Miracle-dz/UniFAR-FTUs huggingface dataset:
KLHL22 maintains PD-1 homeostasis and prevents excessive T cell suppression

Significance Aberrant PD-1 expression is known to inhibit T cell effector activity and plays a pivotal role in tumor immune escape. Since maintaining an appropriate level of PD-1 expression is of great significance, it should be highly regulated at multiple levels. Despite extensive studies to date on this topic, it remains unclear how PD-1 expression is precisely regulated at the posttranslation level both during T cell activation and among the tumor microenvironment. Here, we show that KLHL22 maintains PD-1 protein homeostasis by degrading incompletely glycosylated PD-1, thereby preventing excessive T cell suppression. KLHL22-mediated degradation of PD-1 protein will be ineffective in response to either the tumor microenvironment or treatment with 5-FU, resulting in excessive PD-1 accumulation and reduced T cell activity. Aberrant programmed cell death protein 1 (PD-1) expression on the surface of T cells is known to inhibit T cell effector activity and to play a pivotal role in tumor immune escape; thus, maintaining an appropriate level of PD-1 expression is of great significance. We identified KLHL22, an adaptor of the Cul3-based E3 ligase, as a major PD-1–associated protein that mediates the degradation of PD-1 before its transport to the cell surface. KLHL22 deficiency leads to overaccumulation of PD-1, which represses the antitumor response of T cells and promotes tumor progression. Importantly, KLHL22 was markedly decreased in tumor-infiltrating T cells from colorectal cancer patients. Meanwhile, treatment with 5-fluorouracil (5-FU) could increase PD-1 expression by inhibiting the transcription of KLHL22. These findings reveal that KLHL22 plays a crucial role in preventing excessive T cell suppression by maintaining PD-1 expression homeostasis and suggest the therapeutic potential of 5-FU in combination with anti–PD-1 in colorectal cancer patients.
Medial frontal negativities predict performance improvements during motor sequence but not motor adaptation learning

Abstract Alterations in our environment require us to learn or alter motor skills to remain efficient. Also, damage or injury may require the relearning of motor skills. Two types have been identified: movement adaptation and motor sequence learning. Doyonet al. (2003, Distinct contribution of the cortico‐striatal and cortico‐cerebellar systems to motor skill learning. Neuropsychologia, 41(3), 252‐262) proposed a model to explain the neural mechanisms related to adaptation (cortico‐cerebellar) and motor sequence learning (cortico‐striatum) tasks. We hypothesized that medial frontal negativities (MFNs), event‐related electrocortical responses including the error‐related negativity (ERN) and correct‐response‐related negativity (CRN), would be trait biomarkers for skill in motor sequence learning due to their relationship with striatal neural generators in a network involving the anterior cingulate and possibly the supplementary motor area. We examined 36 participants' improvement in a motor adaptation and a motor sequence learning task and measured MFNs elicited in a separate Spatial Stroop (conflict) task. We found both ERN and CRN strongly predicted performance improvement in the sequential motor task but not in the adaptation task, supporting this aspect of the Doyon model. Interestingly, the CRN accounted for additional unique variance over the variance shared with the ERN suggesting an expansion of the model.
Guillain‐Barré syndrome associated with SARS‐CoV‐2 infection: A systematic review and individual participant data meta‐analysis

Several published reports have described a possible association between Guillain‐Barré syndrome (GBS) and severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection. This systematic review aimed to summarize and meta‐analyze the salient features and prognosis of SARS‐CoV‐2‐associated GBS. We searched the PubMed (Medline), Web of Science and Cochrane databases for articles published between 01 January 2020 and 05 August 2020 using SARS‐CoV‐2 and GBS‐related keywords. Data on sociodemographic characteristics, antecedent symptoms, clinical, serological and electrophysiological features, and hospital outcomes were recorded. We included 45 articles from 16 countries reporting 61 patients with SARS‐CoV‐2‐associated GBS. Most (97.7%) articles were from high‐ and upper‐middle‐income countries. Forty‐two (68.9%) of the patients were male; median (interquartile range) age was 57 (49‐70) years. Reverse transcriptase polymerase chain reaction for SARS‐CoV‐2 was positive in 90.2% of patients. One report of SARS‐CoV‐2‐associated familial GBS was found which affected a father and daughter of a family. Albuminocytological dissociation in cerebrospinal fluid was found in 80.8% of patients. The majority of patients (75.5%) had a demyelinating subtype of GBS. Intravenous immunoglobulin and plasmapheresis were given to 92.7% and 7.3% of patients, respectively. Around two‐thirds (65.3%) of patients had a good outcome (GBS‐disability score ≤ 2) on discharge from hospital. Two patients died in hospital. SARS‐CoV‐2‐associated GBS mostly resembles the classical presentations of GBS that respond to standard treatments. Extensive surveillance is required in low‐ and lower‐middle‐income countries to identify and report similar cases/series. Further large‐scale case‐control studies are warranted to strengthen the current evidence. PROSPERO Registration Number CRD42020201673.
Does the Endotracheal Tube Cuff Pressure Increases with Transesophageal Probe Insertion?

