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Osteosarcoma (OS) is the second most common primary malignant bone tumors in adolescents that causes cancer-related deaths. Previous studies have confirmed the promoting role of lncRNA HCP5 in the development of OS, but the specific mechanism is still not well understood. MiRNA levels were measured via RT-qPCR and protein expression was detected via western blotting. Cell proliferation was analyzed by CCK-8 assays and colony formations assay were conducted to measure colony formation ability. Dual-luciferase reporter assay was performed to detect the targeting relationship between HCP5 and miR-29b-3p, and between miR-29b-3p and LOXL2. Wound healing assays and Transwell assays were conducted to verify the migration and invasion abilities of OS cells. Correlations between the levels of HCP5 and miR-29b-3p, and between miR-29b-3p and LOXL2 were determined by Pearson correlation coefficient analysis. MiR-29b-3p expression was decreased and HCP5 and LOXL2 levels were increased in OS tissues and cell lines. MiR-29b-3p could directly act on LOXL2 and knockdown of LOXL2 restrained the proliferation, migration, and invasion of OS cells. Moreover, transfection with sh-HCP5-1 and sh-HCP5-2 suppressed the malignant biological behavior of OS cells. HCP5 directly targeted miR-29b-3p, and promoted OS proliferation, migration, and invasion via the miR-29b-3p/LOXL2 axis. The lncRNA HCP5 may upregulate LOXL2 expression by targeting miR-29b-3p, thereby promoting OS proliferation, migration, and invasion.

To analyze the tissue morphology around implant-supported prostheses by digital technology and to evaluate the effect of prosthetic contours on the changes in tissues following the free gingiva graft procedure.A total of 53 implants in 32 patients receiving free gingiva grafts were selected. These had previously presented insufficient keratinized mucosa width (KMW). At the follow-up visits (mean: 16.66 ± 9.97 months), the implant position and tissue condition were documented with an oral scanner. Vertical soft tissue thickness (VT), measured from the implant-abutment connection to the marginal tissues, and horizontal soft tissue thickness (HT), at the level of the platform, were calculated. The VT, HT, and emergence angle (EA) of prostheses were assessed by 3Shape analyzing software. The final KMW was measured by clinical assessment. Marginal bone loss (MBL) was calculated in the follow-up bitewing radiographs.The mean VT in the study was 2.65 ± 0.75 mm at the mid-buccal sites, 3.74 ± 1.22 mm at the mesial, 3.16 ± 1.08 mm at the distal, and 2.53 ± 0.92 at the mid-lingual aspects. The mid-buccal HT was 1.45 ± 0.53 mm while the mid-lingual was 1.05 ± 0.43 mm (p = 0.008). Interestingly, prostheses with mid-buccal EAFree gingival grafting is a predictable treatment approach to augmenting soft tissue 3-dimensionally. Prostheses with EA

Coronavirus disease 2019 (COVID-19) vaccines have proven to be safe, effective and life-saving. However, little information is available on the neurological complications of COVID-19 vaccine. Here, we report a case who developed acute encephalomyelitis 1 week after being vaccinated with AstraZeneca COVID-19 vaccine (AZ vaccine). Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) was also suspected. After intravenous dexamethasone and subcutaneous fondaparinux therapy, he returned to normal life without neurological sequelae. Four months later, he received Moderna COVID-19 vaccine without any sequelae.

Angiogenesis and MYC expression associate with poor outcome in diffuse large B-cell lymphoma (DLBCL). MYC promotes neo-vasculature development but whether its deregulation in DLBCL contributes to angiogenesis is unclear. Examination of this relationship may uncover novel pathogenic regulatory circuitry as well as anti-angiogenic strategies in DLBCL. Here, we show that MYC expression positively correlates with vascular endothelial growth factor (VEGF) expression and angiogenesis in primary DLBCL biopsies, independently of dual expressor status or cell-of-origin classification. We found that MYC promotes VEGFA expression, a correlation that was validated in large datasets of mature B-cell tumours. Using DLBCL cell lines and patient-derived xenograft models, we identified the second messenger cyclic-AMP (cAMP) as a potent suppressor of MYC expression, VEGFA secretion and angiogenesis in DLBCL in normoxia. In hypoxia, cAMP switched targets and suppressed hypoxia-inducible factor 1α, a master regulator of VEGFA/angiogenesis in low oxygen environments. Lastly, we used the phosphodiesterase 4b (Pde4b) knockout mouse to demonstrate that the cAMP/PDE4 axis exercises additional anti-angiogenesis by directly targeting the lymphoma microenvironment. In conclusion, MYC could play a direct role in DLBCL angiogenesis, and modulation of cAMP levels, which can be achieved with clinical grade PDE4 inhibitors, has cell and non-cell autonomous anti-angiogenic activity in DLBCL.

