Glycans Function as Anchors for Antibodies and Help Drive HIV Broadly Neutralizing Antibody Development.

Apex broadly neutralizing HIV antibodies (bnAbs) recognize glycans and protein surface close to the 3-fold axis of the envelope (Env) trimer and are among the most potent and broad Abs described. The evolution of apex bnAbs from one donor (CAP256) has been studied in detail and many Abs at different stages of maturation have been described. Using diverse engineering tools, we investigated the involvement of glycan recognition in the development of the CAP256.VRC26 Ab lineage. We found that sialic acid-bearing glycans were recognized by germline-encoded and somatically mutated residues on the Ab heavy chain. This recognition provided an "anchor" for the Abs as the core protein epitope varies, prevented complete neutralization escape, and eventually led to broadening of the response. These findings illustrate how glycan-specific maturation enables a human Ab to cope with pathogen escape mechanisms and will aid in optimization of immunization strategies to induce V2 apex bnAb responses.

A Broadly Neutralizing Antibody Targets the Dynamic HIV Envelope Trimer Apex via a Long, Rigidified, and Anionic ß-Hairpin Structure.

Broadly neutralizing antibodies (bnAbs) to HIV delineate vaccine targets and are prophylactic and therapeutic agents. Some of the most potent bnAbs target a quaternary epitope at the apex of the surface HIV envelope (Env) trimer. Using cryo-electron microscopy, we solved the atomic structure of an apex bnAb, PGT145, in complex with Env. We showed that the long anionic HCDR3 of PGT145 penetrated between glycans at the trimer 3-fold axis, to contact peptide residues from all three Env protomers, and thus explains its highly trimer-specific nature. Somatic hypermutation in the other CDRs of PGT145 were crucially involved in stabilizing the structure of the HCDR3, similar to bovine antibodies, to aid in recognition of a cluster of conserved basic residues hypothesized to facilitate trimer disassembly during viral entry. Overall, the findings exemplify the creative solutions that the human immune system can evolve to recognize a conserved motif buried under a canopy of glycans.

Multiplexed Antibody Glycosylation Profiling Using Dual Enzyme Digestion and Liquid Chromatography-Triple Quadrupole Mass Spectrometry Method.

Antibody glycosylation plays a crucial role in the humoral immune response by regulating effector functions and influencing the binding affinity to immune cell receptors. Previous studies have focused mainly on the immunoglobulin G (IgG) isotype owing to the analytical challenges associated with other isotypes. Thus, the development of a sensitive and accurate analytical platform is necessary to characterize antibody glycosylation across multiple isotypes. In this study, we have developed an analytical workflow using antibody-light-chain affinity beads to purify IgG, IgA, and IgM from 16 µL of human plasma. Dual enzymes, trypsin and Glu-C, were used during on-bead digestion to obtain enzymatic glycopeptides and protein-specific surrogate peptides. Ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry was used in order to determine the sensitivity and specificity. Our platform targets 95 glycopeptides across the IgG, IgA, and IgM isotypes, as well as eight surrogate peptides representing total IgG, four IgG classes, two IgA classes, and IgM. Four stable isotope-labeled internal standards were added after antibody purification to calibrate the preparation and instrumental bias during analysis. Calibration curves constructed using serially diluted plasma samples showed good curve fitting (R2 > 0.959). The intrabatch and interbatch precision for all the targets had relative standard deviation of less than 29.6%. This method was applied to 19 human plasma samples, and the glycosylation percentages were calculated, which were comparable to those reported in the literature. The developed method is sensitive and accurate for Ig glycosylation profiling. It can be used in clinical investigations, particularly for detailed humoral immune profiling.

Molecular phylogeny of deep-sea blind lobsters of the family Polychelidae (Decapoda: Polychelida), with implications for the origin and evolution of these "living fossils".

