ROS-induced imbalance of the miR-34a-5p/SIRT1/p53 axis triggers chronic chondrocyte injury and inflammation.

Osteoarthritis is a chronic degenerative disease based on the degeneration and loss of articular cartilage. Inflammation and aging play an important role in the destruction of the extracellular matrix, in which microRNA (miRNA) is a key point, such as miRNA-34a-5p. Upregulation of miRNA-34a-5p was previously reported in a rat OA model, and its inhibition significantly suppressed interleukin (IL)-1ß-induced apoptosis in rat chondrocytes. However, Oxidative stress caused by reactive oxygen species (ROS) can exacerbate the progression of miRNA regulated OA by mediating inflammatory processes. Thus, oxidative stress effects induced via tert-butyl hydroperoxide (tBHP) in human chondrocytes were assessed in the current research by evaluating mitochondrial ROS production, mitochondrial cyclooxygenase (COX) activity, and cell apoptosis. We also analyzed the activities of antioxidant enzymes including glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD). Additionally, inflammatory factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-8, and IL-24, which contribute to OA development, were detected by enzyme-linked immunosorbent assay (ELISA). The results of this study indicated that miR-34a-5p/silent information regulator 1 (SIRT1)/p53 axis was involved in the ROS-induced injury of human chondrocytes. Moreover, dual-luciferase assay revealed that SIRT1 expression was directly regulated by miR-34a-5p, indicating the presence of a positive feedback loop in the miR-34a-5p/SIRT1/p53 axis that plays an important role in cell survival. However, ROS disrupted the miR-34a-5p/SIRT1/p53 axis, leading to the development of OA, and articular injection of SIRT1 agonist, SRT1720, in a rat model of OA effectively ameliorated OA progression in a dose-dependent manner. Our study confirms that miRNA-34a-5p could participate in oxidative stress responses caused by ROS and further regulate the inflammatory process via the SIRT1/p53 signaling axis, ultimately affecting the onset of OA, thus providing a new treatment strategy for clinical treatment of OA.

Incidence and prognosis of olfactory and gustatory dysfunctions related to SARS-CoV-2 Omicron strain infection in China: A national multicenter survey of 35,566 individuals.

Objective: This cross-sectional study aimed to determine the epidemiology of olfactory and gustatory dysfunctions related to COVID-19 in China. Methods: This study was conducted by 45 tertiary Grade-A hospitals in China. Online and offline questionnaire data were obtained from patients infected with COVID-19 between December 28, 2022, and February 21, 2023. The collected information included basic demographics, medical history, smoking and drinking history, vaccination history, changes in olfactory and gustatory functions before and after infection, and other postinfection symptoms, as well as the duration and improvement status of olfactory and gustatory disorders. Results: Complete questionnaires were obtained from 35,566 subjects. The overall incidence of olfactory and taste dysfunction was 67.75%. Being female or being a cigarette smoker increased the likelihood of developing olfactory and taste dysfunction. Having received four doses of the vaccine or having good oral health or being a alcohol drinker decreased the risk of such dysfunction. Before infection, the average olfactory and taste VAS scores were 8.41 and 8.51, respectively; after infection, they decreased to 3.69 and 4.29 and recovered to 5.83 and 6.55 by the time of the survey. The median duration of dysosmia and dysgeusia was 15 and 12 days, respectively, with 0.5% of patients having symptoms lasting for more than 28 days. The overall self-reported improvement rate was 59.16%. Recovery was higher in males, never smokers, those who received two or three vaccine doses, and those that had never experienced dental health issues, or chronic accompanying symptoms. Conclusions: The incidence of dysosmia and dysgeusia following infection with the SARS-CoV-2 virus is high in China. Incidence and prognosis are influenced by several factors, including sex, SARS-CoV-2 vaccination, history of head-facial trauma, nasal and oral health status, smoking and drinking history, and the persistence of accompanying symptoms.

Clinical evaluation of pulmonary quantitative computed tomography parameters for diagnosing eosinophilic chronic obstructive pulmonary disease: Characteristics and diagnostic performance.