Background The prognostic value of lactate dehydrogenase (LDH) in colorectal cancer patients has remained inconsistent between nonmetastatic and metastatic settings. So far, very few studies have included LDH in the prognostic analysis of curative‐intent surgery for colorectal liver metastases (CRLM). Patients and Methods Five hundred and eighty consecutive metastatic colorectal cancer patients who underwent curative‐intent CRLM resection from Sun Yat‐sen University Cancer Center (434 patients) and Sun Yat‐sen University Sixth Affiliated Hospital (146 patients) in 2000–2019 were retrospectively collected. Overall survival (OS) was the primary end point. Cox regression model was performed to identify the prognostic values of preoperative serum LDH levels and other clinicopathology variables. A modification of the established Fong CRS scoring system comprising LDH was developed within this Chinese population. Results At the median follow‐up time of 60.5 months, median OS was 59.5 months in the pooled cohort. In the multivariate analysis, preoperative LDH >upper limit of normal (250 U/L) was the strongest independent prognostic factor for OS (HR 1.73, 95% confidence interval [CI], 1.22–2.44; p, We retrospectively analyzed 580 patients with colorectal liver metastases (CRLM) who underwent curative‐intent hepatectomy. Our study implicated preoperative LDH level as a reliable and independent laboratory biomarker to predict the clinical outcome of curative‐intent surgery for CRLM. Composite of LDH and Fong score is a potential stratification tool for CRLM resection.

Purpose The aim of this study was to examine the association between obstructive sleep apnea (OSA) diagnosis and diverse types of injuries. Design This population-based retrospective cohort study compared records from 2000 to 2013 in the Taiwan National Health Insurance Research Database. Methods 3025 patients identified with OSA were compared against the control cohort consisting of 12,100 age- and sex-matched patients. Cox proportional hazards regression analysis was performed to estimate the effects of OSA on injury risk. Findings Patients with OSA exhibited a significantly higher overall incidence of injury of 2599 per 100,000 person-years compared to the control cohort (2248 per 100,000 person-years). After the confounding factors were considered, subjects with OSA showed a higher risk of injury than subjects in the control group (adjusted hazard ratio [HR] = 1.78, 95% confidence interval [CI] = 1.64-1.93). The risk of unintentional injury (traffic, poisoning, falls) and intentional injury (suicide) in the group of patients with OSA was higher than that in the controls. Conclusions Our study strongly supports the conclusion that adults with OSA are at increased risk of injury. Clinical relevance The present results indicate the significance of OSA as a predictor of injury risk, which will provide valuable information for clinical practice and injury prevention.

Yi medicine Shekaqi is the most attractive traditional ethnic medicine due to its significant and diverse pharmacological activities. Two novel flavonoids, including 5,2'-dihydroxy-6-methoxy-7-decyloxyflavone and tenaxin II-7-O-β-D-glucuronopyranosyl acid butyl ester, along with six known flavonoids, were isolated from Yi medicine Shekaqi. Their structures were elucidated based on the analysis of their comprehensive spectral data. The in vitro lipid-lowering activities of the eight compounds showed that all the compounds significantly inhibited the lipopolysaccharide (LPS)-induced increase in the total cholesterol (TC) level, while compounds 1, 4, 6, 7, and 8 significantly inhibited the LPS-induced increase in the triglyceride (TG) level.

