Negative life events and sleep disturbance among adolescents: Intolerance of uncertainty as mediator and moderator.

BACKGROUND: While negative life events (NLEs) have been linked to an increased risk of sleep disturbance among adolescents, the mechanisms of this impact still lack further examination. The current study aimed to explore whether intolerance of uncertainty (IU), a dispositional transdiagnostic vulnerability factor for psychopathology, could act as a mediator and/or moderator in the link from NLEs to sleep disturbance. METHODS: A longitudinal nested subsample of 54,240 Chinese adolescents (aged 9-19) were surveyed at baseline (Timepoint 1) and six months later (Timepoint 2). They completed questionnaires to assess their IU, NLEs, sleep disturbance and sociodemographic characteristics. Mediation and moderation analyses were conducted to test our hypotheses. RESULTS: Upon adjusting for covariates, IU was found to mediate the relationship between NLEs and residual changes in sleep disturbance over a six-month period, with the mediation effect accounting for 31.8%. Additionally, the moderating role of IU in this relationship was also identified, suggesting that a high level of IU exacerbated the effect of NLEs on sleep disturbance. CONCLUSIONS: In conclusion, our findings shed light on the dual roles of IU in the link from NLEs to sleep disturbance, holding significant practical implications for preventing and intervening in sleep disturbance among adolescents. To mitigate the risk of sleep disturbance among adolescents experiencing NLEs, timely assessments of IU and tailored interventions to enhance uncertainty tolerance are necessary.

Re-measurement and influencing factors of agricultural eco-efficiency under the 'dual carbon' target in China.

Given that agriculture is both a carbon source and sink, the sustainability goals of carbon peaking and neutrality place high demands on the green and low-carbon agricultural development in China, and the exploration of a realistic path for a sustainable agricultural development is urgently needed. Under the above 'dual carbon' target, this study focused on the key issue of how to improve China's agricultural eco-efficiency (AEE) and constructed an innovative AEE indicator system that can reflect carbon constraint and coordinated agricultural economic development, resource use and ecological environment. The super-efficient slack-based measured Data Envelopment Analysis (SBM-DEA) method, which considers undesirable outputs, was applied to re-measure the AEE of 30 provinces and cities in China from 2001 to 2020, and its spatial and temporal evolution was analysed in conjunction with kernel density estimation. The Tobit regression model was used to explore various influencing factors by region. The results show that the AEE re-measurements, which take into account the 'dual carbon' requirement, are significantly better than the traditional AEE. From 2001 to 2020, China had an overall V-shaped fluctuation curve AEE, with a small decline and several inter-annual fluctuations, and exhibited a large potential to rise. China's AEE showed a spatially uneven regional development at different stages of distribution and evident multi-polar differentiation. Inter-provincial differences were observed in China's AEE, and the vicious circle of low-level green and low-carbon agricultural development was difficult to break. Urbanisation had a significant positive effect on national and eastern AEE but a significant negative effect on central AEE. The agricultural carbon offset rate had a significant effect on AEE nationally and in the three regions. Thus, the introduction of 'dual carbon' target effectively drove the development of AEE. Agricultural industry structure inhibited the improvement of AEE nationally and in the western region. Agricultural economic development hindered the national AEE improvement but promoted that of the central region, where China showed an environment Kuznets curve. Hopefully, this study can provide data support and theoretical reference for the green and low-carbon agricultural development and help achieve the 'dual carbon' target.

Functionality of pea protein isolate solutions is affected by reconstitution conditions.

