Discovery of Novel Spike Inhibitors against SARS-CoV-2 Infection.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current coronavirus disease pandemic. With the rapid evolution of variant strains, finding effective spike protein inhibitors is a logical and critical priority. Angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS-CoV-2 viral entry, and thus related therapeutic approaches associated with the spike protein-ACE2 interaction show a high degree of feasibility for inhibiting viral infection. Our computer-aided drug design (CADD) method meticulously analyzed more than 260,000 compound records from the United States National Cancer Institute (NCI) database, to identify potential spike inhibitors. The spike protein receptor-binding domain (RBD) was chosen as the target protein for our virtual screening process. In cell-based validation, SARS-CoV-2 pseudovirus carrying a reporter gene was utilized to screen for effective compounds. Ultimately, compounds C2, C8, and C10 demonstrated significant antiviral activity against SARS-CoV-2, with estimated EC50 values of 8.8 µM, 6.7 µM, and 7.6 µM, respectively. Using the above compounds as templates, ten derivatives were generated and robust bioassay results revealed that C8.2 (EC50 = 5.9 µM) exhibited the strongest antiviral efficacy. Compounds C8.2 also displayed inhibitory activity against the Omicron variant, with an EC50 of 9.3 µM. Thus, the CADD method successfully discovered lead compounds binding to the spike protein RBD that are capable of inhibiting viral infection.

Correlation of Disease Severity, Proinflammatory Cytokines, and Reduced Brain Gray Matter Volumes in Patients with Atopic Dermatitis.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease. However, few studies have investigated brain changes associated with chronic inflammation. We hypothesized that chronic inflammation might be related to brain structural alterations in patients with AD. Objectives: To investigate the association between disease severity (Eczema Area and Severity Index [EASI]), proinflammatory cytokines, and differences in brain gray matter (GM) volume in patients with AD. Methods: Nineteen patients with AD and 19 age- and sex-matched healthy subjects were enrolled. All participants underwent clinical assessment and brain magnetic resonance imaging. Voxel-based morphometry was performed to analyze GM volume differences. Results: Patients with AD exhibited significantly decreased GM volume in many brain regions, such as bilateral precentral gyrus, right frontal pole, and right middle temporal gyrus (P < 0.001), compared with healthy subjects. Notably, in patients with AD, the GM volume in right middle temporal gyrus was negatively associated with both EASI score and proinflammatory cytokines (sIL-2R [soluble interleukin 2 receptor] and TNF-α receptor-1), whereas the GM volume in left precentral gyrus was negatively associated with both EASI score and proinflammatory cytokines (sIL-2R and CRP). Conclusion: Patients with AD demonstrated significant brain GM volume reduction in many brain regions, which is related to disease severity and proinflammatory cytokines.

Lack of effects of eight-week left dorsolateral prefrontal theta burst stimulation on white matter macro/microstructure and connection in autism.

Whether brain stimulation could modulate brain structure in autism remains unknown. This study explored the impact of continuous theta burst stimulation (cTBS) over the left dorsolateral prefrontal cortex (DLPFC) on white matter macro/microstructure in intellectually able children and emerging adults with autism. Sixty autistic participants were randomized (30 active) and received active or sham cTBS for eight weeks twice per week, 16 total sessions using a double-blind (participant-, rater-, analyst-blinded) design. All participants received high-angular resolution diffusion MR imaging at baseline and week 8. Twenty-eight participants in the active group and twenty-seven in the sham group with good imaging quality entered the final analysis. With longitudinal fixel-based analysis and network-based statistics, we found no significant difference between the active and sham groups in changes of white matter macro/microstructure and connections following cTBS. In addition, we found no association between baseline white matter macro/microstructure and autistic symptom changes from baseline to week 8 in the active group. In conclusion, we did not find a significant impact of left DLPFC cTBS on white matter macro/microstructure and connections in children and emerging adults with autism. These findings need to be interpreted in the context that the current intellectually able cohort in a single university hospital site limits the generalizability. Future studies are required to investigate if higher stimulation intensities and/or doses, other personal factors, or rTMS parameters might confer significant brain structural changes visible on MRI in ASD.

Neural substrates of L2-L1 transfer effects on phonological awareness in young Chinese-English bilingual children.