We consider the problem of extracting a few desired eigenpairs of the buckling eigenvalue problem $Kx = \lambda K_Gx$, where $K$ is symmetric positive semi-definite, $K_G$ is symmetric indefinite, and the pencil $K - \lambda K_G$ is singular, namely, $K$ and $K_G$ share a non-trivial common nullspace. Moreover, in practical buckling analysis of structures, bases for the nullspace of $K$ and the common nullspace of $K$ and $K_G$ are available. There are two open issues for developing an industrial strength shift-invert Lanczos method: (1) the shift-invert operator $(K - \sigma K_G)^{-1}$ does not exist or is extremely ill-conditioned, and (2) the use of the semi-inner product induced by $K$ drives the Lanczos vectors rapidly towards the nullspace of $K$, which leads to a rapid growth of the Lanczos vectors in norms and cause permanent loss of information and the failure of the method. In this paper, we address these two issues by proposing a generalized buckling spectral transformation of the singular pencil $K - \lambda K_G$ and a regularization of the inner product via a low-rank updating of the semi-positive definiteness of $K$. The efficacy of our approach is demonstrated by numerical examples, including one from industrial buckling analysis.

Objective To report a case series of calcaneal fracture–dislocations, which have not been described previously in China, and to provide a systematic review to explore the clinic manifestations, methods for diagnoses, and treatments. Methods Between January 2018 and December 2019, 4 patients (4 men; average age, 33.0 ± 16.67 years; range, 15–50 years) were diagnosed with fracture–dislocation of the calcaneus and treated by surgery. We also reviewed published cases and studies of calcaneal fracture–dislocations through the databases of PubMed and Web of Science between January 1977 and December 2019. Results Between January 2018 and December 2019, 4 cases were identified as calcaneal fracture–dislocations in our hospital. The main clinical manifestations include hindfoot pain, swelling, and deformity. The diagnoses were confirmed via radiographic examination. Two patients underwent open reduction and internal fixation (ORIF) and two were treated with a minimally invasive approach. Diagnosis had been missed in one patient and, consequently, presented with early signs of post‐traumatic arthritis, which may require extra subtalar arthrodesis in the future. Two patients were diagnosed inaccurately but achieved satisfactory outcomes through open reduction and internal fixation. The average follow‐up period was 9.75 ± 5.19 months. Except for the 1 misdiagnosed patient, the other 3 patients showed functional improvement. Only 23 fracture–dislocations of calcaneus cases were reported in the literature between January 1977 and December 2019. There were 15 Sanders type II fractures (65.22%) and 7 (30.43%) Sanders type III fractures, and there was 1 grade II open calcaneal fracture. Among them, 1 was a medial dislocation and 2 were “joint‐elevation” dislocations; the rest of them (20/23, 86.96%) were lateral dislocations. A total of 11 patients (47.83%) exhibited the double‐density sign, and varus tilt of the talus was revealed on plain radiographs for 9 patients (39.13%). Increased Bohler's angle was evident in lateral X‐ray films for 2 patients (2/23, 8.70%). A total of 21 cases (86.96%) were treated with surgical intervention and achieved satisfactory outcomes. Only 1 patient was treated with external fixation. Another 2 patients were treated conservatively and had poor clinic outcomes. Conclusion Calcaneal fracture–dislocation is a rare injury that is challenging to treat. Clinical manifestations such as fibular tendon dislocation, the double‐density sign on profile radiography, and abnormal talar tilt in the distal talofibular joint are important signs that may indicate this rare injury pattern. Timely surgical intervention is essential for satisfactory clinic outcomes. Orthopaedic surgeons should be aware of this uncommon injury to avoid misdiagnosis or inappropriate treatment., Fracture‐dislocation of calcaneus is a rare injury. The mechanism involves axial compression on an inverted foot. Fibular tendon dislocation, the double‐density sign, and abnormal talar tilt on profile radiography are important clinical signs that may indicate this rare injury pattern. Timely surgical interventions are essential to treat this injury.