Context: The cuff pressure (CP) of the endotracheal tube (ETT) exceeding 30 cm of H2O results in reduced perfusion of lateral mucosa of trachea leading to complications. As the posterior tracheal wall is in contact with the esophagus, there is a possibility that the insertion of transesophageal echo (TEE) probe may compress the tracheal wall and increase CP. Aims: This study was aimed to assess the impact of TEE probe insertion on CP in adults undergoing cardiac surgery. Settings and Design: Prospective observational study of 65 patients at tertiary care level hospital. Subjects and Methods: After balanced general anesthesia, patients were intubated with high volume low-pressure ET.TEE probe was then inserted with gentle jaw thrust. CP was measured by standard invasive pressure monitoring device at four points: T1 at baseline before TEE probe insertion; T2 maximum CP noted at TEE probe insertion; T3 at 5 min post TEE probe insertion; and T4 at post-TEE exam. Statistical Analysis Used: CP was compared between pairs of time points (T1 vs. T2; T1 vs. T3; and T1 vs. T4) using Mann-Whitney U test. Factors predicting CP >30 cm of H2O at T4 were assessed by backward stepwise regression. Results: CP (mean ± S.D.) at T1, T2, T3, and T4 was 22 ± 3, 38 ± 10, 30 ± 6, and 30 ± 7, respectively. CP increased significantly from T1 to T2 (P < 0.001), T1 to T3 (P < 0.001), and T1 to T4 (P < 0.001). There were 26 patients (40%) with CP >30 cm of H2O at end of TEE exam (T4). On multivariate analysis baseline, CP (T1) >20 cm of H2O was significantly associated with CP >30 cm of H2O at end of TEE exam with Odd's Ratio (OR) of 8.5 (1.76–41.06, P = 0.008). Conclusions: To conclude, the CP increases significantly with TEE probe insertion in 40% of patients exceeding a safe limit of 30 cm of H2O. The monitoring and optimization of CP is advisable.
Shorter incubation period is associated with severe disease progression in patients with COVID-19

ABSTRACT The diagnosed COVID-19 cases revealed that the incubation periods (IP) varied a lot among patients. However, few studies had emphasized on the different clinical features and prognosis of patients with different IP. A total of 330 patients with laboratory-confirmed COVID-19 were enrolled and classified into immediate onset group(IP<3 days, I group, 57 cases) and late onset group(IP>10 days, L group, 75 cases) based on IP. The difference of clinical characteristics and prognosis of the two groups were compared. There were more patients with fever in I group than in L group(P = 0.003), and counts of all the total lymphocytes, total T lymphocytes, CD4 + and CD8 + T lymphocytes were significantly different between the two groups(all P < 0.01). Besides, patients in L group had more GGOs in CT scan than I group and there were more patients in I group receiving antibiotic treatment than in L group(P < 0.001). For disease aggravation, the median CT scores were comparable between the two groups, but individually, there were more patients with increased CT score during hospitalization in I group than in L group. The aggravation incidence of CT presentation was 21.1% in I group, significantly higher than L group(8.0%, P = 0.042). Multivariable COX models suggested that IP was the only independent factors for CT aggravation. Conclusively, patients with different IP were different in clinical symptoms, laboratory tests, and CT presentations. Shorter IP was associated with the aggravation of lung involvement in CT scan.
Modeling flexible behavior in childhood to adulthood shows age-dependent learning mechanisms and less optimal learning in autism in each age group