Pea protein isolate (PPI), a high-concentration protein ingredient derived from peas, is increasingly utilized in food applications, including beverages, meat or dairy alternatives, and baked goods. The protein extraction process typically used to manufacture PPI renders the protein highly denatured, which can have a negative impact on its functionality. Therefore, it is critical to understand how to prepare and utilize PPI to maximize its functionality. The current study evaluates the effect of select reconstitution conditions on the structure and functionality of PPI, across a range of protein concentrations (4%-10%) relevant to a variety of food applications. Temperature during reconstitution with water and hydration time impacted both protein hydration and its functionality. Increasing reconstitution temperature from 20 to 60°C and increasing hydration time from 10 to 40 min decreased PPI particle size in solution and increased PPI solubility. Viscosity of PPI solutions also increased with mild heating and longer hydration time, whereas their flow behavior was highly dependent on protein concentration. Experimental data demonstrates that reconstitution conditions have a significant impact on PPI functionality. These findings can help food formulators develop high-quality food products that utilize PPI as a functional ingredient. PRACTICAL APPLICATION: Protein in commercially available pea protein isolates (PPIs) is usually highly denatured, and thus, it is important to find ways to maximize its functionality in practical applications. The findings of this study inform food scientists how to leverage PPI at various protein concentrations with optimal reconstitution conditions to develop high-quality products. Generally, mild heating and longer hydration times improve PPI functional performance.

Crystallization Selectivity of Ribavirin Solution and Amorphous Phase.

Crystallization selectivity is an important principle in polymorph control. Ribavirin Form I, Form II, DMSO solvate, and amorphous ribavirin are prepared, and the short-range order similarities between these solid forms and ribavirin aqueous solution and DMSO solution are compared via mid-frequency Raman difference spectra (MFRDS). The crystallization process from amorphous ribavirin to Form I and from solution to amorphous phase is explained. Reasons for the difficulty in preparing the DMSO solvate are proposed. The rationale provided for the crystallization selectivity provides a foundation for the synthesis of metastable phases with a robust and convenient method.

Profiles of Intolerance of Uncertainty Among 108,540 Adolescents: Associations with Sociodemographic Variables and Mental Health.

Intolerance of uncertainty (IU) is widely considered a transdiagnostic risk and maintaining factor for psychiatric disorders. However, little is known about the overall nature and profile of IU among adolescents. This study aims to investigate the profiles of IU among Chinese adolescents and explore their associations with sociodemographic characteristics and mental health problems. A sample of 108,540 adolescents provided data on IU, sociodemographic characteristics, and mental health via an online platform. Latent profile analysis revealed three profiles: Low IU, Medium IU, and High IU. Girls, older adolescents, and those with specific sociodemographics were more likely to belong to the "High IU" profile. Furthermore, the "High IU" profile was associated with the highest risk of several mental health problems. These findings provided valuable information for early prevention and intervention strategies targeting IU and highlighted the importance of IU-based interventions for mental health among adolescents.

A large Stokes shift NIR fluorescent probe for visual monitoring of mitochondrial peroxynitrite during inflammation and ferroptosis and in an Alzheimer's disease model.

The excessive formation of peroxynitrite (ONOO-) in mitochondria has been implicated in various pathophysiological processes and diseases. However, owing to short emission wavelengths and small Stokes shifts, previously reported fluorescent probes pose significant challenges for mitochondrial ONOO- imaging in biological systems. In this study, a near-infrared (NIR) fluorescent probe, denoted as DCO-POT, is designed for the visual monitoring of mitochondrial ONOO-, displaying a remarkable Stokes shift of 170 nm. The NIR fluorophore of DCO-CHO is released by DCO-POT upon the addition of ONOO-, resulting in off-on NIR fluorescence at 670 nm. This phenomenon facilitates the high-resolution confocal laser scanning imaging of ONOO- generated in biological systems. The practical applications of DCO-POT as an efficient fluorescence imaging tool are verified in this study. DCO-POT enables the fluorometric visualization of ONOO- in organelles, cells, and organisms. In particular, ONOO- generation is analyzed during cellular and organism-level (zebrafish) inflammation during ferroptosis and in an Alzheimer's disease mouse model. The excellent visual monitoring performance of DCO-POT in vivo makes it a promising tool for exploring the pathophysiological effects of ONOO-.

Dicoumarol is an effective post-exposure prophylactic for SARS-CoV-2 Omicron infection in human airway epithelium.