Hymenoptera stings can induce dysregulated inflammation and immediate hypersensitivity reactions including anaphylaxis. However, the molecular mechanisms underlying peripheral immune responses during Hymenoptera venom allergy (HVA) remain elusive.Here we determined the single-cell transcriptomic profiling from highly heterogeneous peripheral blood cells in patients with HVA through unbiased single-cell RNA sequencing and multiple models of computational analyses.Through clustering analysis by uniform manifold approximation and projection, we revealed an increased number of monocytes in the acute phase and identified innate immune responses, leukocyte activation, and cellular detoxification as the main involved biological processes. We used filter analysis to identify that CLU that encodes clusterin was highly expressed in monocytes, and the co-expressed genes of CLU further supported the key role of monocyte. We further used pseudo-temporal ordering of cells and scRNA velocity analysis to delineate disease-associated monocyte lineages and states in patients with HVA.Our comprehensive molecular profiling of blood samples from patients with HVA revealed previously unknown molecular changes, providing important insights into the mechanism of venom allergy and potential therapeutic targets.

Amaranth species (Amaranthus spp.) serve as pseudo cereals and also as traditional leafy vegetables worldwide. In addition to high vigor and richness in nutrients, drought and salinity tolerance makes amaranth a promising vegetable to acclimatize to the effects of global climate change. The World Vegetable Center gene bank conserves ∼1,000 amaranth accessions, and various agronomic properties of these accessions were recorded during seed regeneration over decades. In this study, we verified the taxonomic annotation of the germplasm based on a 15K single-nucleotide polymorphism (SNP) set. Given that the yield components of grain amaranth are different from those of leaf amaranth, we observed that grain amaranth species presented larger inflorescences and earlier flowering than leaf amaranth species. Dual-purpose amaranth showed larger leaves than leaf amaranth and later flowering than grain amaranth, which seemed reasonable because farmers can harvest more leaves during the prolonged vegetable stage, which also provides recovery time to enrich grain production. Considering frequent interspecific hybridization among species of the grain amaranth complex, we performed an interspecific genome-wide association study (GWAS) for days to flowering, identifying a AGL20/SOC1 homolog. Another GWAS using only A. tricolor L. accessions revealed six candidate genes homologous to lba1, bri1, sgs1, and fca. These homologous genes were involved in the regulation of flowering time in Arabidopsis thaliana (L.) Heynh. This study revealed the usefulness of genotypic data for species demarcation in the genus Amaranthus and the potential of interspecific GWAS to detect quantitative trait loci (QTL) across different species, opening up the possibility of targeted introduction of specific genetic variants into different Amaranthus species.

Background The efficacy of Djulis for skin care is currently based on cellular or animal models, and the clinical aspect is not in place. Aim This clinical study is to investigate the synergistic effect of fish collagen and Djulis (Chenopodium formosanum Koidz.) for improvement of skin parameters. We used the combination of hydrolyzed collagen and Djulis to develop a new functional formula for skin improvement. Patients/methods Fifty volunteers were randomly allocated (in a 1:1 ratio) to the placebo or collagen drink group. Volunteers were required to consume a 50 mL of a collagen drink or placebo drink daily for 8 weeks. For measurements, the indexes of skin conditions were measured at the baseline and 4 and 8 weeks. Results The improvements of skin hydration, brightness, crow's feet, texture, wrinkles, pores, spots, and collagen content after 8 weeks in collagen group were 17.8%, 5.4%, 14.9%, 9.9%, 29.3%, 10.4%, 9.9%, and 22.3%, respectively. Noticeably, over 68% of subjects got improved for their skin parameters after 8-week intake of collagen drink. The improvement levels indicated competitive skin improvement effects in comparison with previous studies. Conclusion This clinical study demonstrates the synergistic effect of fish collagen and Djulis (the main components) for the substantial improvements in hydration, brightness, crow's feet, texture, wrinkles, pores, surface spots, and collagen content in skin. The collagen drink comprehensively improved skin parameters for most subjects after 4-week intake and manifested competitive efficiency in comparison with other similar studies. We convince that the collagen drink may delay skin aging process and improve skin aging parameters.