Aims: To investigate the characteristics and diagnostic performance of quantitative computed tomography (QCT) parameters in eosinophilic chronic obstructive pulmonary disease (COPD) patients. Methods: High-resolution CT scans of COPD patients were retrospectively analyzed, and various emphysematous parenchyma measurements, including lung volume (LC), lung mean density (LMD), lung standard deviation (LSD), full-width half maximum (FWHM), and lung relative voxel number (LRVN) were performed. The QCT parameters were compared between eosinophilic and noneosinophilic COPD patients, using a definition of eosinophilic COPD as blood eosinophil values ≥ 300 cells·µL-1 on at least three times. Receiver operating characteristic curves and area under the curve (ROC-AUC) and python were used to evaluate discriminative efficacy of QCT. Results: Noneosinophilic COPD patients had a significantly lower TLMD (-846.3 ± 47.9 Hounsfield Unit [HU]) and TFWHM(162.5 ± 30.6 HU) compared to eosinophilic COPD patients (-817.8 ± 54.4, 177.3 ± 33.1 HU, respectively) (p = 0.018, 0.03, respectively). Moreover, the total LC (TLC) and TLSD were significantly lower in eosinophilic COPD group (3234.4 ± 1145.8, 183.8 ± 33.9 HU, respectively) than the noneosinophilic COPD group (5600.2 ± 1248.4, 203.5 ± 20.4 HU, respectively) (p = 0.009, 0.002, respectively). The ROC-AUC values for TLC, TLMD, TLSD, and TFWHM were 0.91 (95% confidence interval [CI], 0.828-0.936), 0.66 (95% CI, 0.546-0.761), 0.64 (95% CI, 0.524-0.742), and 0.63 (95% CI, 0.511-0.731), respectively. When the TLC value was 4110 mL, the sensitivity was 90.7% (95% CI, 79.7-96.9), specificity was 77.8% (95% CI, 57.7-91.4) and accuracy was 86.4%. Notably, TLC demonstrated the highest discriminative efficiency with an F1 Score of 0.79, diagnostic Odds Ratio of 34.3 and Matthews Correlation Coefficient of 0.69, surpassing TLMD (0.55, 3.66, 0.25), TLSD (0.56, 3.95, 0.26), and TFWHM (0.56, 4.16, 0.33). Conclusion: Eosinophilic COPD patients exhibit lower levels of emphysema and a more uniform density distribution throughout the lungs compared to noneosinophilic COPD patients. Furthermore, TLC demonstrated the highest diagnostic efficiency and may serve as a valuable diagnostic marker for distinguishing between the two groups.

Post-COVID-19 Pandemic Rebound of Macrolide-Resistant Mycoplasma pneumoniae Infection: A Descriptive Study.

The rebound characteristics of respiratory infections after lifting pandemic control measures were uncertain. From January to November 2023, patients presenting at a teaching hospital were tested for common respiratory viruses and Mycoplasma pneumoniae using a combination of antigen, nucleic acid amplification, and targeted next-generation sequencing (tNGS) tests. The number and rate of positive tests per month, clinical and microbiological characteristics were analyzed. A rapid rebound of SARS-CoV-2 was followed by a slower rebound of M. pneumoniae, with an interval of 5 months between their peaks. The hospitalization rate was higher, with infections caused by respiratory viruses compared to M. pneumoniae. Though the pediatric hospitalization rate of respiratory viruses (66.1%) was higher than that of M. pneumoniae (34.0%), the 4094 cases of M. pneumoniae within 6 months posed a huge burden on healthcare services. Multivariate analysis revealed that M. pneumoniae-infected adults had more fatigue, comorbidities, and higher serum C-reactive protein, whereas children had a higher incidence of other respiratory pathogens detected by tNGS or pathogen-specific PCR, fever, and were more likely to be female. A total of 85% of M. pneumoniae-positive specimens had mutations detected at the 23rRNA gene, with 99.7% showing A2063G mutation. Days to defervescence were longer in those not treated by effective antibiotics and those requiring a change in antibiotic treatment. A delayed but significant rebound of M. pneumoniae was observed after the complete relaxation of pandemic control measures. No unusual, unexplained, or unresponsive cases of respiratory infections which warrant further investigation were identified.

Digital measuring the ocular morphological parameters of guinea pig eye in vivo with Python.