Repurposing existing drugs to inhibit SARS-CoV-2 infection in airway epithelial cells (AECs) is a quick way to find novel treatments for COVID-19. Computational screening has found dicoumarol (DCM), a natural anticoagulant, to be a potential SARS-CoV-2 inhibitor, but its inhibitory effects and possible working mechanisms remain unknown. Using air-liquid interface culture of primary human AECs, we demonstrated that DCM has potent antiviral activity against the infection of multiple Omicron variants (including BA.1, BQ.1 and XBB.1). Time-of-addition and drug withdrawal assays revealed that early treatment (continuously incubated after viral absorption) of DCM could markedly inhibit Omicron replication in AECs, but DCM did not affect the absorption, exocytosis and spread of viruses or directly eliminate viruses. Mechanistically, we performed single-cell sequencing analysis (a database of 77,969 cells from different airway locations from 10 healthy volunteers) and immunofluorescence staining, and showed that the expression of NAD(P)H quinone oxidoreductase 1 (NQO1), one of the known DCM targets, was predominantly localised in ciliated AECs. We further found that the NQO1 expression level was positively correlated with both the disease severity of COVID-19 patients and virus copy levels in cultured AECs. In addition, DCM treatment downregulated NQO1 expression and disrupted signalling pathways associated with SARS-CoV-2 disease outcomes (e.g., Endocytosis and COVID-19 signalling pathways) in cultured AECs. Collectively, we demonstrated that DCM is an effective post-exposure prophylactic for SARS-CoV-2 infection in the human AECs, and these findings could help physicians formulate novel treatment strategies for COVID-19.

Effects of time-restricted feeding and walking exercise on the physical health of female college students with hidden obesity: a randomized trial.

Purpose: Time-restricted feeding (TRF) is an emerging dietary pattern with many potential effects. This study focused on the effects of TRF and walking on the physical health of female college students with hidden obesity. Methods: A total of 77 female college students with hidden obesity, aged 18-22 years, were randomly assigned to a control group (CON, N = 19), time-restricted feeding group (TRF, N = 19), exercise group (EXE, N = 20), and TRF combined with exercise group (TRF + EXE, N = 19). The interventions lasted for 8 weeks. Tests assessing body shape, body composition, bone mineral density, blood lipid levels, and blood pressure were performed before and after the intervention. Results: (1) Intragroup comparison before and after the intervention revealed that the TRF, EXE, and TRF + EXE groups had significantly reduced body weight (p < 0.01), body mass index (BMI) (p < 0.05), and lean tissue mass (LTM) (p < 0.01) but increased total cholesterol (TC) levels (p < 0.05) after the intervention. Body fat percentage (BF%) increased considerably in the EXE and TRF + EXE groups (p < 0.01). (2) Post-intervention comparisons of body weight, BMI, LTM, adipose tissue mass (ATM), total bone mineral density (TBMD), blood lipid levels, and blood pressure between the intervention groups (TRF, EXE, and TRF + EXE) and the CON group showed no significant differences (p > 0.05). (3) A comparison of the changes between the groups before and after the intervention showed significant decreases in body weight in the TRF and TRF + EXE groups (p < 0.05) and in both BMI and LTM in the TRF, EXE, and TRF + EXE groups (p < 0.05) compared to those in the CON group. The BF% change in the EXE and TRF + EXE groups were significantly greater than that in the TRF group (p < 0.01). Conclusion: TRF effectively decreased body weight and BMI in female college students with hidden obesity. However, increased blood lipid levels and decreased LTM levels were also observed. The effects of TRF combined with exercise were not superior to those of TRF or walking alone in terms of body weight, body mass index, body composition, TBMD, or blood lipid levels. Therefore, TRF cannot be considered the best option for fat reduction in female college students with hidden obesity.

A turn-on NIR fluorescent probe for risk-assessing oxidative stress in cabbage roots under abiotic stress.