A comprehensive molecular analysis of the deep-sea blind lobsters of the family Polychelidae, often referred to as "living fossils", is conducted based on all six modern genera and 27 of the 38 extant species. Using six genetic markers from both mitochondrial and nuclear genomes, the molecular phylogenetic results differ considerably from previous morphological analyses and reveal the genera Polycheles and Pentacheles to be para- or polyphyletic. As the splitting of Polycheles has strong support from both molecular and morphological data, two new genera, Dianecheles and Neopolycheles, are erected for those species excluded from the clade containing the type species of Polycheles. The pattern of polyphyly of Pentacheles, however, is not robustly resolved, so it is retained as a single genus. Fossil evidence suggests that fossil polychelids inhabited deep-sea environments as early as the Early to Middle Jurassic, demonstrating the enduring adaptation of extant polychelid species to the deep-sea. Time-calibrated phylogeny suggested that modern polychelids probably had an Atlantic origin during the Jurassic period. Since their emergence, this ancient lobster group has continued to diversify, particularly in the West Pacific, and has colonized the abyssal zone, with the deepest genus, Willemoesia, representing the more 'derived' members among extant polychelids. Differences in eye reduction among extant polychelid genera highlight the necessity for ongoing investigations to ascertain the relative degree of functionality of their eyes, if they indeed retain any function.

Association of insulin resistance indicators with hepatic steatosis and fibrosis in patients with metabolic syndrome.

BACKGROUND: To investigate the association of four insulin resistance (IR) indicators with hepatic steatosis and fibrosis in patients with metabolic syndrome (MetS), as well as to compare the diagnostic value of these indicators in identifying hepatic steatosis and fibrosis in individuals with MetS. METHODS: This cross-sectional study used the data from the National Health and Nutrition Examination Survey 2017-2018. IR indicators included homeostasis model assessment of IR (HOMA-IR), triglyceride/glucose (TyG) index, triglyceride glucose-waist-to-height ratio (TyG-WHtR), and metabolic score for IR (METS-IR). The main endpoints of this study were hepatic steatosis and hepatic fibrosis. Weighted univariate and multivariate logistic regression models were employed to evaluate the association between four IR indicators and both hepatic steatosis, hepatic fibrosis. The efficacy of various IR indicators in the detection of hepatic steatosis and hepatic fibrosis were assessed using receiver operating characteristics curve (ROC). RESULTS: A total of 876 participants with MetS were enrolled. Among the participants, hepatic steatosis was observed in 587 MetS individuals, while hepatic fibrosis was identified in 151 MetS individuals. In multivariate logistic regression model, HOMA-IR, TyG, TyG-WHtR, and METS-IR were related to the increased odd of hepatic steatosis. Additionally, HOMA-IR, TyG-WHtR, and METS-IR were associated with increased odd of hepatic fibrosis. According to the ROC analysis, the area under the curve (AUC) of the TyG-WHtR (AUC = 0.705, 95%CI: 0.668-0.743) was higher than HOMA-IR (AUC = 0.693, 95%CI: 0.656-0.730), TyG (AUC = 0.627, 95%CI: 0.587-0.666), and METS-IR (AUC = 0.685, 95%CI: 0.648-0.722) for identifying hepatic steatosis of MetS patients. Likewise, TyG-WHtR was also higher than HOMA-IR, TyG, and METS-IR for identifying hepatic fibrosis of MetS patients. CONCLUSION: HOMA-IR, TyG-WHtR, and METS-IR may be associated with the risk of hepatic steatosis and fibrosis among the U.S. adult population with MetS. In addition, TyG-WHtR may have a good predictive value for hepatic steatosis and hepatic fibrosis.

Effects of internet-based digital health interventions on the physical activity and quality of life of colorectal cancer survivors: a systematic review and meta-analysis.

PURPOSE: The recent trend of Internet-based digital health interventions has driven researchers to implement them to promote physical activity (PA) and improve patients' health outcomes. This systematic review and meta-analysis aim to evaluate the effects of Internet-based digital health interventions on PA and quality of life (QoL) in colorectal cancer (CRC) survivors. METHODS: We searched for relevant studies investigating the effects of internet-based digital health interventions published until Dec. 2022 in electronic databases (PubMed, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and CEPS) according to PRISMA guidelines. The Joanna Briggs Institute critical appraisal checklist was used to examine the quality of the included studies. We performed the fixed and random effects model for meta-analysis. RESULTS: Among 746 identified studies, eight published between 2018 and 2022 were included. These covered 991 internet-based digital health interventions and 875 controls. After 6 months of internet-based digital health interventions, CRC survivors' performance in PA (standardized mean difference (SMD) = 0.23, 95% confidence interval [CI] = 0.09-0.38) and QoL (SMD = 0.11, 95% CI = 0.01-0.22) indicators improved significantly. CONCLUSIONS: Internet-based digital health improved the PA behaviour and QoL of patients with CRC. Because of differences in intervention outcomes, additional randomized controlled trials are warranted to provide suggestions for clinical practice. Internet-based digital health interventions are promising for promoting PA in CRC survivors.