Flexible behavior is critical for everyday decision-making and has been implicated in restricted, repetitive behaviors (RRB) in autism spectrum disorder (ASD). However, how flexible behavior changes developmentally in ASD remains largely unknown. Here, we used a developmental approach and examined flexible behavior on a probabilistic reversal learning task in 572 children, adolescents, and adults (ASD N = 321; typical development [TD] N = 251). Using computational modeling, we quantified latent variables that index mechanisms underlying perseveration and feedback sensitivity. We then assessed these variables in relation to diagnosis, developmental stage, core autism symptomatology, and associated psychiatric symptoms. Autistic individuals showed on average more perseveration and less feedback sensitivity than TD individuals, and, across cases and controls, older age groups showed more feedback sensitivity than younger age groups. Computational modeling revealed that dominant learning mechanisms underpinning flexible behavior differed across developmental stages and reduced flexible behavior in ASD was driven by less optimal learning on average within each age group. In autistic children, perseverative errors were positively related to anxiety symptoms, and in autistic adults, perseveration (indexed by both task errors and model parameter estimates) was positively related to RRB. These findings provide novel insights into reduced flexible behavior in relation to clinical symptoms in ASD.
Effect of handling and crowding on the susceptibility of Atlantic salmon (Salmo salar L.) to Lepeophtheirus salmonis (Krøyer) copepodids

Abstract Lepeophtheirus salmonis is an ectoparasite causing economic concerns in Atlantic salmon farming. Salmon lice infestation management methods can be stressful and impact fish welfare. This work investigated the stress effect on the attachment of L. salmonis copepodids to Atlantic salmon through two approaches: (a) handling by netting and air exposure (acute stress), and (b) crowding with restricted surface access in a tank (chronic stress). In the first experiment, we compared the number of attached L. salmonis and cortisol levels between a group of handled salmon and a control group. In the second experiment, a group of densely packed salmon was compared to a control group based on the number of attached copepodids, cortisol levels and neutrophil:lymphocyte ratios. Handled salmon showed significantly higher plasma cortisol levels (p < .001) and more attached copepodids (p = .01) than control salmon. Conversely, the cortisol level and number of attached copepodids were not significantly different between the densely packed and control salmon (p > .05). The neutrophil:lymphocyte ratio was significantly higher (p = .0014) in the densely packed salmon than in the control salmon. Handling salmon increased their risk of infestation by L. salmonis. This has implications for reinfestation rates following delousing treatments in commercial salmon aquaculture, which often involve crowding and handling salmon.
Recurrent bioprosthetic mitral valve thrombosis treated with anticoagulation

Bioprosthetic valve thrombosis (BPVT) is more common than previously thought and likely underreported. BPVT can be accurately diagnosed with cardiac imaging and treated successfully with anticoagulation, thus preventing reoperation. We hereby report a case of recurrent BPVT in the mitral position successfully treated with anticoagulation along with review of literature.
Constitutive LH receptor activity impairs NO mediated penile smooth muscle relaxation.

Timely activation of the luteinizing hormone receptor (LHCGR) is critical for fertility. Activating mutations in LHCGR cause familial male-limited precocious puberty (FMPP) due to premature synthesis of testosterone. A mouse model of FMPP (KiLHRD582G), expressing a constitutively activating mutation in LHCGR, was previously developed in our laboratory. KiLHRD582G mice became progressively infertile due to sexual dysfunction and exhibited smooth muscle loss and chondrocyte accumulation in the penis. In this study we tested the hypothesis that KiLHRD582G mice had erectile dysfunction due to impaired smooth muscle function. Apomorphine-induced erection studies determined that KiLHRD582G mice had erectile dysfunction. Penile smooth muscle and endothelial function were assessed using penile cavernosal strips. Penile endothelial cell content was not changed in KiLHRD582G mice. The maximal relaxation response to acetylcholine and the nitric oxide donor, sodium nitroprusside, was significantly reduced in KiLHRD582G mice indicating an impairment in the nitric oxide (NO)- mediated signaling. Cyclic guanosine monophosphate (cGMP) levels were significantly reduced in KiLHRD582G mice in response to acetylcholine, sodium nitroprusside and the soluble guanylate cyclase stimulator, BAY 41-2272. Expression of NOS1, NOS3 and PKRG1 were unchanged. The Rho-kinase signaling pathway for smooth muscle contraction was not altered. Together, these data indicate that KiLHRD582G mice have erectile dysfunction due to impaired NO-mediated activation of soluble guanylate cyclase resulting in decreased levels of cGMP and penile smooth muscle relaxation. These studies in the KiLHRD582G mice demonstrate that activating mutations in the mouse LHCGR cause erectile dysfunction due to impairment of the NO-mediated signaling pathway in the penile smooth muscle.
Evaluation of Fontan failure by classifying the severity of Fontan-associated liver disease: a single-centre cross-sectional study.