Oxidative stress is closely related to the crop health status under stress conditions. H2O2 is an important signaling molecule in plants under stress. Therefore, monitoring H2O2 fluctuations is of great significance when risk-assessing oxidative stress. However, few fluorescent probes have been reported for the in situ tracking of H2O2 fluctuations in crops. Herein, we designed a "turn-on" NIR fluorescent probe (DRP-B) to detect and in situ-image H2O2 in living cells and crops. DRP-B exhibited good detection performance for H2O2 and could image endogenous H2O2 in living cells. More importantly, it could semi-quantitatively visualize H2O2 in cabbage roots under abiotic stress. Visualization of H2O2 in cabbage roots revealed H2O2 upregulation in response to adverse environments (metals, flood, and drought). This study provides a new method for risk-assessing oxidative stress in plants under abiotic stress and is expected to provide guidance for the development of new antioxidant defense strategies to enhance plant resistance and crop productivity.

Mitochondria-targeting fluorescent sensor with high photostability and permeability for visualizing viscosity in mitochondrial malfunction, inflammation, and AD models.

Viscosity changes in mitochondria are closely associated with numerous cellular processes and diseases. Currently available fluorescence probes used in mitochondrial viscosity imaging are not very photostable or sufficiently permeable. Herein, a highly photostable and permeable mitochondria-targeting red fluorescent probe (Mito-DDP) was designed and synthesized for viscosity sensing. Viscosity was imaged in living cells using a confocal laser scanning microscope, and the results suggested that Mito-DDP penetrated the membrane and stained the living cells. Importantly, practical applications of Mito-DDP were demonstrated: viscosity visualization was realized for mitochondrial malfunction, cellular and zebrafish inflammation, and Drosophila Alzheimer's disease models, i.e., for subcellular organelles, cells, and organisms. The excellent analytical and bioimaging performance of Mito-DDP in vivo makes it an effective tool for exploring the physiological and pathological effects of viscosity.

An Integrated Analysis Reveals Ciliary Abnormalities in Antrochoanal Polyps.

Objective: The mechanisms underlying the antrochoanal polyps (ACPs) remained unclear. We aimed to identify the differentially expressed genes (DEGs) profile, the cilia-related genes expression levels and the morphological characteristics of ciliated cells in patients with ACPs. Methods: We obtained ACPs biopsy samples from 28 patients and uncinate process from 27 healthy controls. Whole-transcriptome RNA sequencing, immunofluorescence staining, quantitative polymerase chain reaction, and scanning electron microscopy were performed. Results: 3739 DEGs were detected between ACPs and controls, and Gene Ontology analysis on these DEGs implicated cilium assembly, cilium motility, cilia component, cilia function, inflammatory response and immune system process were included in ACPs pathogenesis. Gene set enrichment analysis implicated sets of genes regulated in processes associated with cilium organization, cilium morphogenesis, cilium movement, axoneme assembly, axonemal dynein complex assembly and cell projection assembly. The expression levels of cilia-related genes (FOXJ1, DNAI1, DNAH9, RSPH1, RSPH9 and RSPH4A) were validated by quantitative polymerase chain reaction (Fold change >2, P<0.05) and FOXJ1 was positive correlated with DNAI1, DNAH9, RSPH4, RSPH1, RSPH9, DNAH5, DNALI1 in ACPs (all P < 0.05). Based on our semi-quantitative scoring system, median scores of α-Tubulin, DNAI1 and RSPH4A were significantly higher in ACPs than in controls. In addition, loss of ciliated cells and a shorter cilia pattern were further confirmed by immunofluorescence staining and scanning electron microscopy in ACPs. Conclusion: The aberrant expression of cilia-related genes and ciliary structural impairment are an important pathological phenomenon in ACPs, and our findings may provide novel insights into understanding the mysterious mechanisms underlying ACPs.

The Influence of Annealing on the Microstructural and Textural Evolution of Cold-Rolled Er Metal.