We study incentives for innovations that enable firms to enter backward into the input market. Such innovations are disruptive in that they lead to structural changes and even reversal of supply-customer relationships. We first show that Arrow's replacement effect is also present in our vertical setting which gives rise to two general results: (1) vertical integration lowers the RD and (2) vertical integration raises the R&D incentive of the non-integrated downstream firm. We then identify, respectively, situations for strategic integration, which is driven by the motive to preempt R&D of the target firm, and for strategic separation, which occurs as a means to not trigger R&D by the downstream rival. An otherwise profitable raising rival's cost strategy may not be chosen for fear of counterattack by the rival in the form of disruptive R&D.

Acupuncture has a good effect on improving neurological function after cerebral ischemia‐reperfusion, but there are few studies on the neuroprotective effect of acupuncture from the perspective of ion channel cellular electrophysiology. Studies have shown that the over activation of large‐conductance Ca2+‐activated potassium channel （BKCa） after cerebral ischemia‐reperfusion can reduce the excitability of neurons and induce apoptosis. This study intends to establish middle cerebral artery occlusion/reperfusion (MCAO/R) model, with acupuncture at GV26 as the intervention measure, using patch‐clamp technique to record the electrophysiological changes of BKCa channel. The results showed that the neurological function score of MCAO/R rats was significantly decreased, and the conductance, open dwell time and open probability of BKCa channel in hippocampal CA1 neurons of MCAO/R rats were significantly increased. Acupuncture at GV26 could significantly improve the neurological function scores of MCAO/R rats, and reduce the conductance, open dwell time, and open probability of BKCa channel. The effect of acupuncture at GV26 was significantly better than acupuncture at non‐acupuncture point. The neuroprotective effect of acupuncture at GV26 after cerebral ischemia‐reperfusion may be related to regulating the electrophysiological characteristics of BKCa channel opening., Acupuncture ameliorates neurological function in rats with cerebral ischemia‐reperfusion by regulating the opening of large‐conductance Ca2+‐activated potassium channels

Dual-specificity phosphatases (DUSPs) regulate the activity of various downstream kinases through serine or threonine or tyrosine dephosphorylation. Loss of function and aberrant expression of DUSPs has been implicated in cancer progression and poor survival, yet the function of DUSP22 in prostate cancer (PCa) cells is not clear. Gene Expression Omnibus and cBioPortal microarray database analyses showed that DUSP22 expression was lower in PCa tissues than normal prostate tissues, and altered DUSP22 expression was associated with shorter progression-free and disease-free survival of patients with PCa. Exogenous DUSP22 expression in LNCaP, PC3, and C4-2B PCa cells inhibited cellular proliferation and colony formation, supporting a growth inhibitory role for DUSP22 in PCa cells. DUSP22 expression significantly attenuated epidermal growth factor (EGF) receptor (EGFR) and its downstream ERK1/2 signaling by dephosphorylation. However, DUSP22 failed to suppress the growth of CWR22Rv1 and DU145 cells with elevated phosphorylated (p-)ERK1/2 levels. A serine-to-alanine mutation at position 58, a potential ERK1/2-targeted phosphorylation site in DUSP22, was sufficient to suppress growth of CWR22Rv1 cells with elevated p-ERK1/2 levels, suggesting a mutually antagonistic relationship between DUSP22 and ERK1/2 dependent on phosphorylation status. We showed that DUSP22 can suppress prostate-specific antigen gene expression through phosphatase-dependent pathways, suggesting that DUSP22 is an important regulator of the androgen receptor (AR) in PCa cells. Mechanistically, DUSP22 can interact with AR as a regulatory partner and interfere with EGF-induced AR phosphorylation at Tyr534, suggesting that DUSP22 serves as a crucial suppressor of both EGFR and AR-dependent signaling in PCa cells