The growing trend of bilingual education between Chinese and English has contributed to a rise in the number of early bilingual children, who were exposed to L2 prior to formal language instruction of L1. The L2-L1 transfer effect in an L1-dominant environment has been well established. However, the threshold of L2 proficiency at which such transfer manifests remains unclear. This study investigated the behavioral and neural processes involved when manipulating phonemes in an auditory phonological task to uncover the transfer effect in young bilingual children. Sixty-two first graders from elementary schools in Taiwan were recruited in this study (29 Chinese monolinguals, 33 Chinese-English bilinguals). The brain activity was measured using fNIRS (functional near-infrared spectroscopy). Bilingual children showed right lateralization to process Chinese and left lateralization to process English, which supports more on the accommodation effect within the framework of the assimilation-accommodation hypothesis. Also, compared to monolinguals, bilingual children showed more bilateral frontal activation in Chinese, potentially reflecting a mixed influence from L2-L1 transfer effects and increased cognitive load of bilingual exposure. These results elucidate the developmental adjustments in the neural substrates associated with early bilingual exposure in phonological processing, offering valuable insights into the bilingual learning process.

Depressive symptoms and daily living dependence in older adults with type 2 diabetes mellitus: the mediating role of positive and negative perceived stress.

BACKGROUND: Higher stress is associated with higher levels of depression and instrumental-activities-of-daily-living (IADL) dependence, and depression is strongly associated with specific IADL disabilities. Accordingly, the aim of this study was to investigate the mediating effect of perceived stress on the association between depression and IADL dependence among older adults with diabetes mellitus (DM). METHODS: We examined baseline data collected from a longitudinal study that recruited 110 patients with DM aged ≥ 65 years from the endocrinology outpatient clinic of a district hospital. The instruments used for our measurement processes comprised a demographic data sheet and Chinese versions of the Perceived Stress Scale (PSS), the short form of the Geriatric Depression Scale (GDS-S), and the Lawton IADL Scale. We assessed the mediating effects of positive perceived stress (PPS) and negative perceived stress (NPS) after controlling for five covariates by using a regression-based model run through the SPSS macro PROCESS. RESULTS: We observed negative correlations between GDS-S scores and PPS and between PPS and IADL dependence; we noted positive correlations between GDS-S scores and NPS and between NPS and IADL dependence (all P < 0.01). The indirect effect is coefficient = 0.12, [95% confidence interval = (0.0, 0.33)], suggesting that PPS achieves a mediating effect between depressive symptoms and IADL dependence. However, the NPS does not achieve a mediating effect in the relationship between depressive symptoms and IADL dependence (coefficient = 0.06, 95% CI = - 0.03, 0.15). CONCLUSIONS: Personal PPS mediates the association between depression and IADL dependence in older adults with DM. This finding suggests that providing patients with psychological education to promote their PPS may help prevent their functional decline.

Associations of Atopic Dermatitis with Attention Deficit/Hyperactivity Disorder and Autism Spectrum Disorder: A Systematic Review and Meta-Analysis.

BACKGROUND: Atopic dermatitis (AD) shares similarities with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) regarding pathogenesis involving neuroinflammation and genetics. Nevertheless, evidence on the associations of AD with ADHD and/or ASD is inconclusive. This study aimed to systematically examine the existing evidence on the associations between AD, ADHD, and ASD. METHODS: The Meta-Analysis of Observational Studies in Epidemiology guideline was followed. We searched MEDLINE, Embase, Cochrane Library, and Web of Science databases from their respective inceptions to March 4, 2022. Observational studies providing adjusted estimates and/or prevalences for ADHD and ASD in patients with AD were enrolled. A random-effects model meta-analysis was conducted to calculate pooled odds ratios (ORs) and confidence intervals (CIs). Subgroup analyses according to AD severity, age, geographic location, and study design were performed. RESULTS: Overall, a total of 24 studies with 71,373,639 subjects were enrolled. Our meta-analysis demonstrated significant associations of AD with ADHD (pooled OR: 1.28; 95% CI: 1.18-1.40) and ASD (pooled OR: 1.87; 95% CI: 1.30-2.68). Subgroup analyses revealed that the associations for ADHD were the most prominent in studies evaluating severe AD patients as well as in studies focusing on school-age children and adolescents. Among patients with AD, the pooled prevalence of ADHD was 6.6%, and the respective prevalence of ASD was 1.6%. CONCLUSION: The evidence to date suggests significant associations of AD with ADHD and ASD. Psychiatric consultation and an interdisciplinary approach would benefit patients with AD presented with behavioral symptoms suggestive of ADHD or ASD.

Violaceous Nodules on the Right Leg and Foot.

A patient with a history of bullous pemphigoid treated with oral prednisolone presented with multiple round, dark brown to violaceous-colored firm nodules on the right leg and 2 nodular masses with hemorrhagic crusts on the right foot. Complete blood cell count and creatinine and liver function test results were normal, and results of HIV antibody testing were negative. What is the diagnosis and what would you do next?