The microstructural and textural evolution of 60% cold-rolling-deformation Er metal (purity ≥ 99.7%) during annealing were investigated by electron-backscattered diffraction (EBSD) and X-ray diffraction (XRD). The research results showed that the texture of the (0001) plane orientation was strengthened, but there was no apparent enhancement of the (011¯0) and (1¯21¯0) plane orientations with increasing the annealing temperature. The recrystallization frequency and grain sizes gradually stabilized after the annealing duration of more than 1 h at 740 °C; the annealing duration and the recrystallization frequency were fitted to the equation: y=1 − exp (−0.3269x0.2506). HAGBs were predominant, and the distribution of grain sizes was the most uniform after annealing at 740 °C × 1 h, which was the optimal annealing process of the Er metal with 60% cold-rolling deformation. However, the recrystallization was transferred to the substructure due to grain boundary migration and twining under an excessive annealing temperature and duration.

Effect of Lanthanum Addition on Formation Behaviors of Inclusions in Q355B Weathering Steel.

The effect of lanthanum addition on the formation behaviors of inclusions in Q355B weathering steel was investigated by laboratory experiments and thermodynamic calculations. The results demonstrate that the main inclusions in weathering steel without La addition are large-sized irregular Al2O3 and MnS, with an average size of about 5.35 µm. As La content increases from 0.0075 to 0.0184 wt.%, the dominant inclusions transform from MnS, LaAlO3, and Al2O3-LaAlO3 into MnS, La2O3, and LaAlO3-La2O3. Meanwhile, the average size of inclusions significantly decreases from 3.4 to 2.48 µm and the distribution is more dispersive. When the La content increases to 0.0425 wt.%, the original MnS and Al2O3 inclusions are completely modified into La2O2S and La2O3 but the inclusions demonstrate serious agglomeration and growth. The thermodynamic calculations indicate that Al2O3 and various lanthanum-containing inclusions are formed in the liquid phase. As the La content in molten steel increases from 0 to 0.0425 wt.%, the Al2O3 inclusion is inclined to be modified into lanthanum oxide and lanthanum oxysulfide and the modification process is Al2O3 → LaAlO3 → La2O3 → La2O2S, which is very consistent with the experimental observations.

Efficacy and safety of mycophenolate mofetil in the treatment of moderate to severe Graves' orbitopathy: a meta-analysis.

The role of mycophenolate mofetil (MMF) in the treatment of Graves' orbitopathy (GO) has attracted much attention. This study is to evaluate the benefit and safety of MMF in moderate-to-severe GO. A meta-analysis of clinical control trials comparing MMF (with or without glucocorticoid (GC)) for the treatment of GO with GC was conducted. We searched the databases, including PubMed, EMBASE, the Cochrane Library, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI), for articles published up to 15 June 2022. The primary outcome is referred to the improvement in overall response, and secondary outcomes included the change in clinical activity score (CAS) and adverse events (AEs). Of the 289 articles initially searched, 6 studies were finally eligible for inclusion. The results showed that MMF (with or without GC) was superior to GC in the treatment of GO (OR 3.34, 95% CI 2.17-5.14; p < 0.00001). Subgroup analyses also showed that MMF monotherapy was more effective than GC (OR 4.46, 95% CI 2.52-7.87; p < 0.00001). Compared to methylprednisolone (MP) monotherapy, a combination of MP and MMF was more effective. CAS decreased even more significantly (WMD 0.29, 95% CI 0.10-0.48; p = 0.002) and fewer AEs occurred (OR 0.2, 95% CI 0.06-0.72; p = 0.01) in patients receiving MMF. The pooled data suggested that MMF treatment in GO might be promising. Compared with GC therapy, MMF is safer and more effective. However, more large-sample and high-quality studies targeting MMF use in GO patients and long-term surveillance of prognosis are urgently needed.

A Bibliometric and Visualization Analysis of Intermittent Fasting.

CiteSpace software was utilized to visually analyze the literature on intermittent fasting from Web of Science from 2000 to 2020 in order to reveal the current status, research hotspots and emerging trends of intermittent fasting. The results show that: (1) intermittent fasting research results are increasing year by year; (2) the United States is at the core of this field and has a high influence; (3) intermittent fasting research is mainly concentrated in the fields of nutrition, cell biology and kinesiology, which embodies interdisciplinary characteristics; (4) the literature of Sutton, Mattson and Trepanowski that were published in the same period have the highest co-citation frequencies, however, their research perspectives are quite different, reflecting that the research in this field is still in a state of continuous development; (5) from the perspective of citation bursts, the evolution of research hotspots in this field in the last 20 years can be divided into 3 stages; (6) the keyword timeline mapping shows that time restricted feeding is at the forefront of this research field. This study can help researchers explore the field for the first time to quickly grasp the frontiers and obtain more valuable data, thereby providing facilitation for the follow-up research.