Objective Ala97Ser (A97S) is the major transthyretin (TTR) mutation in Taiwanese patients of familial amyloid polyneuropathy (FAP), characterized by a late‐onset but rapidly deteriorated neuropathy. Tafamidis can restore the stability of some mutant TTR tetramers and slow down the progression of TTR‐FAP. However, there is little understanding of the biophysical features of A97S‐TTR mutant and the pharmacological modulation effect of tafamidis on it. This study aims to delineate the biophysical characteristics of A97S‐TTR and the pharmacological modulation effect of tafamidis on this mutant. Method The stability of TTR tetramers was assessed by urea denaturation and differential scanning calorimetry. Isothermal titration calorimetry (ITC) was used to measure the binding constant of tafamidis to TTR. Nuclear magnetic resonance spectroscopy (NMR) titration experiment was used to map out the tafamidis binding site. Results Chemical and thermal denaturation confirmed the destabilization effect of A97S. Consistent with other the amyloidogenic mutant, A97S‐TTR has slightly lower conformational stability. NMR revealed the binding site of A97S‐TTR with tafamidis is at the thyroxine binding pocket. The ITC experiments documented the high affinity of the binding which can effectively stabilize the A97S‐TTR tetramer. Interpretation This study confirmed the structural modulation effect of tafamidis on A97S‐TTR and implied the potential therapeutic benefit of tafamidis for A97S TTR‐FAP. This approach can be applied to investigate the modulation effect of tafamidis on other rare TTR variants and help to make individualized choices of available treatments for FAP patients.

Objective Charcot‐Marie‐Tooth disease (CMT) is a clinically and genetically heterogeneous group of inherited neuropathies. Mutations in more than 90 genes have been implicated in CMT; however, the mutational spectrum of CMT in Chinese population remains obscure. This study aims to provide a comprehensive overview of the frequency of mutations in Taiwanese patients with CMT and look for genotype‐phenotype correlations. Methods Mutational analyses were performed on 427 unrelated Taiwanese patients with CMT by polymorphic microsatellite markers analysis or real‐time fluorescent PCR for PMP22 duplication, Sanger sequencing for GJB1 mutations, and targeted sequencing covering 124 genes causing or relevant to inherited neuropathies. We also correlated the genotypes with the phenotypic features, such as age at disease onset and ulnar motor nerve conduction velocity. Results Pathogenic mutations were identified in 312 patients (73.1%; 312/427), including 208 patients with a PMP22 duplication, 40 patients with a GJB1 mutation, and 64 patients with a mutation in one of other 18 CMT genes. A confirmed molecular diagnosis was achieved in 84.4% (266/315) of the patients with demyelinating CMT and 41.1% (46/112) of the patients with axonal CMT. Mutations in MPZ, MFN2, or NEFL are the most frequent disease causes in patients with infantile‐onset CMT (≤2 years), while PMP22 duplications and mutations in GJB1, MFN2, or MPZ are the frequent causes among patients with childhood‐ or adolescence‐onset CMT (3–9 years). Interpretation This study provides a genotype‐phenotype landscape of CMT in Taiwan and highlights the unique spectrum of CMT genes frequencies among patients of Chinese origin.

Aim To investigate the association between specific dental therapy for periodontal disease and the risk of ischaemic stroke. Materials and methods We conducted a population-based cohort study that used data from the Taiwan National Health Insurance Research Database 2005 for the period of 2000-2013. Our observations focused on patients with the diagnoses of gingivitis or periodontitis with and without specific treatment and subsequent incidence of ischaemic stroke. Dental care services include dental scaling, intensive treatment (subgingival curettage and root planing) and tooth extraction. Multivariate Cox regression analysis was used to estimate the hazard ratios and corresponding 95% confidence intervals (95% CI). Results Compared with those in the gingivitis cohort, patients with periodontitis have a higher risk of ischaemic stroke and a lower survival rate of stroke over the 10-year follow-up period. After integrative dental care, both dental scaling and intensive treatment, the risk was reduced, especially in patients with periodontitis, while patients with periodontal disease may have an increased risk of stroke after tooth extraction therapy. Conclusions Our study showed that periodontitis is a risk factor for ischaemic stroke. Both dental scaling and intensive treatment for periodontal disease are associated with a lower risk of further ischaemic stroke events.

