrocyte and microglial phenotypes across brain regions early in SCA1. We found reduced expression of homeostatic astrocytic genes Kcnj10, Aqp4, Slc1a2 and Gja1 in 12 week old Atxn1 mice, all of which are key for neuronal function, in the hippocampus and medulla. At the same age, the expression of these genes was increased in the cortex, indicating region-specific astrocyte reactive phenotypes. We have found altered microglial density throughout the brain, with decreases in cerebellar white matter but increases in medulla, motor cortex and corpus callosum. On the other hand, neuronal pathology was evident only in cerebellar Purkinje cells at this early stage of SCA1. We have previously shown that expression of brain-derived neurotrophic factor (BDNF), an astrocyte-released growth factor important for the survival and function of neurons, is reduced in the cerebellum, and exogenous BDNF treatment has therapeutic potential for cerebellar aspects of disease in Purkinje cells specific transgenic mouse model of SCA1 (Pcp2-ATXN1[82Q] line). We report here that BDNF expression is decreased in the cerebellar Bergmann glia of patients with SCA1. Moreover, we found brain region specific changes in BDNF expression in Atxn1 mice with decreased expression in the cerebellum and hippocampus, and increased expression in the medulla and cortex. Using ALZET pumps to deliver BDNF, we have found that BDNF treatment ameliorated several aspects of SCA1 pathogenesis, including motor deficits, learning and problem-solving strategy development, hippocampal neurogenesis, and expression of astrocyte homeostatic genes in the hippocampus.
Interfacial tension driven open droplet microfluidics

We developed an open channel droplet microfluidic system that autonomously generates droplets at low Ca (~10-4-10-3) by leveraging competing hydrostatic and capillary pressure. With only our open channel polytetrafluoroethylene (PTFE) device, pipettes, and commercially available carrier fluid, we produce hundreds of microliter droplets; tubing, electronics, or pumps are not required, making droplet technology feasible for research labs without external flow generators. Furthermore, we demonstrated conceptual applications that showcase the process of droplet generation, splitting, transport, incubation, mixing, and sorting in our system. Unlike conventional droplet microfluidics, the open nature of the device enables the use of physical tools such as tweezers and styli to directly access the system; with this, we developed a new method of droplet sorting and transfer that capitalizes on the Cheerios effect, the aggregation of buoyant objects along a liquid interface. Our platform offers enhanced usability, direct access to the droplet contents, easy manufacturability, compact footprint, and high customizability. This design is a first step in exploring the space of power-free open droplet microfluidic systems and provide design rules for similar channel designs.
Astragaloside IV Relieves Atherosclerosis and Hepatic Steatosis via MAPK/NF-κB Signaling Pathway in LDLR−/− Mice

Astragaloside IV (AS-IV) is the main active compound of Astragalus membranaceus. In this study, we investigated whether AS-IV could attenuate atherosclerosis and hepatic steatosis in LDLR−/−mice and its potential mechanisms. After 12 weeks of high fat diet, the LDLR−/−mice were randomly divided into four groups. Then, the mice were administrated with 0.9% saline or AS-IV (10 mg/kg) or atorvastatin (1.3 mg/kg) for 12 weeks. Serum lipid profiles and inflammatory cytokines were detected by ELISA, hepatic TC and TG by colorimetric enzymatic kits, gene expression by RT-qPCR, plaque sizes by H&E staining, Oil Red O, liver pathology by H&E staining, collagen content by Masson, α-SMA, caspase-3 and NF-κB p65 production by immunofluorescence staining. MAPK/NF-κB pathway and inflammation related proteins were detected by Western Blot. The results showed that AS-IV decreased the levels of serum lipids, reduced plaque area and increased plaque stability in HFD-induced LDLR−/− mice. AS-IV also decreased the levels of inflammatory cytokines in the serum, aortas and liver tissue, and NF-κB p65 in aortic roots. The phosphorylation of JNK, ERK1/2, p38 and NF-κB, and inflammatory proteins (iNOS, VCAM-1and IL-6) was inhibited in AS-IV-treated group. In summary, AS-IV inhibited inflammation to attenuate atherosclerosis and hepatic steatosis via MAPK/NF-κB signaling pathway in LDLR−/− mice.
Dose-Intensified Stereotactic Ablative Radiation for Localized Prostate Cancer