Neurological manifestations of SARS-CoV-2 infection in children in Taiwan: A cross-section, multicenter study.

BACKGROUND: The SARS-CoV-2 virus has been a global public health threat since December 2019. This study aims to investigate the neurological characteristics and risk factors of coronavirus disease 2019 (COVID-19) in Taiwanese children, using data from a collaborative registry. METHODS: A retrospective, cross-sectional, multi-center study was done using an online network of pediatric neurological COVID-19 cohort collaborative registry. RESULTS: A total of 11160 COVID-19-associated emergency department (ED) visits and 1079 hospitalizations were analyzed. Seizures were the most common specific neurological symptom, while encephalitis and acute disseminated encephalomyelitis (ADEM) was the most prevalent severe involvement. In ED patients with neurological manifestations, severe neurological diagnosis was associated with visual hallucination, seizure with/without fever, behavior change, decreased GCS, myoclonic jerk, decreased activity/fatigue, and lethargy. In hospitalized patients with neurological manifestations, severe neurological diagnosis was associated with behavior change, visual hallucination, decreased GCS, seizure with/without fever, myoclonic jerk, fatigue, and hypoglycemia at admission. Encephalitis/ADEM was the only risk factor for poor neurological outcomes at discharge in hospitalized patients. CONCLUSION: Neurological complications are common in pediatric COVID-19. Visual hallucination, seizure, behavior change, myoclonic jerk, decreased GCS, and hypoglycemia at admission are the most important warning signs of severe neurological involvement such as encephalitis/ADEM.

Presence of depression and anxiety with distinct patterns of pharmacological treatments before the diagnosis of chronic fatigue syndrome: a population-based study in Taiwan.

OBJECTIVE: An increased prevalence of psychiatric comorbidities (including depression and anxiety disorder) has been observed among patients with chronic fatigue syndrome (CFS). However, few studies have examined the presence of depression and anxiety disorder before the diagnosis of CFS. This study aimed to clarify the preexisting comorbidities and treatments associated with patients with subsequent CFS diagnosis in a population-based cohort in Taiwan. METHODS: An analysis utilizing the National Health Insurance Research Database of Taiwan was conducted. Participants included were 6303 patients with CFS newly diagnosed between 2000 and 2010 and 6303 age-/sex-matched controls. RESULTS: Compared with the control group, the CFS group had a higher prevalence of depression and anxiety disorder before the diagnosis of CFS. Sampled patients who took specific types of antidepressants, namely, selective serotonin reuptake inhibitors (adjusted odds ratio [aOR] = 1.21, 95% confidence interval [CI] 1.04-1.39), serotonin antagonists and reuptake inhibitors (SARI; aOR = 1.87, 95% CI 1.59-2.19), and tricyclic antidepressants (aOR = 1.46, 95% CI 1.09-1.95), had an increased risk of CFS. CFS risk was also higher among participants taking benzodiazepine, muscle relaxants, and analgesic drugs. A sub-group analysis revealed that SARI use was related to an increased risk of CFS in the depression, anxiety disorder, male, and female groups. In the depression and anxiety disorder groups, analgesic drug use was associated with an increased CFS risk. Nonpharmacological treatment administration differed between men and women. CONCLUSION: This population-based retrospective cohort study revealed an increased risk of CFS among populations with preexisting depression and anxiety disorder, especially those taking SARI and analgesic drugs.

Protective mechanism of ferulic acid against neomycin-induced ototoxicity in zebrafish.