Objective The clinical and genetic profiles of hereditary transthyretin amyloidosis (ATTR) in Chinese populations remain elusive. We aim to characterize the features of ATTR in a Taiwanese cohort of Han Chinese descent. Methods Seventy‐nine patients with molecularly confirmed ATTR from 57 Taiwanese families were identified by sequencing the transthyretin gene (TTR). The clinical and electrophysiological data were scrutinized. Cardiac involvement of ATTR was evaluated by echocardiography and cardiac scintigraphy. Four microsatellite and seven single‐nucleotide polymorphism markers flanking TTR were genotyped to investigate the founder effect of the TTR Ala97Ser mutation. Results Most of the patients had a peripheral neuropathy with variable autonomic symptoms. The average age at disease onset (AO) was 58.2 ± 7.2 years, and the male patients had an earlier AO than female patients (56.6 ± 5.7 years vs. 61.8 ± 8.9 years, P = 0.013). Electrophysiological studies revealed a generalized axonal sensorimotor polyneuropathy and isolated median neuropathy in 84.5% and 15.5% of the patients, respectively. Up to 80% of the patients with ATTR had symptomatic or subclinical cardiac involvement. Six TTR mutations were identified in the participants including one novel mutation Glu89Asp. Among them, Ala97Ser was the most common mutation, accounting for 91.2% of the ATTR pedigrees. Detailed haplotype analyses demonstrated a shared haplotype in the 47 patients with the Ala97Ser mutation, suggesting a founder effect. Interpretation The present study delineates the distinct features of ATTR in Taiwan and provides useful information for the diagnosis and management of ATTR, especially in patients of Chinese descent.

Bicyclic peptides are attractive scaffolds for the design of potent protein binders and new therapeutics. However, peptide bicycles constrained through disulfide bonds are rarely stable or tolerant to sequence manipulation owing to disulfide isomerization, especially for peptides lacking a regular secondary structure. Herein, we report the discovery and identification of a class of bicyclic peptide scaffolds with ordered but irregular secondary structures. These peptides have a conserved cysteine/proline framework for directing the oxidative folding into a fused bicyclic structure that consists of four irregular turns and a 310 helix (characterized by NMR spectroscopy). This work shows that bicyclic peptides can be stabilized into ordered structures by manipulating both the disulfide bonds and proline-stabilized turns. In turn, this could inspire the design and engineering of multicyclic peptides with new structures and benefit the development of novel protein binders and therapeutics.

A new metal-free procedure allowing a Csp 3-N bond formation through coupling of pyridotriazoles and weakly nucleophilic anilines has been developed. This sustainable reaction shows high tolerance towards functional groups (ketones, free alcohols) leading to 2-picolylamines derivatives. The key to our success is the use of a catalytic amount of TBAB and water as a co-solvent leading to the formation of pyridyl-alkylamines derivatives. As this coupling tolerates the presence of Csp 2-Br bond on both partner of the reaction, this allowed us to perform a sequential one-pot reaction between functionalized triazolopyridines and anilines followed by a second coupling with N-tosylhydrazones leading to the formation of Csp 3-N and Csp 2-Csp 2 bonds.

Aims and objectives To observe the psychological status of pregnant women during COVID-19 pandemic, and to test a hypothetical model that estimates the influence of psychological response to COVID-19 and security sense on pregnancy stress. Background COVID-19 advanced rapidly and then spread worldwide. Pregnant women were more susceptible to the COVID-19 infection. Furthermore, it is not clear whether this infection will increase the risk of congenital monstrosity, foetal growth restriction, premature delivery or cause other long-term adverse effects. Design A descriptive, cross-sectional survey. Methods A total of 331 pregnant women participated in this study. And this research adhered to the STROBE guideline. The psychological questionnaire for emergent events of public health, pregnancy stress scale and security questionnaire were used to collect data. The hypothetical path model was tested using the SPSS version 25.0 software and AMOS version 26.0 software. Results Fear and depression were the most common psychological responses among pregnant women during the COVID-19 pandemic. The hypothesis model of this study fitted the data well, and the results showed that psychological response positively affected pregnancy stress, while security sense negatively affected pregnancy stress; security sense mediated between psychological response and pregnancy stress. Conclusion Nurses and midwives can help reduce the stress in pregnant women by alleviating their psychological response to the COVID-19 pandemic and by improving their security sense. Relevance to clinical practice It is essential for the health staff to build trust with pregnant women and their families, and communicate accurate information to them. Nurses should promptly conduct a psychological response evaluation and psychological guidance for pregnant women to alleviate their fears and hypochondria related to COVID-19.