AIM: To quantitatively measure ocular morphological parameters of guinea pig with Python technology. METHODS: Thirty-six eyeballs of eighteen 3-week-old guinea pigs were measured with keratometer and photographed to obtain the horizontal, coronal, and sagittal planes respectively. The corresponding photo pixels-actual length ratio was acquired by a proportional scale. The edge coordinates were identified artificially by ginput function. Circle and conic curve fitting were applied to fit the contour of the eyeball in the sagittal, coronal and horizontal view. The curvature, curvature radius, eccentricity, tilt angle, corneal diameter, and binocular separation angle were calculated according to the geometric principles. Next, the eyeballs were removed, canny edge detection was applied to identify the contour of eyeball in vitro. The results were compared between in vivo and in vitro. RESULTS: Regarding the corneal curvature and curvature radius on the horizontal and sagittal planes, no significant differences were observed among results in vivo, in vitro, and the keratometer. The horizontal and vertical binocular separation angles were 130.6°±6.39° and 129.8°±9.58° respectively. For the corneal curvature radius and eccentricity in vivo, significant differences were observed between horizontal and vertical planes. CONCLUSION: The Graphical interface window of Python makes up the deficiency of edge detection, which requires too much definition in Matlab. There are significant differences between guinea pig and human beings, such as exotropic eye position, oblique oval eyeball, and obvious discrepancy of binoculus. This study helps evaluate objectively the ocular morphological parameters of small experimental animals in emmetropization research.

Organoid forming potential as complementary parameter for accurate evaluation of breast cancer neoadjuvant therapeutic efficacy.

BACKGROUND: 13-15% of breast cancer/BC patients diagnosed as pathological complete response/pCR after neoadjuvant systemic therapy/NST suffer from recurrence. This study aims to estimate the rationality of organoid forming potential/OFP for more accurate evaluation of NST efficacy. METHODS: OFPs of post-NST residual disease/RD were checked and compared with clinical approaches to estimate the recurrence risk. The phenotypes of organoids were classified via HE staining and ER, PR, HER2, Ki67 and CD133 immuno-labeling. The active growing organoids were subjected to drug sensitivity tests. RESULTS: Of 62 post-NST BC specimens, 24 were classified as OFP-I with long-term active organoid growth, 19 as OFP-II with stable organoid growth within 3 weeks, and 19 as OFP-III without organoid formation. Residual tumors were overall correlated with OFP grades (P < 0.001), while 3 of the 18 patients (16.67%) pathologically diagnosed as tumor-free (ypT0N0M0) showed tumor derived-organoid formation. The disease-free survival/DFS of OFP-I cases was worse than other two groups (Log-rank P < 0.05). Organoids of OFP-I/-II groups well maintained the biological features of their parental tumors and were resistant to the drugs used in NST. CONCLUSIONS: The OFP would be a complementary parameter to improve the evaluation accuracy of NST efficacy of breast cancers.

Adaptation cannot keep pace with projected temperature increase.

An emerging argument is that since humans can readily adapt to changing climatic conditions, there is less need to pursue aggressive emissions mitigation strategies. As temperature adaptation is a function of repeated exposure over time, we need empirical approaches that can depict individuals' temperature history to rigorously examine this claim. Using a longitudinal dataset representative of China, we construct lifetime temperature exposure unique to each individual based on their birth-dates, birth-locations, and movement history. We show that a 1°C increase in individualized temperature anomalies cause a 2% decrease in 1 standard deviation (S.D.) of well-being, where most of the impacts are driven by "hotter-than-expected" weather. In turn, while the adverse impacts of future temperature changes wane after accommodating for adaptation, acclimatization is unlikely to keep pace with future temperature increases except in the net-zero emissions scenario, indicating that stringent greenhouse gas (GHG) emissions cuts are still needed even in this less-pessimistic scenario.

[Investigation of Antigen and Gene Frequency of Kell(K) and Rh(D) Blood Groups in Xinjiang].