Ototoxicity refers to damage of sensory hair cells and functional hearing impairment following aminoglycosides exposure. Previously, we have determined that ferulic acid (FA) protected hair cells against serial concentrations of neomycin-induced ototoxic damage. The aim of the present study is to assess the mechanism and effects of FA on neomycin-induced hair cells loss and impact on mechanosensory-mediated behaviors alteration using transgenic zebrafish (pvalb3b: TagGFP). We first identified the optimal protective condition as pre/co-treatment method in early fish development. Pretreatment of the larvae with FA significantly protected against neomycin-induced hair cells loss through preventing neomycin passed through the cytoplasm of hair cells, and subsequently decreased reactive oxygen species production and TUNEL signals in 4 day post-fertilization (dpf) transgenic zebrafish larvae. Moreover, preservation of functional hair cells correlated directly with rescue of the altered swimming behavior, indicates FA pretreatment protects against neomycin ototoxic damage in 7-dpf transgenic zebrafish larvae. Together, our findings unravel the otoprotective role of FA as an effective agent against neomycin-induced ototoxic effects and offering the theoretical foundation for discovering novel candidates for hearing protection.

Sleep quality mediates the relationship between lower urinary tract symptoms and health-related quality of life in women with type-II diabetes.

AIM: To examine the mediating effect of sleep quality on the relationship between lower urinary tract symptoms and health-related quality of life in women with type-II diabetes. DESIGN: A cross-sectional study. METHODS: A study questionnaire comprising three valid instruments was used to obtain data about lower urinary tract symptoms, sleep quality and physical and mental component summary health-related quality of life between July 2017 and December 2018 (n = 343). Pearson's correlation coefficients were estimated initially to examine the relationships between the three variables. Multiple regression models were tested using a regression-based approach Hayes PROCESS macro for SPSS to examine the significance of proposed mediation effects. RESULTS: Most participants experienced at least one urinary symptom (n = 268, 78.1%). The total number of types of lower urinary tract symptoms experienced by participants was significantly inversely correlated with physical and mental component summary health-related quality of life, and sleep quality. Participants' sleep quality was significantly correlated with physical and mental component summary health-related quality of life. The relationships of lower urinary tract symptoms with physical and mental component summary health-related quality of life were, respectively, fully and partially mediated by sleep quality. CONCLUSION: Sleep quality played a mediating role on the relationship between lower urinary tract symptoms and health-related quality of life. Our findings could lead to improvements of diabetes care in nursing and healthcare practices. IMPACT: Understanding the role of sleep quality in the adverse effects of lower urinary tract symptoms on health-related quality of life contributes to the development and delivery of appropriate strategies to promote optimal health-related quality of life. We recommended including assessments of lower urinary tract symptoms, sleep and health-related quality of life in routine diabetes management. Nurses and healthcare professionals should concurrently reduce lower urinary tract symptoms and improve sleep to achieve this population's optimal health-related quality of life. PATIENTS OR PUBLIC CONTRIBUTION: We recruited a sample of older women with type-II diabetes at the endocrinology and metabolism outpatient departments of two hospitals. Study participants provided responses on the study questionnaires. The two hospitals provided needed supports (e.g., height/weight scales, suitable places for interview) during the data collection process.

Working Memory Ability Evaluation Based on Fuzzy Support Vector Regression.

One's working memory process is a fundamental cognitive activity which often serves as an indicator of brain disease and cognitive impairment. In this research, the approach to evaluate working memory ability by means of electroencephalography (EEG) analysis was proposed. The result shows that the EEG signals of subjects share some characteristics when performing working memory tasks. Through correlation analysis, a working memory model describes the changes in EEG signals within alpha, beta and gamma waves, which shows an inverse tendency compared to Zen meditation. The working memory ability of subjects can be predicted using multi-linear support vector regression (SVR) with fuzzy C-mean (FCM) clustering and knowledge-based fuzzy support vector regression (FSVR), which reaches the mean square error of 0.6 in our collected data. The latter, designed based on the working memory model, achieves the best performance. The research provides the insight of the working memory process from the EEG aspect to become an example of cognitive function analysis and prediction.

Treatment-associated survival outcomes in real-world patients with de novo metastatic triple-negative breast cancer: Age as a significant treatment effect-modifier.