Purpose Stereotactic ablative radiation (SAbR) has been increasingly used in prostate cancer (PCa) given its convenience and cost efficacy. Optimal doses remain poorly defined with limited prospective comparative trials and long-term safety/efficacy data at higher dose levels. We analyzed toxicity and outcomes for SAbR in men with localized PCa at escalated 45 Gy in 5 fractions. Methods and Materials This study retrospectively analyzed men from 2015 to 2019 with PCa who received linear-accelerator-based SAbR to 45 Gy in 5 fractions, along with perirectal hydrogel spacer, fiducial placement, and MRI-based planning. Disease control outcomes were calculated from end of treatment. Minimally important difference (MID) assessing patient-reported quality of life was defined as greater than a one-half standard deviation increase in American Urological Association (AUA) symptom score after SAbR. Results Two-hundred and forty-nine (249) low-, intermediate-, and high-risk PCa patients with median follow-up of 14.9 months for clinical toxicity were included. Acute urinary grade II toxicity occurred in 20.4% of patients. Acute grade II GI toxicity occurred in 7.3% of patients. For follow-up > 2 years (n = 69), late GU and GI grade ≥III toxicity occurred in 5.8% and 1.5% of patients, respectively. MID was evident in 31.8%, 23.4%, 35.8%, 37.0%, 33.3%, and 26.7% of patients at 3, 6, 12, 24, 36, and 48 months, respectively. The median follow-up for biochemical recurrence was 22.6 months with biochemical failure-free survival of 100% at 1 year (n = 226) and 98.7% for years 2 (n = 113) and 3 (n = 54). Conclusions SAbR for PCa at 45 Gy in 5 fractions shows an encouraging safety profile. Prospective studies with longer follow-up are warranted to establish this dose regimen as standard of care for PCa.
Sporoderm-Broken Spores of Ganoderma lucidum Sensitizes Ovarian Cancer to Cisplatin by ROS/ERK Signaling and Attenuates Chemotherapy-Related Toxicity

Although platinum-based chemotherapeutics such as cisplatin are the cornerstone of treatment for ovarian cancer, their clinical application is profoundly limited due to chemoresistance and severe adverse effects. Sporoderm-broken spores of Ganoderma lucidum (SBSGL) have been reported to possess antitumor effects. However, the function and mechanism of SBSGL and its essential composition, ganoderic acid D (GAD), in the cisplatin therapy on ovarian cancer have yet to be investigated. Here, we investigated the combined effect of SBSGL and cisplatin in an ovarian tumor xenograft model. The results showed that combining SBSGL with cisplatin reduced tumor growth and ameliorated cisplatin-induced intestinal injury and myelosuppression. We also confirmed that GAD could enhance the therapeutic effect of cisplatin in SKOV3 and cisplatin-resistant SKOV3/DDP cells by increasing the intracellular reactive oxygen species (ROS). Mechanistically, we proved that ROS-mediated ERK signaling inhibition played an important role in the chemo-sensitization effect of GAD on cisplatin in ovarian cancer. Taken together, combining SBSGL with cisplatin provides a novel therapeutic strategy against ovarian cancer.
Guard Cell-Specific Pectin METHYLESTERASE53 Is Required for Abscisic Acid-Mediated Stomatal Function and Heat Response in Arabidopsis

Pectin is a major component of the plant cell wall, forming a network that contributes to cell wall integrity and flexibility. Pectin methylesterase (PME) catalyzes the removal of methylester groups from the homogalacturonan backbone, the most abundant pectic polymer, and contributes to intercellular adhesion during plant development and different environmental stimuli stress. In this study, we identified and characterized an Arabidopsis type-II PME, PME53, which encodes a cell wall deposited protein and may be involved in the stomatal lineage pathway and stomatal functions. We demonstrated that PME53 is expressed explicitly in guard cells as an abscisic acid (ABA)-regulated gene required for stomatal movement and thermotolerance. The expression of PME53 is significantly affected by the stomatal differentiation factors SCRM and MUTE. The null mutation in PME53 results in a significant increase in stomatal number and susceptibility to ABA-induced stomatal closure. During heat stress, the pme53 mutant highly altered the activity of PME and significantly lowered the expression level of the calmodulin AtCaM3, indicating that PME53 may be involved in Ca2+-pectate reconstitution to render plant thermotolerance. Here, we present evidence that the PME53-mediated de-methylesterification status of pectin is directed toward stomatal development, movement, and regulation of the flexibility of the guard cell wall required for the heat response.
Affect-Driven Learning of Robot Behaviour for Collaborative Human-Robot Interactions