OBJECTIVE: To investigate the phenotypes and gene frequencies of Kell blood group system K antigen and Rh blood group system D antigen in Xinjiang, and summarize and understand the distribution of Kell(K) blood type and Rh(D) blood type in this area. METHODS: A total of 12 840 patients who met the inclusion criteria during physical examination and treatment in our hospital and 18 medical institutions in our district from January 1, 2019 to December 31, 2019 were collected for identification of Kell blood group system K antigen and Rh blood group System D antigen, and the distribution of K and D blood groups in different regions, genders and nationalities were investigated and statistically analyzed. RESULTS: The proportion of K positive in the samples was 1.39%, the highest was 1.91% in southern Xinjiang, and the lowest was 1.03% in northern Xinjiang(P<0.01). The proportion of Rh(D) negative samples was 2.75% and the gene frequency was 16.64%. The proportion of Rh(D) negative samples was 4.03% and the gene frequency was 20.10% in southern Xinjiang, followed by eastern Xinjiang and the lowest in northern Xinjiang (P<0.01). The frequency of K antigen in Uygur nationality was the highest, reaching 2.16%, Kirgiz 1.54%, and the distribution trend of D/d antigen was similar to that of K antigen. Among women, the K positive frequency of Kazak nationality was slightly higher than that of Mongolian nationality. The highest proportion of K positive in Uygur women was 2.38%, which was higher than that in Uygur men (1.86%). The frequency of d phenotype in Kazak women was 3.15%, which was higher than that in Kirgiz （2.89%） (P<0.01). CONCLUSION: The distributions of Kell(K) and Rh(D) blood groups in northern and southern Xinjiang and eastern Xinjiang had its own unique characteristics and differences. There are significant differences in blood group distribution among different ethnic groups and gender groups. In the future, k antigen detection can be included to further improve the investigation on the distribution of Kell blood group system in this region.

miR-124 delivered by BM-MSCs-derived exosomes targets MCT1 of tumor-infiltrating Treg cells and improves ovarian cancer immunotherapy.

Metabolic rewiring of tumor cells leads to an enrichment of lactate in the tumor microenvironment (TME). This lactate-rich environment of solid tumors has been reported to support tumor-infiltrating regulatory T (Treg) cells. Therefore, agents that modify the lactate metabolism of Treg cells have therapeutic potential. Monocarboxylate transporter 1 (MCT1), which Treg cells predominantly express, plays an essential role in the metabolism of tumor-infiltrating Treg cells. In this study, we show that miR-124 directly targets MCT1 and reduces lactate uptake, eventually impairing the immune-suppressive capacity of Treg cells. Particularly, exosomal miR-124 derived from bone marrow mesenchymal stromal cells (BM-MSCs) slows tumor growth and increases response to PD-1 blockade therapy. These data indicate a potential treatment strategy for improving immune checkpoint blockade therapy using miR-124-carried BM-MSCs-derived exosomes.

Global, regional, and national prevalence of hearing loss from 1990 to 2019: A trend and health inequality analyses based on the Global Burden of Disease Study 2019.

As a severe public health issue, hearing loss has caused an increasingly disease burden, especially in the elderly population. Hearing loss may inevitably induce asymmetric hearing, which makes it difficult for elderly individuals to locate sound sources, therefore resulting in increased postural instability and falling risk. To emphasize the public health emergence of hearing loss, we investigated the temporal trend of prevalence of hearing loss over the last 30 years and further predicted its changes in the next 20 years, decomposed the trend according to demographic factors and epidemiological changes, and quantified the cross-country healthy inequalities, using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. In 2019, there were more than 140 million cases of hearing loss worldwide, a 93.89% increase from 70 million cases in 1990. The age-standardized rate (ASR) also increased with an estimated annual percentage change of 0.08% per year. Population growth and aging are the major drivers contributing to the changes, accounting for 60.83% and 35.35%. Of note, the contribution of aging varies showing a gradual increasing trend with sociodemographic index (SDI) elevating. Also notable, there were significant health inequalities across 204 countries and territories, with slope index of inequality rising over time. Projection of the global burden of hearing loss from 2020 to 2040 indicated progressive increases in both case number and ASR. These reflect the heavy disease burden of hearing loss that needed more targeted and efficient strategies in its prevention and management.

Nanoscale effects of TiO2 nanoparticles on the rheological behaviors of ultra-high molecular weight polyethylene (UHMWPE).