PURPOSE: Evidence for optimizing the first-line chemotherapy for patients with metastatic triple-negative breast cancer (mTNBC) is lacking. This study assessed the utilization patterns of chemotherapy and associated survival outcomes in de novo mTNBC patients. METHODS: Taiwan's cancer registry was utilized to extract study patients with newly-diagnosed breast cancer during 2011-2015 and confirmed metastatic triple-negative status. The patients' medical records (e.g., diseases, treatments) and death status were obtained from the National Health Insurance Research Database. Utilization of first-line chemotherapy regimens was analyzed and associated survival outcomes were assessed using Cox models. RESULTS: 93.60% of the mTNBC patients (n = 297) received chemotherapy, where combination regimens (75.54%) were more common than single-agent regimens (24.46%) in the first-line setting. A non-statistically lower all-cause death associated with combination versus single-agent chemotherapy (hazard ratio: 0.830 [0.589, 1.168]) was observed. Age was identified as a significant effect-modifier in treatment-associated survival outcomes (p = 0.008); younger patients (aged < 40 and 40-59 years) versus older patients (aged ≥ 60 years) had a lower all-cause mortality when receiving combination versus single-agent chemotherapy. A lower all-cause mortality associated with taxane- versus non-taxane-based therapy was revealed among those on single-agent chemotherapy (hazard ratio: 0.557 [0.311, 0.999]). CONCLUSION: Generally, single-agent and combination chemotherapies yielded comparable survival outcomes as the first-line treatment for de novo mTNBC. Younger patients may benefit more from combination regimens, in terms of better survival outcomes. Single-agent chemotherapy may be preferable as the first-line choice for elderly patients who are vulnerable to the toxicity of multiple chemotherapy agents.

Bevacizumab and atezolizumab as first-line therapy for advanced hepatocellular carcinoma: A Taiwanese subgroup analysis on efficacy and safety.

BACKGROUND: The combination of bevacizumab and atezolizumab has been established as a standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). We examined the treatment outcomes of patients in Taiwan who received the combination in 2 pivotal clinical trials. METHODS: All patients who resided in Taiwan, were enrolled in the IMbrave150 and GO30140 studies, and received bevacizumab and atezolizumab as the first-line systemic therapy for unresectable HCC were included. We extracted and pooled anonymous raw data from the study records. RESULTS: We enrolled 40 patients, with the median age of 62.5 years; 36 (90%) had Barcelona Clinic Liver Cancer stage C disease. The response rate was 37.5%, including 3 (7.5%) complete responses. The disease control rate was 85%. The median duration of response was 21.4 months (95% confidence interval [CI], 16.6-not estimable). The median progression-free survival (PFS) and overall survival (OS) were 8.6 (95% CI, 5.6-18.6) and 24.9 months (95% CI, 14.2-not estimable), respectively. The most common adverse events of all grades were proteinuria (50%) and hypertension (37.5%), the median onset of which were 157 and 127 days, respectively. Bevacizumab and atezolizumab treatment had to be interrupted in 20 (50%) and 13 (32.5%) patients, respectively. Among patients whose treatment duration was ≥6 months, 50% of them had to skip bevacizumab, but no signal of poorer PFS or OS was observed. CONCLUSION: In Taiwanese patients with advanced HCC, the efficacy and safety outcomes of bevacizumab and atezolizumab treatment were generally consistent with the global intent-to-treat populations.

Eye motor manifestations in children with neurometabolic disorders.

Neurometabolic diseases are complex group of rare neurogenetic disorders, which are difficult to diagnose. Patients may have toxic metabolite accumulation, inadequate energy supply, or neurotransmitter deficiency, resulting in a variety of clinical manifestations and severity with enzyme activity or transporter function defects. Multiple organ involvement is frequently seen, among which neurological symptoms and signs are one of the most encountered problems. Ocular motor problems deserve special attention for it occurs in some inborn error of metabolism. Furthermore, some are early signs or characteristic findings of certain diseases, such as the gaze palsy in Niemann-Pick disease type C and Gaucher disease or oculogyric crisis in neurotransmitter diseases. Early recognition and intervention are important for better prognosis in treatable neurometabolic disorders. In addition, ways to evaluate and describe eye movement problems also help to demonstrate the severity or clinical progression for those diagnosed with certain neurometabolic diseases. However, the complexity of eye movement and ocular motor control renders our clinical observation, recording and even anatomic localization of abnormal eye movements. Clinicians are more likely to detect early signs and unravel problems by gaining awareness of abnormal eye movement. This study amied to approach neurometabolic diseases in children via eye motor manifestations.