OBJECTIVES Fontan-associated liver disease (FALD) is a hallmark of the failing Fontan circulation, but no general classification of FALD severity exists. In this study, we propose a scoring system to grade the severity of FALD and analyse its applicability for evaluation of Fontan failure. METHODS From 2017 to 2019, a total of 129 successive Fontan patients received a comprehensive hepatic assessment. The FALD score was based on results from laboratory testing, hepatic ultrasound and transient elastography by assigning scoring points for each abnormality detected. FALD severity was graded mild, moderate and severe. Haemodynamic assessment was performed using echocardiography, cardiopulmonary exercise testing and catheterization. RESULTS FALD was graded absent/ mild, moderate and severe in 53, 26 and 50 patients, respectively. Cardiopulmonary capacity was significantly impaired in patients with severe FALD compared to patients with absent/mild FALD (P = 0.001). The FALD score significantly correlated with pulmonary artery pressure (P = 0.001), end-diastolic ventricular pressure (P < 0.001), hepatic venous pressure (P = 0.004) and wedged hepatic venous pressure (P = 0.009). Fontan failure was present in 21 patients. FALD was graded moderate in 2 and severe in 19 of these patients. The FALD score accurately discriminated patients with and without Fontan failure (sensitivity 90.5%, specificity 71.3%). CONCLUSIONS The FALD score significantly correlates with impaired Fontan haemodynamics. A cut-off value ≥6.0 has a high diagnostic accuracy in detecting Fontan failure. CLINICAL TRIAL REGISTRY DRKS (GCTR, German clinical trial registry). CLINICAL TRIAL REGISTRATION NUMBER DRKS00015039.
Acid‐sensing ion channels regulate nucleus pulposus cell inflammation and pyroptosis via the NLRP3 inflammasome in intervertebral disc degeneration

Lactate accumulation is an important factor in the intervertebral disc degeneration (IVDD). Currently, the effect and underlying mechanism of action of lactate on nucleus pulposus (NP) cell inflammation during IVDD are unclear. Previous studies have found that the NLRP3 inflammasome plays an important role in the regulation of NP inflammation. This study focused on the regulation of acid‐sensitive ion channels (ASICs) in relation to inflammation and the effect of NLRP3 on pyroptosis levels in NP cells under acidic conditions.
An Information-Theory-Based Approach for Optimal Model Reduction of Biomolecules

In theoretical modeling of a physical system, a crucial step consists of the identification of those degrees of freedom that enable a synthetic yet informative representation of it. While in some cases this selection can be carried out on the basis of intuition and experience, straightforward discrimination of the important features from the negligible ones is difficult for many complex systems, most notably heteropolymers and large biomolecules. We here present a thermodynamics-based theoretical framework to gauge the effectiveness of a given simplified representation by measuring its information content. We employ this method to identify those reduced descriptions of proteins, in terms of a subset of their atoms, that retain the largest amount of information from the original model; we show that these highly informative representations share common features that are intrinsically related to the biological properties of the proteins under examination, thereby establishing a bridge between protein structure, energetics, and function.
Nutrient sensing in Leishmania: Flagellum and cytosol

Parasites are by definition organisms that utilize resources from a host to support their existence, thus, promoting their ability to establish long‐term infections and disease. Hence, sensing and acquiring nutrients for which the parasite and host compete is central to the parasitic mode of existence. Leishmania are flagellated kinetoplastid parasites that parasitize phagocytic cells, principally macrophages, of vertebrate hosts and the alimentary tract of sand fly vectors. Because nutritional supplies vary over time within both these hosts and are often restricted in availability, these parasites must sense a plethora of nutrients and respond accordingly. The flagellum has been recognized as an “antenna” that plays a core role in sensing environmental conditions, and various flagellar proteins have been implicated in sensing roles. In addition, these parasites exhibit non‐flagellar intracellular mechanisms of nutrient sensing, several of which have been explored. Nonetheless, mechanistic details of these sensory pathways are still sparse and represent a challenging frontier for further experimental exploration.
Dose–response association between sugar- and artificially sweetened beverage consumption and the risk of metabolic syndrome: a meta-analysis of population-based epidemiological studies