Considering the molar mass between entanglements to be an intrinsic property of ultra-high molecular weight polyethylene (UHMWPE), the number of entanglements per chain increases with increasing molar mass, correspondingly making the UHMWPE intractable. Herein, we dispersed TiO2 nanoparticles with different characteristics into UHMWPE solutions to disentangle the molecular chains. Compared with the UHMWPE pure solution, the viscosity of the mixture solution declines by 91.22%, and the critical overlap concentration increases from 1 wt% to 1.4 wt%. A rapid precipitation method was utilized to obtain UHMWPE and UHMWPE/TiO2 composites from the solutions. The melting index of UHMWPE/TiO2 is 68.85 mg, which is in sharp contrast to that of UHMWPE which is 0 mg. We characterized the microstructures of UHMWPE/TiO2 nanocomposites using TEM, SAXS, DMA, and DSC. Accordingly, this significant improvement in processability contributed to the reduction of entanglements and a schematic model was proposed to explain the mechanism by which nanoparticles disentangle molecular chains. Simultaneously, the composite demonstrated better mechanical properties than UHMWPE. In summary, we provide a strategy to promote the processability of UHMWPE without sacrificing its outstanding mechanical properties.

Effectiveness of the recurrent laryngeal nerve monitoring during endoscopic thyroid surgery: systematic review and meta-analysis.

BACKGROUND: Thyroid disease is a common endocrine disorder, and thyroid surgeries and postoperative complications have increased recently. This study aimed to explore the effectiveness of intraoperative nerve monitoring (IONM) in endoscopic thyroid surgery using subgroup analysis and determine confounding factors. MATERIALS AND METHODS: Two researchers individually searched for relevant studies published till November 2022 in the PubMed, Embase, Web of Science and Cochrane Library databases. Eventually, eight studies met the inclusion criteria. Heterogeneity was assessed using the Cochran's Q test, and a funnel plot was implemented to evaluate publication bias. The odds ratio or risk difference were calculated using fixed-effects models. The weighted mean difference of continuous variables was calculated. Subgroup analysis was performed according to the disease type. RESULTS: Eight eligible papers included 915 patients and 1242 exposed nerves. The frequencies of transient, permanent and total recurrent laryngeal nerve (RLN) palsy were 2.64, 0.19 and 2.83%, respectively, in the IONM group and 6.15, 0.75 and 6.90%, respectively, in the conventional exposure group. In addition, analysis of the secondary outcome indicators for the average total length of surgery, localisation time of the RLN, recognition rate of the superior laryngeal nerve and length of incision revealed that IONM reduced the localisation time of the RLN and increased the identification rate of the superior laryngeal nerve. Subgroup analysis showed that IONM significantly reduced the incidence of RLN palsy in patients with malignancies. CONCLUSIONS: The use of IONM significantly reduced the incidence of transient RLN palsy during endoscopic thyroid surgery, but it did not significantly reduce the incidence of permanent RLN palsy. However, the reduction in the total RLN palsy was statistically significant. In addition, IONM can effectively reduce the location time of the RLN and increase the recognition rate of the superior laryngeal nerve. Therefore, the application of IONM for malignant tumours is recommended.

[Clinical observation on treatment of PC-BPPV by dynamic and static acupuncture method combined with manual reduction].

OBJECTIVE: To observe the clinical effect and advantages of dynamic and static acupuncture method combined with manual reduction on posterior semicircular canal benign paroxysmal positional vertigo (PC-BPPV). METHODS: Ninety patients with PC-BPPV who met the inclusion criteria were randomly divided into manual reduction control group, acupuncture control group and experimental group, with 30 cases in each group. Epley reduction method was used for manual reduction control treatment of patients in the manual reduction control group, until there was no obvious vertigo of patients. Patients in the acupuncture control group received ordinary acupuncture treatment, while patients in the experiment group received dynamic and static acupuncture treatment, both on the basis of manual reduction control treatment. Baihui(GV20) and Yintang(GV24+), Sanyinjiao(SP6), Zhongzhu(TE3), Houxi(SI3) and Waiguan(TE5) on the healthy side, and the vertigo-auditory area and Fengchi(GB20) on the affected side were selected for acupuncture intervention, which was performed once a day, with needles retained for 30 minutes in two acupuncture groups. Every six times was taken as a session and two sessions were required. Dizziness handicap inventory (DHI) scale and visual analogue score (VAS) were used to evaluate the degree of vertigo before, after 1 and 2 sessions of treatment respectively. RESULTS: Compared with those before treatment, the DHI score and VAS score of each group after 1 and 2 sessions of treatment were both significantly decreased (P<0.05). Compared with the acupuncture control group and the manual reduction control group, the DHI score of the experiment group was significantly decreased (P<0.05) after 1 and 2 sessions of treatment. VAS score of the experiment group was significantly decreased compared with that of the manual reduction control group(P<0.05) after 1 and 2 sessions of treatment. The total effective rate of the experiment group was 86.67%, better than those of the acupuncture control group (83.33%, P<0.05) and the manual reduction control group(66.67%, P<0.05). CONCLUSION: The dynamic and static acupuncture method combined with manual reduction effectively improved vertigo symptoms in PC-BPPV with rapid and lasting effects, which is worthy of further clinical promotion and application.