Cichoric Acid May Play a Role in Protecting Hair Cells from Ototoxic Drugs.

Ototoxic hearing loss due to antibiotic medication including aminoglycosides and excess free radical production causes irreversible hair cell injury. Cichoric acid, a naturally occurring phenolic acid, has recently been found to exert anti-oxidative and anti-inflammatory properties through its free radical scavenging capacity. The present study aimed to investigate the protective effects of cichoric acid against neomycin-induced ototoxicity using transgenic zebrafish (pvalb3b: TagGFP). Our results indicated that cichoric acid in concentrations up to 5 µM did not affect zebrafish viability during the 2 h treatment period. Therefore, the otoprotective concentration of cichoric acid was identified as 5 µM under 2 h treatment by counting viable hair cells within the neuromasts of the anterior- and posterior-lateral lines in the study. Pretreatment of transgenic zebrafish with 5 µM of cichoric acid for 2 h significantly protected against neomycin-induced hair cell death. Protection mediated by cichoric acid was, however, lost over time. A terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and FM4-64 staining, respectively, provided in situ evidence that cichoric acid ameliorated apoptotic signals and mechanotransduction machinery impairment caused by neomycin. A fish locomotor test (distance move, velocity, and rotation frequency) assessing behavioral alteration after ototoxic damage revealed rescue due to cichoric acid pretreatment before neomycin exposure. These findings suggest that cichoric acid in 5 µM under 2 h treatment has antioxidant effects and can attenuate neomycin-induced hair cell death in neuromasts. Although cichoric acid offered otoprotection, there is only a small difference between pharmacological and toxic concentrations, and hence cichoric acid can be considered a rather prototypical compound for the development of safer otoprotective compounds.

Are ESG-committed hotels financially resilient to the COVID-19 pandemic? An autoregressive jump intensity trend model.

Given that the United Nations views environmental, social, and governance (ESG) as a practical framework for anchoring responsible corporate behavior to achieve its sustainable development goals, this study constructs an autoregressive jump intensity trend (ARJI-trend) model to determine if ESG can improve future resilience and create crisis-resilient value for chained-brand hotel corporations from the effects of COVID-19. The findings indicate that the ARJI-trend model indeed captures both the permanent and transitory components of the hotel corporation's ESG performance related to stock return dynamics. When ESG rating is taken into account, the following conclusions emerge: 1) the transitory component of time-varying return variance decreases but the permanent component does not; 2) the hotel corporation portfolios with a lower transitory component experiences a higher return, implying that the hotel corporations with a higher ESG rating appear to be more defensiveness; and 3) with proper asset reallocation, a portfolio centered on strong ESG-conscious hotel corporations is a safe-haven asset during market turmoil.

Long, Noncoding RNA SRA Induces Apoptosis of ß-Cells by Promoting the IRAK1/LDHA/Lactate Pathway.

Long non-coding RNA steroid receptor RNA activators (LncRNA SRAs) are implicated in the ß-cell destruction of Type 1 diabetes mellitus (T1D), but functional association remains poorly understood. Here, we aimed to verify the role of LncRNA SRA regulation in ß-cells. LncRNA SRAs were highly expressed in plasma samples and peripheral blood mononuclear cells (PBMCs) from T1D patients. LncRNA SRA was strongly upregulated by high-glucose treatment. LncRNA SRA acts as a microRNA (miR)-146b sponge through direct sequence-structure interactions. Silencing of lncRNA SRA increased the functional genes of Tregs, resulting in metabolic reprogramming, such as decreased lactate levels, repressed lactate dehydrogenase A (LDHA)/phosphorylated LDHA (pLDHA at Tyr10) expression, decreased reactive oxygen species (ROS) production, increased ATP production, and finally, decreased ß-cell apoptosis in vitro. There was a positive association between lactate level and hemoglobin A1c (HbA1c) level in the plasma from patients with T1D. Recombinant human interleukin (IL)-2 treatment repressed lncRNA SRA expression and activity in ß-cells. Higher levels of lncRNA-SRA/lactate in the plasma are associated with poor regulation in T1D patients. LncRNA SRA contributed to T1D pathogenesis through the inhibition of miR-146b in ß-cells, with activating signaling transduction of interleukin-1 receptor-associated kinase 1 (IRAK1)/LDHA/pLDHA. Taken together, LncRNA SRA plays a critical role in the function of ß-cells.