Collaborative interactions require social robots to share the users’ perspective on the interactions and adapt to the dynamics of their affective behaviour. Yet, current approaches for affective behaviour generation in robots focus on instantaneous perception to generate a one-to-one mapping between observed human expressions and static robot actions. In this paper, we propose a novel framework for affect-driven behaviour generation in social robots. The framework consists of (i) a hybrid neural model for evaluating facial expressions and speech of the users, forming intrinsic affective representations in the robot, (ii) an Affective Core, that employs self-organising neural models to embed behavioural traits like patience and emotional actuation that modulate the robot’s affective appraisal, and (iii) a Reinforcement Learning model that uses the robot’s appraisal to learn interaction behaviour. We investigate the effect of modelling different affective core dispositions on the affective appraisal and use this affective appraisal as the motivation to generate robot behaviours. For evaluation, we conduct a user study (n = 31) where the NICO robot acts as a proposer in the Ultimatum Game. The effect of the robot’s affective core on its negotiation strategy is witnessed by participants, who rank a patient robot with high emotional actuation higher on persistence, while an impatient robot with low emotional actuation is rated higher on its generosity and altruistic behaviour.
Assessment of Combination of Automated Pupillometry and Heart Rate Variability to Detect Driving Fatigue

Objectives Approximately 20~30% of all traffic accidents are caused by fatigue driving. However, limited practicability remains a barrier for the real application of available techniques to detect driving fatigue. Use of pupillary light reflex (PLR) may be potentially effective for driving fatigue detection. Methods A 90 min monotonous simulated driving task was utilized to induce driving fatigue. During the task, PLR measurements were performed at baseline and at an interval of 30 min. Subjective rating scales, heart rate variability (HRV) were monitored simultaneously. Results Thirty-two healthy volunteers in China participated in our study. Based on the results of subjective evaluation and behavioral performances, driving fatigue was verified to be successfully induced by a simulated driving task. Significant variations of PLR and HRV parameters were observed, which also showed significant relevance with the change in Karolinska Sleepiness Scale at several timepoints (|r| = 0.55 ~ 0.72, P < 0.001). Furthermore, PLR variations had excellent ability to detect driving fatigue with high sensitivity and specificity, of which maximum constriction velocity variations achieved a sensitivity of 85.00% and specificity of 72.34% for driving fatigue detection, vs. 82.50 and 78.72% with a combination of HRV variations, a nonsignificant difference (AUC = 0.835, 0.872, P > 0.05). Conclusions Pupillary light reflex variation may be a potential indicator in the detection of driving fatigue, achieving a comparative performance compared with the combination with heart rate variability. Further work may be involved in developing a commercialized driving fatigue detection system based on pupillary parameters.
MyotonPro Is a Valid Device for Assessing Wrist Biomechanical Stiffness in Healthy Young Adults

Background The MyotonPro is a portable device for measuring biomechanical and viscoelastic properties in superficial soft tissues. The aims of this study are firstly to validate the MyotonPro compared to a reliable gold-standard frame and secondly to observe the influence of MyotonPro measurement on the total wrist viscoelasticity. Methods Three silicone polymers with different elastic properties were assessed with the MyotonPro and with a reference rheometer (Universal Tribometer Mod). Then, a free oscillations method was used to measure the passive elastic and viscous stiffness of the wrist and compared to MyotonPro forearm measurements. Results A one-way ANOVA demonstrated the validity of the MyotonPro's stiffness (p = 0.001), decrement (p < 0.001), and relaxation (p = 0.008) parameters for measuring the elastic stiffness (k) of the three polymers. The MyotonPro parameters demonstrated excellent reliability on the forearm. Proximal and distal anterior myofascial measurements of the MyotonPro were moderately correlated to the elastic stiffness (p = 0.0027–0.0275, absolute r = from 0.270 to 0.375) of the wrist while the postero-distal myofascial tissues of the forearm demonstrated a moderate correlation with the viscous stiffness of the wrist (p = 0.0096–0.0433, absolute r = from 0.257 to 0.326). Discussion The MyotonPro is a valid device for measuring elastic stiffness as well as a portable, affordable, and easy-to-use tool for quantifying the biomechanical properties and viscoelasticity of myofascial tissue in healthy subjects.
Comamonas thiooxydans Expressing a Plasmid-Encoded IMP-1 Carbapenemase Isolated From Continuous Ambulatory Peritoneal Dialysis of an Inpatient in Japan