[Effects of electroacupuncture at "Siguan" points on the expression of colonic 5-hydroxytryptamine and fecal short-chain fatty acids in rats with post-stroke depression].

OBJECTIVE: To observe the effects of electroacupuncture at "Siguan" points on behavior, colonic 5-hydroxytryptamine (5-HT) and fecal short-chain fatty acids (SCFAs) in rats with post-stroke depression (PSD), and explore the effect mechanism of electroacupuncture at Siguan points on PSD. METHODS: Fifty SD rats were randomly divided into a sham-operation group, a stroke group, a PSD group, a drug group and an electroacupuncture group, with 10 rats in each one. The stroke model was established by middle cerebral artery occlusion (MCAO) method in the stroke group; except for the sham-operation group, the rats in the other groups were intervened with MCAO combined with solitary and chronic unpredictable mild stress (CUMS) to establish PSD model. In the electroacupuncture group, electroacupuncture was delivered at "Hegu" (LI 4) and "Taichong" (LR 3), with disperse-dense wave, 2 Hz/10 Hz in frequency, for 30 min in each intervention, once daily, for consecutive 21 days. Simultaneously, distilled water (0.01 L•kg-1•d-1) was administrated intragastrically. Fluoxetine solution (2.33 mg•kg-1•d-1) was given by gavage , once a day and for 21 days in the drug group. The same procedure of fixation and gavage with distilled water were adopted in the sham-operation group, the stroke group and the PSD group. Separately, before stroke modeling, after PSD modeling and after 21-day intervention, the consumption of sugar water and the scores of horizontal movement and vertical movement in open-field test were observed. After 21-day intervention, the content of colonic 5-HT was detected by immunohistochemical method, and that of fecal SCFAs was determined by gas chromatography mass spectrometry. RESULTS: After PSD modeling, compared with the stroke group, the sugar water consumption, the horizontal movement scores and vertical movement scores of the open-field test were all reduced in the PSD group, the drug group and the electroacupuncture group (P<0.05). After 21-day intervention, the sugar water consumption and the scores of horizontal movement and vertical movement of the open-field test were increased in the drug group and the electroacupuncture group (P<0.05) when compared with the PSD group; and the horizontal movement score in the electroacupuncture group was lower than that of the drug group (P<0.05). Compared with the sham-operation group, the contents of total fecal SCFAs and acetic acid were lower in the stroke group (P<0.05), and the contents of colonic 5-HT and total fecal SCFAs, acetic acid, propionic acid and butyric acid were reduced in the PSD group (P<0.05). In comparison with the PSD group, the contents of colonic 5-HT and total fecal SCFAs, acetic acid and propionic acid were increased in the drug group and the electroacupuncture group (P<0.05); and the content of colonic 5-HT in the electroacupuncture group was lower than that of the drug group (P<0.05). The level of colonic 5-HT was positively correlated with the contents of total fecal SCFAs and propionic acid (r=0.424, P=0.005; r=0.427, P=0.004). CONCLUSION: Electroacupuncture at "Siguan" points can relieve the depression-like behavior of PSD rats, and its underlying mechanism may be related to the regulation of fecal SCFAs, which affects the release of colonic 5-HT.

Co-Crystallization between Aliphatic Polyesters through Co-Inclusion Complexation with Small Molecule.