Molecular networking approach was applied for the targeted isolation of new sterigmatocystin derivatives, sterigmatocystins A-C, from the marine sponge-derived fungus Aspergillus versicolor. Sterigmatocystin A features a rare 6/6/6/6/5 polycyclic system. The structures of sterigmatocystins A-C, including absolute configurations, were determined on the basis of spectroscopic data and ECD calculations. Sterigmatocystin A showed more stronger promoting angiogenesis activity than the positive control at 1.25 μM level in transgenic fluorescent zebrafish. Sterigmatocystins A-C also exhibited moderate antiviral activity by the inhibition of HSV-2.

Exaggerated sexually selected traits are assumed to decrease the mobility of bearers. However, previous empirical studies have often failed to support this assumption, possibly because locomotor performance represents the integration of numerous morphological, physiological and behavioural traits. Males of a flower beetle Dicronocephalus wallichii Pouillaude 1914 (Coleoptera: Scarabaeidae: Cetoniinae) possess elongated forelegs and a pair of exaggerated horns, which are used as dual weapons in male–male competition for mates. We investigated whether these two sexual traits impede the maximum sprint speed on bamboo branches with different angles and thicknesses under laboratory conditions. Our results suggested that no negative relationship exists between relative foreleg length or horn length and sprint speed. Elongated forelegs and horns may entail negligible locomotor costs. Males with longer horns and forelegs were found to have longer midlegs and hindlegs independent of body size. Thus, elongated midlegs and hindlegs in males may enhance balance, stabilize running on bamboo branches and compensate for the locomotor costs of bearing exaggerated weapons. Furthermore, a positive relationship was found between horn length and sprint speed on a horizontal branch. Males with longer horns probably have more energy and/or invest more heavily in appendage musculature. As is known in other animals, male horns of D. wallichii may act as honest indicators of body condition.

INTRODUCTION The sonographic changes of the median nerve after steroid injection for carpal tunnel syndrome (CTS) still require investigation. METHODS Sixty-two patients with CTS were included. The Boston Carpal Tunnel Questionnaire was administered, and ultrasonographic examinations were performed before and at 2, 6, and 12 weeks after steroid injection. At 12 weeks, general improvement was scored on a 6-point Likert scale. RESULTS After treatment, the cross-sectional area (CSA) of the median nerve was significantly reduced at 2-, 6-, and 12-week follow-ups (for each, P

Background and purpose Macropinocytosis is involved in many pathologies, including cardiovascular disorders, cancer, allergic diseases, viral and bacterial infections. Unfortunately, the currently available pharmacological inhibitors of macropinocytosis interrupt other endocytic processes and have non-specific endocytosis-independent effects. Here we have sought to identify new, clinically relevant inhibitors of macropinocytosis, using an FDA-approved drug library. Experimental approach In the present study, 640 FDA-approved compounds were tested for their ability to inhibit macropinocytosis. A series of secondary assays were performed to confirm inhibitory activity, determine IC50 values and investigate cell toxicity. The ability of identified hits to inhibit phagocytosis and clathrin-mediated and caveolin-mediated endocytosis was also investigated. Scanning electron microscopy and molecular biology techniques were utilized to examine the mechanisms by which selected compounds inhibit macropinocytosis. Key results The primary screen identified 14 compounds that at ~10 μM concentration inhibit >95% of macropinocytotic solute internalization. Three compounds - imipramine, phenoxybenzamine and vinblastine - potently inhibited (IC50 ≤ 131 nM) macropinocytosis without exerting cytotoxic effects or inhibiting other endocytic pathways. Scanning electron microscopy imaging indicated that imipramine inhibits membrane ruffle formation, a critical early step leading to initiation of macropinocytosis. Finally, imipramine has been shown to inhibit macropinocytosis in several cell types, including cancer cells, dendritic cells and macrophages. Conclusions and implications Our results identify imipramine as a new pharmacological tool to study macropinocytosis in cellular and biological systems. This study also suggests that imipramine could be a good candidate for repurposing as a therapeutic agent in pathological processes involving macropinocytosis.