A HORT1 Retrotransposon Insertion in the PeMYB11 Promoter Causes Harlequin/Black Flowers in Phalaenopsis Orchids.

The harlequin/black flowers in Phalaenopsis orchids contain dark purple spots and various pigmentation patterns, which appeared as a new color in 1996. We analyzed this phenotype by microscopy, HPLC, gene functional characterization, genome structure analysis, and transient overexpression system to obtain a better understanding of the black color formation in Phalaenopsis orchids. Most mesophyll cells of harlequin flowers showed extremely high accumulation of anthocyanins as well as a high expression of Phalaenopsis equestris MYB11 (PeMYB11) as the major regulatory R2R3-MYB transcription factor for regulating the production of the black color. In addition, we analyzed the expression of basic helix-loop-helix factors, WD40 repeat proteins, and MYB27- and MYBx-like repressors for their association with the spot pattern formation. To understand the high expression of PeMYB11 in harlequin flowers, we isolated the promoter sequences of PeMYB11 from red and harlequin flowers. A retrotransposon, named Harlequin Orchid RetroTransposon 1 (HORT1), was identified and inserted in the upstream regulatory region of PeMYB11 The insertion resulted in strong expression of PeMYB11 and thus extremely high accumulation of anthocyanins in the harlequin flowers of the Phalaenopsis Yushan Little Pearl variety. A dual luciferase assay showed that the insertion of HORT1 enhanced PeMYB11 expression by at least 2-fold compared with plants not carrying the insertion. Furthermore, the presence of HORT1 explains the high mutation rates resulting in many variations of pigmentation patterning in harlequin flowers of Phalaenopsis orchids.

Symptoms of prolonged grief and major depressive disorders: Distinctiveness and temporal relationship in the first 2 years of bereavement for family caregivers of terminally ill cancer patients.

OBJECTIVE: Prolonged grief disorder (PGD) and major depressive disorder (MDD) are common syndromes shaping bereaved caregivers' quality of life (QOL). However, distinctiveness of these syndromes warrants confirmation, and the temporal relationship of PGD and MDD symptoms has not been established. To fill these knowledge gaps, we conducted this longitudinal study. METHODS: PGD symptoms, depressive symptoms, and psychological QOL were measured over 398 caregivers' first 2 years of bereavement using the Prolonged Grief-13 (PG-13) scale, Center for Epidemiologic Studies-Depression (CES-D) scale, and Short Form-36 Health Survey mental health summary, respectively. To clarify the distinctiveness of PGD and MDD symptoms, we examined their associations with psychological QOL by incremental validity testing. Distinctiveness and temporal relationship of PGD and MDD symptoms were also examined using longitudinal, lower-level mediation analysis with a lagged approach. RESULTS: After the variance in psychological QOL was explained by CES-D scores (pseudo-R2 = 44.19%, P < .001), PG-13 scores significantly, incrementally increased the explained variance in psychological QOL (pseudo-R2 = 0.21%, P < .001), confirming the distinctiveness of PGD and MDD symptoms. CES-D scores mediated 40.7% of the time vs PG-13 score relationship, whereas PG-13 scores mediated 78.2% of the time vs CES-D score relationship with a better model fit, indicating that PG-13 scores assessed earlier mediated caregivers' current depressive status rather than vice versa. CONCLUSIONS: PGD and MDD are distinct constructs, and PGD precedes onset of MDD. Clinicians should distinguish between these two disorders and address bereaved caregivers' PGD to reduce PGD-associated distress and morbidity and to prevent MDD onset, thereby improving their QOL.