Deep Learning-Based Link Quality Estimation for RIS-Assisted UAV-Enabled Wireless Communications System.

In recent years, unmanned aerial vehicles (UAVs) have become a valuable platform for many applications, including communication networks. UAV-enabled wireless communication faces challenges in complex urban and dynamic environments. UAVs can suffer from power limitations and path losses caused by non-line-of-sight connections, which may hamper communication performance. To address these issues, reconfigurable intelligent surfaces (RIS) have been proposed as helpful technologies to enhance UAV communication networks. However, due to the high mobility of UAVs, complex channel environments, and dynamic RIS configurations, it is challenging to estimate the link quality of ground users. In this paper, we propose a link quality estimation model using a gated recurrent unit (GRU) to assess the link quality of ground users for a multi-user RIS-assisted UAV-enabled wireless communication system. Our proposed framework uses a time series of user channel data and RIS phase shift information to estimate the quality of the link for each ground user. The simulation results showed that the proposed GRU model can effectively and accurately estimate the link quality of ground users in the RIS-assisted UAV-enabled wireless communication network.

Risk of Incident Venous Thromboembolism Among Patients With Bullous Pemphigoid or Pemphigus Vulgaris: A Nationwide Cohort Study With Meta-Analysis.

Background Bullous pemphigoid (BP) and pemphigus vulgaris (PV) share similar pathophysiology with venous thromboembolism (VTE) involving platelet activation, immune dysregulation, and systemic inflammation. Nevertheless, their associations have not been well established. Methods and Results To examine the risk of incident VTE among patients with BP or PV, we performed a nationwide cohort study using Taiwan's National Health Insurance Research Database and enrolled 12 162 adults with BP or PV and 12 162 controls. A Cox regression model considering stabilized inverse probability weighting was used to calculate the hazard ratios (HRs) for incident VTE associated with BP or PV. To consolidate the findings, a meta-analysis that incorporated results from the present cohort study with previous literature was also conducted. Compared with controls, patients with BP or PV had an increased risk for incident VTE (HR, 1.87 [95% CI, 1.55-2.26]; P<0.001). The incidence of VTE was 6.47 and 2.20 per 1000 person-years in the BP and PV cohorts, respectively. The risk for incident VTE significantly increased among patients with BP (HR, 1.85 [95% CI, 1.52-2.24]; P<0.001) and PV (HR, 1.99 [95% CI, 1.02-3.91]; P=0.04). In the meta-analysis of 8 studies including ours, BP and PV were associated with an increased risk for incident VTE (pooled relative risk, 2.17 [95% CI, 1.82-2.62]; P<0.001). Conclusions BP and PV are associated with an increased risk for VTE. Preventive approaches and cardiovascular evaluation should be considered particularly for patients with BP or PV with concomitant risk factors such as hospitalization or immobilization.

Phonological and morphological literacy skills in English and Chinese: A cross-linguistic neuroimaging comparison of Chinese-English bilingual and monolingual English children.

Over the course of literacy development, children learn to recognize word sounds and meanings in print. Yet, they do so differently across alphabetic and character-based orthographies such as English and Chinese. To uncover cross-linguistic influences on children's literacy, we asked young Chinese-English simultaneous bilinguals and English monolinguals (N = 119, ages 5-10) to complete phonological and morphological awareness (MA) literacy tasks. Children completed the tasks in the auditory modality in each of their languages during functional near-infrared spectroscopy neuroimaging. Cross-linguistically, comparisons between bilinguals' two languages revealed that the task that was more central to reading in a given orthography, such as phonological awareness (PA) in English and MA in Chinese, elicited less activation in the left inferior frontal and parietal regions. Group comparisons between bilinguals and monolinguals in English, their shared language of academic instruction, revealed that the left inferior frontal was less active during phonology but more active during morphology in bilinguals relative to monolinguals. MA skills are generally considered to have greater language specificity than PA skills. Bilingual literacy training in a skill that is maximally similar across languages, such as PA, may therefore yield greater automaticity for this skill, as reflected in the lower activation in bilinguals relative to monolinguals. This interpretation is supported by negative correlations between proficiency and brain activation. Together, these findings suggest that both the structural characteristics and literacy experiences with a given language can exert specific influences on bilingual and monolingual children's emerging brain networks for learning to read.

Intravascular Ultrasound Guided Intervention in Calcified Coronary Lesions Showed Good Clinical Outcomes during One Year Follow-Up.