Angiotensin-converting enzyme 2 in peripheral lung club cells modulates the susceptibility to SARS-CoV-2 in chronic obstructive pulmonary disease.

Accumulating evidence has confirmed that chronic obstructive pulmonary disease (COPD) is a risk factor for development of severe pathological changes in the peripheral lungs of patients with COVID-19. However, the underlying molecular mechanisms remain unclear. Because bronchiolar club cells are crucial for maintaining small airway homeostasis, we sought to explore whether the altered susceptibility to SARS-CoV-2 infection of the club cells might have contributed to the severe COVID-19 pneumonia in COPD patients. Our investigation on the quantity and distribution patterns of angiotensin-converting enzyme 2 (ACE2) in airway epithelium via immunofluorescence staining revealed that the mean fluorescence intensity of the ACE2-positive epithelial cells was significantly higher in club cells than those in other epithelial cells (including ciliated cells, basal cells, goblet cells, neuroendocrine cells, and alveolar type 2 cells). Compared with nonsmokers, the median percentage of club cells in bronchiolar epithelium and ACE2-positive club cells was significantly higher in COPD patients. In vitro, SARS-CoV-2 infection (at a multiplicity of infection of 1.0) of primary small airway epithelial cells, cultured on air-liquid interface, confirmed a higher percentage of infected ACE2-positive club cells in COPD patients than in nonsmokers. Our findings have indicated the role of club cells in modulating the pathogenesis of SARS-CoV-2-related severe pneumonia and the poor clinical outcomes, which may help physicians to formulate a novel therapeutic strategy for COVID-19 patients with coexisting COPD.

Effect of Cold Rolling and Annealing on the Microstructure and Texture of Erbium Metal.

Erbium metal with purity ≥ 99% was cold rolled to 30%, 40%, 50%, and 60% deformations and the Er metal of 60% deformation was annealed at different temperatures for 1 h. The effect of cold rolling deformation and annealing on the microstructure and texture evolution of Er metal was investigated by XRD, EBSD, Microhardness tester, and OM. P is the orientation index, which is used to judge the preferred orientation. The research results showed that grains were broken and refined gradually with increasing deformation, the average grain size was 3.37 µm, and the orientation distribution was uniform for 60% deformation; deformation twins appeared in the grain when the deformation was less than 40%, which contributed to the generation of (0001) plane orientation. Comparing with the initial state, the (011-0) plane orientation gradually weakened and the (111-0) plane orientation had a trend of further strengthening with the increasing deformation; the (1-21-0) plane orientation remained unchanged, but there was a gradual weakening trend when the deformation was greater than 50%. For 60% deformation of Er metal, the deformed microstructure was replaced by fine equiaxed grains with the increasing annealing temperature, and the high-performance Er metal with fine and uniform equiaxed grains can be obtained under annealing at 740 °C for 1 h.

Mucus Hypersecretion and Ciliary Impairment in Conducting Airway Contribute to Alveolar Mucus Plugging in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease attributed to the complex interplay of genetic and environmental risks. The muco-ciliary clearance (MCC) system plays a critical role in maintaining the conduit for air to and from the alveoli, but it remains poorly understood whether the MCC abnormalities in conducting airway are involved in IPF pathogenesis. In this study, we obtained the surgically resected bronchi and peripheral lung tissues from 31 IPF patients and 39 control subjects, and we sought to explore the morphologic characteristics of MCC in conducting airway by using immunostaining and scanning and transmission electron microscopy. In the submucosal regions of the bronchi, we found that the areas of mucus glands (MUC5B+) were significantly larger in IPF patients as compared with control subjects (p < 0.05). In the surface epithelium of three airway regions (bronchi, proximal bronchioles, and distal bronchioles), increased MUC5B and MUC5AC expression of secretory cells, decreased number of ciliated cells, and increased ciliary length were observed in IPF patients than control subjects (all p < 0.05). In addition, the mRNA expression levels of MUC5B were up-regulated in both the bronchi and peripheral lung of IPF patients than those of control subjects (p < 0.05), accompanied with 93.55% IPF subjects who had obvious MUC5B+ mucus plugs in alveolar regions. No MUC5B rs35705950 single-nucleotide polymorphism allele was detected in both IPF patients and control subjects. Our study shows that mucus hypersecretion and ciliary impairment in conducting airway are major causes of mucus plugs in alveolar regions and may be closely related to the alveolar injuries in IPF patients.