Abstract Objective: The associations between sugar-sweetened beverage (SSB) and artificially sweetened beverage (ASB) consumption and the risk of metabolic syndrome (MetS) remain controversial. A quantitative assessment of dose–response associations has not been reported. This study aims to assess the associations between the risk of MetS and SSB, ASB, and total sweetened beverage (TSB, the combination of SSB and ASB) consumption by reviewing population-based epidemiological studies. Design: Meta-analysis. Setting: We searched PubMed, Embase and Web of Science databases prior to 4 November 2019, for relevant studies investigating the SSB–MetS and ASB–MetS associations. A random effects model was used to estimate pooled relative risks (RR) and 95 % CI. Dose–response association was assessed using a restricted cubic splines model. Participants: We identified seventeen articles (twenty-four studies, including 93 095 participants and 20 749 MetS patients). Results: The pooled RR for the risk of MetS were 1·51 (95 % CI 1·34, 1·69), 1·56 (1·32, 1·83) and 1·44 (1·19, 1·75) in high consumption group of TSB, SSB and ASB, respectively; and 1·20 (1·13, 1·28), 1·19 (1·11, 1·28) and 1·31 (1·05, 1·65) per 250 ml/d increase in TSB, SSB and ASB consumption, respectively. Additionally, we found evidence of non-linear, TSB–MetS and SSB–MetS dose–response associations and a linear ASB–MetS dose–response association. Conclusions: TSB, SSB and ASB consumption was associated with the risk of MetS. The present findings provide evidence that supports reducing intake of these beverages to lower the TSB-, SSB- and ASB-related risk of MetS.
Novel cytokine–antibody fusion protein, N-820, to enhance the functions of ex vivo expanded natural killer cells against Burkitt lymphoma

Background The prognosis of patients with relapsed or progressive B cell (CD20+) non-Hodgkin’s lymphoma (B-NHL), including Burkitt lymphoma (BL), is dismal due to chemoradiotherapy resistance. Novel therapeutic strategies are urgently needed. N-820 is a fusion protein of N-803 (formerly known as ALT-803) to four single-chains of rituximab. This agent has tri-specific binding activity to CD20 and enhanced antibody-dependent cell-mediated cytotoxicity. Methods We investigated the anti-tumor combinatorial effects of N-820 with ex vivo expanded peripheral blood natural killer (exPBNK) cells against rituximab-sensitive and rituximab-resistant CD20+ BL in vitro using cytoxicity assays and in vivo using human BL xenografted NOD/SCID/IL2rγnull (NSG) mice. We also investigated the cytokines/chemokines/growth factors released using ELISA and multiplex assay. Gene expression changes were examined using real-time PCR arrays. Results N-820 significantly enhanced the expression of NK activating receptors (p<0.001) and the proliferation of exPBNK cells with enhanced Ki67 expression and Stat5 phosphorylation (p<0.001). N-820 significantly enhanced the secretion of cytokines, chemokines, and growth factors including GM-CSF, RANTES, MIP-1B (p<0.001) from exPBNK cells as compared with the combination of rituximab+N-803. Importantly, N-820 significantly enhanced in vitro cytotoxicity (p<0.001) of exPBNK with enhanced granzyme B and IFN-γ release (p<0.001) against BL. Gene expression profiles in exPBNK stimulated by N-820+Raji-2R showed enhanced transcription of CXCL9, CXCL1, CSF2, CSF3, GZMB, and IFNG. Moreover, N-820 combined with exPBNK significantly inhibited rituximab-resistant BL growth (p<0.05) and extended the survival (p<0.05) of BL xenografted NSG mice. Conclusions Our results provide the rationale for the development of a clinical trial of N-820 alone or in combination with endogenous or ex vivo expanded NK cells in patients with CD20+ B-NHL failing prior rituximab containing chemoimmunotherapy regimens.