Citation: Suzuki Y, Nakano R, Nakano A, Tasaki H, Asada T, Horiuchi S, Saito K, Watanabe M, Nomura Y, Kitagawa D, Lee S-T, Ui K, Koizumi A, Nishihara Y, Sekine T, Sakata R, Ogawa M, Ohnishi M, Tsuruya K, Kasahara K and Yano H (2022) Comamonas thiooxydans Expressing a Plasmid-Encoded IMP-1 Carbapenemase Isolated From Continuous Ambulatory Peritoneal Dialysis of an Inpatient in Japan. Front. Microbiol. 13:808993. doi: 10.3389/fmicb.2022. 808993 Comamonas thiooxydans Expressing a Plasmid-Encoded IMP-1 Carbapenemase Isolated From Continuous Ambulatory Peritoneal Dialysis of an Inpatient in Japan
Pediatric Prediction Model for Low Immunoglobulin G Level Based on Serum Globulin and Illness Status

Hypogammaglobulinemia is a condition that requires prompt diagnosis and treatment. Unfortunately, serum immunoglobulin (Ig) measurements are not widely accessible in numerous developing countries. Serum globulin is potentially the best candidate for screening of low IgG level (IgGLo) due to its high availability, low cost, and rapid turnover time. However, multiple factors may influence the probability of prediction. Our study aimed to establish a simple prediction model using serum globulin to predict the likelihood of IgGLo in children. For retrospective data of patients who were suspected of having IgGLo, both serum IgG and globulin were simultaneously collected and measured. Potential factors interfering with serum globulin and IgG levels were investigated for their impact using bivariate binary logistic regression. A multivariate binary logistic regression was used to generate a formula and score to predict IgGLo. We obtained 953 samples from 143 pediatric patients. A strong positive correlation between serum globulin and IgG levels was observed (r=0.83, p < 0.001). A screening test model using serum globulin and illness status was constructed to predict IgGLo. The formula for predicting IgGLo was generated as follows; Predicted score = (2 x globulin (g/dl)) – illness condition score (well=0, sick=1). When the score was <4, the patient has the probability of having IgGLo with a sensitivity of 0.78 (0.71, 0.84), a specificity of 0.71 (0.68, 0.74), PPV of 0.34 (0.29, 0.40) and NPV of 0.94 (0.92, 0.96). This formula will be useful as rapid and inexpensive screening tool for early IgGLo detection, particularly in countries/locations where serum IgG measurement is inaccessible.
Management of Hyperglycemia in Hospitalized Patients Receiving Parenteral Nutrition

Almost half of inpatients on parenteral nutrition experience hyperglycemia, which increases the risk of complications and mortality. The blood glucose target for hospitalized patients on parenteral nutrition is 7.8 to 10.0 mmol/L (140 to 180 mg/dL). For patients with diabetes, the same parenteral nutrition formulae as for patients without diabetes can be used, as long as blood glucose levels can be adequately controlled using insulin. Insulin can be delivered via the subcutaneous or intravenous route or, alternatively, added to parenteral nutrition admixtures. Combining parenteral with enteral and oral nutrition can improve glycemic control in patients with sufficient endogenous insulin stores. Intravenous insulin infusion is the preferred route of insulin delivery in critical care as doses can be rapidly adjusted to altered requirements. For stable patients, insulin can be added directly to the parenteral nutrition bag. If parenteral nutrition is infused continuously over 24 hours, the subcutaneous injection of a long-acting insulin combined with correctional bolus insulin may be adequate. The aim of this review is to give an overview of the management of parenteral nutrition-associated hyperglycemia in inpatients with diabetes.