BACKGROUND: Calcified coronary lesions can cause stent under-expansion, malapposition, and polymer degradation, hence increasing the risk of adverse clinical outcomes. Percutaneous coronary intervention (PCI) guided by intravascular ultrasound (IVUS) has been used regularly to improve outcomes. Our primary aim was to evaluate the clinical efficacy of IVUS-guided PCI in calcified coronary lesions. METHODS: From August 2018 to December 2021, we prospectively included 300 patients in the CAPIRO study (CAlcified plaque in patients receiving Resolute Onyx®) at three educational hospitals in Jeonbuk Province. We studied 243 patients (265 lesions) who were followed up for over a year. Based on coronary calcification by IVUS analysis, the patient population was categorized into two groups (Group I: non/mild calcification; Group II: moderate/severe calcification (maximum calcium arc >180° and calcium length > 5 mm)). One-to-one Propensity Score Matching was used to match the baseline characteristics. The stent expansion rate was analyzed by recent criteria. The primary clinical outcome was Major Adverse Cardiac Events (MACE), which included Cardiac death, Myocardial Infarction (MI), and Target Lesion Revascularization (TLR). RESULTS: After follow-up time, the MACE rate in Group I was 1.99%, comparable to Group II's 1.09% (p = 0.594). The components of MACE did not significantly differ between the two groups. Based on absolute MSA or MSA/MVA at MSA site criteria, the stent expansion rate in Group II was lower than that of Group I. Nevertheless, based on recent relative criteria, the stent expansion rate in both groups was comparable. CONCLUSIONS: After more than a year of follow-up, IVUS-guided PCI in moderate/severe calcification lesions was associated with good clinical outcomes, which was comparable with non/mild calcification lesions. Future studies with a larger sample size and a more extended follow-up period are required to clarify our findings.

OsBBX19-OsBTB97/OsBBX11 module regulates spikelet development and yield production in rice.

Spikelet and floral-related organs are important agronomic traits for rice grain yield. BTB (broad-complex, tram track, and bric-abrac) proteins control various developmental functions in plants; however, the molecular mechanism of BTB proteins underlying grain development and yield production is still unknown. Here, we evaluated the molecular mechanism of a previously unrecognized functional gene, namely OsBTB97 that regulates the floral and spikelet-related organs which greatly affect the final grain yield. We found that the knockdown of the OsBTB97 gene had significant impacts on the development of spikelet-related organs and grain size, resulting in a decrease in yield, by altering the transcript levels of various spikelet- and grain-related genes. Furthermore, we found that the knockout mutants of two BBX genes, OsBBX11 and OsBBX19, which interact with the OsBTB97 protein at translation and transcriptional level, respectively, displayed lower OsBTB97 expression, suggesting the genetic relationship between the BTB protein and the BBX transcription factors in rice. Taken together, our study dissects the function of the novel OsBTB97 by interacting with two BBX proteins and an OsBBX19-OsBTB97/OsBBX11 module might function in the spikelet development and seed production in rice. The outcome of the present study provides promising knowledge about BTB proteins in the improvement of crop production in plants.

Sources of Heterogeneity in Functional Connectivity During English Word Processing in Bilingual and Monolingual Children.

Diversity and variation in language experiences, such as bilingualism, contribute to heterogeneity in children's neural organization for language and brain development. To uncover sources of such heterogeneity in children's neural language networks, the present study examined the effects of bilingual proficiency on children's neural organization for language function. To do so, we took an innovative person-specific analytical approach to investigate young Chinese-English and Spanish-English bilingual learners of structurally distinct languages. Bilingual and English monolingual children (N = 152, M(SD)age = 7.71(1.32)) completed an English word recognition task during functional near-infrared spectroscopy neuroimaging, along with language and literacy tasks in each of their languages. Two key findings emerged. First, bilinguals' heritage language proficiency (Chinese or Spanish) made a unique contribution to children's language network density. Second, the findings reveal common and unique patterns in children's patterns of task-related functional connectivity. Common across all participants were short-distance neural connections within left hemisphere regions associated with semantic processes (within middle temporal and frontal regions). Unique to more proficient language users were additional long-distance connections between frontal, temporal, and bilateral regions within the broader language network. The study informs neurodevelopmental theories of language by revealing the effects of heterogeneity in language proficiency and experiences on the structure and quality of emerging language neural networks in linguistically diverse learners.

Recurrent pineal parenchymal tumor of intermediate differentiation with intratumoral hemorrhage: A case report and review of the literature.