Epidemiology and Genetic Variabilities of Human Adenovirus Type 55 Reveal Relative Genome Stability Across Time and Geographic Space in China.

After the first outbreak in China in 2006, human adenovirus type 55 (HAdV-B55) has become a common pathogen causing life threatening pneumonia in northern China. However, HAdV-B55 infection has been rarely reported in southern China. Here, we collected throat swabs from 3,192 hospitalized children with acute respiratory disease (ARD) from May 2017 to April 2019 in Guangzhou, southern China, tested them for HAdV-B55 infection. Only one of 1,399 patients from May 2017 to April 2018 was HAdV-B55 positive; HAdV-B55 infections significantly increased with 10 of 1,792 patients testing positive since May 2018. HAdV-B55-267, isolated from a case of death, was sequenced for whole genomic analysis. Three other strains, HAdV-B55-Y16, -TY12, and -TY26, isolated earlier in patients from Shanxi, northern China, were also sequenced and analyzed. The four HAdV-B55 strains formed similar plaques, grew to similar titers, and resulted in similar typical cell pathogenic effects. HAdV-B55-267 formed a subclade with the prototype strain QS-DLL; strains HAdV-B55-Y16, -TY12, and -TY26 were closely related to strain QZ01. HAdV-B55 could be divided into two subtypes (HAdV-B55-a and -b) according to the presence or absence of the insertion of "CCATATCCGTGTT"; all strains isolated from China except for strain BJ01 belong to subtype b. HAdV-B55-267 had only one non-synonymous substitution comparing with strain QS-DLL, and all HAdV-B55 strains had highly conserved capsid proteins and few non-synonymous substitutions. This study suggests that HAdV-B55 is an important pathogen associated with ARD in Guangzhou since 2018, exhibiting the relative genome stability across time and geographic space in China.

Macrocyclization of an all-d linear α-helical peptide imparts cellular permeability.

Peptide-based molecules hold great potential as targeted inhibitors of intracellular protein-protein interactions (PPIs). Indeed, the vast diversity of chemical space conferred through their primary, secondary and tertiary structures allows these molecules to be applied to targets that are typically deemed intractable via small molecules. However, the development of peptide therapeutics has been hindered by their limited conformational stability, proteolytic sensitivity and cell permeability. Several contemporary peptide design strategies are aimed at addressing these issues. Strategic macrocyclization through optimally placed chemical braces such as olefinic hydrocarbon crosslinks, commonly referred to as staples, may improve peptide properties by (i) restricting conformational freedom to improve target affinities, (ii) improving proteolytic resistance, and (iii) enhancing cell permeability. As a second strategy, molecules constructed entirely from d-amino acids are hyper-resistant to proteolytic cleavage, but generally lack conformational stability and membrane permeability. Since neither approach is a complete solution, we have combined these strategies to identify the first examples of all-d α-helical stapled and stitched peptides. As a template, we used a recently reported all d-linear peptide that is a potent inhibitor of the p53-Mdm2 interaction, but is devoid of cellular activity. To design both stapled and stitched all-d-peptide analogues, we used computational modelling to predict optimal staple placement. The resultant novel macrocyclic all d-peptide was determined to exhibit increased α-helicity, improved target binding, complete proteolytic stability and, most notably, cellular activity.