Pineal apoplexy is a rare clinical condition. Its common symptoms include headaches, nausea, vomiting, ataxia, and gaze paralysis. These symptoms are mainly caused by obstructive hydrocephalus or direct compression of the cerebellum or midbrain. There have been no previous reports on the development of a recurrent pineal parenchymal tumor of intermediate differentiation (PPTID) with intratumoral hemorrhage. We report a case of PPTID with intratumoral hemorrhage. A 44-year-old woman developed recurrent PPTID following tumor removal and ventriculoperitoneal shunting in 2010. She visited the emergency department in April 2021 for sudden-onset dizziness and generalized weakness. Blurring of vision occurred and progressed over the previous month. Neurological examination revealed upward conjugate gaze paralysis. Brain computed tomography revealed a hyperdense lesion in the pineal region, and a recurrent tumor with hemorrhage was suspected. Magnetic resonance imaging of the brain confirmed a pineal tumor with intratumoral hemorrhage. The pineal tumor and hematoma were surgically removed via the suboccipital transtentorial approach. The patient was discharged from the hospital 2 weeks after the surgery. The pathological findings were consistent with the diagnosis of recurrent PPTID. PPTID is a rare tumor, accounting for less than 0.1% of primary central nervous system tumors. Pineal apoplexy is rare, and its incidence and clinical significance remain unclear. There have only been nine reported cases of pineal apoplexy, associated with pineal parenchymal tumors. The recurrence of PPTID with apoplectic hemorrhage after 10 years has not been reported. Despite its rarity, PPTID with apoplexy should be considered in patients with PPTID who develop sudden-onset neurological symptoms.

Combined phacovitrectomy versus sequential surgery for idiopathic macular holes: systematic review and meta-analysis.

OBJECTIVE: To compare the best-corrected visual acuity (BCVA) change, idiopathic macular (IMH) closure, and complications in IMH patients receiving combined phacovitrectomy and sequential surgery (vitrectomy followed by phacoemulsification). DESIGN: Systematic review and meta-analysis. METHODS: PubMed, Ovid EMBASE, and Cochrane Library databases were searched from their inception through February 2022. Randomized, controlled trials and observational studies that presented results of BCVA change, IMH closure, and surgery-related complications were included. A random-effects meta-analysis was conducted to calculate effect estimates with 95% CIs. RESULTS: One randomized, controlled trials and 7 cohort studies with 585 patients were included. Overall, the meta-analyses of BCVA change (mean difference, -0.03; 95% CI, -0.10-0.04) and IMH closure (risk ratio = 1.04; 95% CI, 0.96-1.13) revealed no significant differences between combined phacovitrectomy and sequential surgery. The pooled risk ratios for various surgical complications such as postoperative retinal detachment, inflammation, and intraocular pressure elevation showed no significant differences between the 2 groups. CONCLUSIONS: Similar visual gain and IMH closure rates were achieved after both combined phacovitrectomy and sequential surgery, with similar complication risks. The anatomic and functional outcomes of combined surgery were not better than those of sequential surgery. These results could serve as a reference for future trials.

Relation of environmental factors with activity limitations and participation restrictions in older adults with diabetes mellitus over time: an international classification of functioning framework perspective.

BACKGROUND: Activity limitations and participation restrictions were observed in patients with diabetes, which may impact their quality of life. Environmental factors such as seasonal effects, resources and perceived stress may play important role in activity limitations and participation restrictions. In this study, a variant of International Classification of Functioning (ICF) model was used to clarify the associations of function/structure factors, personal factors and environmental factors with activity limitations and participation restrictions. METHODS: This was a longitudinal design with 1 year follow-up. The Mini-Mental State Examination (MMSE), Geriatric Depression Scale- short form, Perceived Stress Scale, and Instrumental Activities of Daily Living assessments were measured at 3-month intervals for long-term follow-up in 110 patients with diabetes aged ≥ 65 years. RESULTS: Hierarchical linear regression models revealed that age (p = 0.001), perceived health status, MMSE scores (p < 0.01), and positive perceived stress (p < 0.001) were predictors of activity limitations (adjusted R2 = 53%). GDS-S (p < 0.05) and positive perceived stress (p < 0.01) were predictors of participation restrictions (adjusted R2 = 30%). Generalized estimating equation analysis indicated that seasonal effects, age, perceived health status, MMSE predicted the changes of slopes in activity limitations. Seasonal effects and GDS-S were predictors of the changes of slopes for participation restrictions (all p < 0.001). CONCLUSIONS: The ICF can be used to identify the risk factors for activity limitations and participation restrictions in older adults with diabetes. Practitioners should provide individualized interventions with consideration of these risk factors.