Crystalline/crystalline blends of polymer have shown advantages in the preparation of new polymeric materials. However, the regulation of co-crystallization in a blend is still full of challenges due to the preferential self-crystallization driven by thermodynamics. Here, an inclusion complex approach is proposed to facilitate the co-crystallization between crystalline polymers, because the crystallization process displays a prominent kinetics advantage when polymer chains are released from the inclusion complex. Poly(butylene succinate) (PBS), poly(butylene adipate) (PBA) and urea are chosen to form co-inclusion complexes, where PBS and PBA chains play as isolated guest molecules and urea molecules construct the host channel framework. The coalesced PBS/PBA blends are obtained by fast removing the urea framework and systematically investigated by differential scanning calorimetry, X-ray diffraction, proton nuclear magnetic resonance and Fourier transformation infrared spectrometry. It is demonstrated that PBA chains are co-crystallized into PBS extended-chain crystals in the coalesced blends, while such a phenomenon has not been detected in simply co-solution-blended samples. Though PBA chains could not be totally accommodated in the PBS extended-chain crystals, their co-crystallized content increases with the initial feeding ratio of PBA. Consequently, the melting point of the PBS extended-chain crystal gradually declines from 134.3 °C to 124.2 °C with an increasing PBA content. The PBA chains playing as defects mainly induce lattice expansion along the a-axis. In addition, when the co-crystals are soaked in tetrahydrofuran, some of the PBA chains are extracted out, leading to damage to the correlative PBS extended-chain crystals. This study shows that co-inclusion complexation with small molecules could be an effective way to promote co-crystallization behavior in polymer blends.

USP9X expression is functionally related to laryngeal cancer.

An increasing number of studies have shown that USP9X is closely related to cancer. However, its role in carcinogenesis and progression of laryngeal cancer has not yet been investigated. In this study, we found that USP9X was upregulated in laryngeal cancer tissues. The expression of USP9X was significantly correlated with degree of laryngeal cancer differentiation and lymphatic metastasis. USP9X knockdown led to a decrease in the ability of proliferation, migration, and invasion of FaDu cells. The proportion of FaDu apoptotic cells increased by interfering with the endogenous expression of USP9X. We speculated that inhibiting USP9X might induce apoptosis in FaDu cells by downregulating Mcl-1 and upregulating Bax protein expression. Our findings for the first time suggest the expression level and trend of USP9X in laryngeal cancer tissue and USP9X may plays an important role in promoting the occurrence and progression of laryngeal cancer. USP9X may be a potential target for intervention in treatment of laryngeal cancer.

Rationalizing the Dependence of Poly (Vinylidene Difluoride) (PVDF) Rheological Performance on the Nano-Silica.

Research on the rheological performance and mechanism of polymer nanocomposites (PNCs), mainly focuses on non-polar polymer matrices, but rarely on strongly polar ones. To fill this gap, this paper explores the influence of nanofillers on the rheological properties of poly (vinylidene difluoride) (PVDF). The effects of particle diameter and content on the microstructure, rheology, crystallization, and mechanical properties of PVDF/SiO2 were analyzed, by TEM, DLS, DMA, and DSC. The results show that nanoparticles can greatly reduce the entanglement degree and viscosity of PVDF (up to 76%), without affecting the hydrogen bonds of the matrix, which can be explained by selective adsorption theory. Moreover, uniformly dispersed nanoparticles can promote the crystallization and mechanical properties of PVDF. In summary, the viscosity regulation mechanism of nanoparticles for non-polar polymers, is also applicable to PVDF, with strong polarity, which is of great value for exploring the rheological behavior of PNCs and guiding the process of polymers.

Characterization of welding fume and airborne heavy metals in electronic manufacturing workshops in Hangzhou, China: implication for occupational population exposure.

Occupational exposure to contaminants created by electronic manufacturing process is not well characterized. The aim of this study was to carry out risk assessments of exposure to welding fume and airborne heavy metals (HMs) in electronic manufacturing workshops. Seventy-six air samples were collected from five sites in Hangzhou, China. In welding workshops, the most abundant contaminant found was welding fume, followed by Fe, Mn, Zn, Cu, Pb, Cd, and Cr. The concentration of Mn was positively correlated with Fe (r = 0.906). When compared with non-welding workshops, the Fe content in the air of welding workshops increased significantly (P < 0.05), while the Cu content decreased significantly (P < 0.05). Singapore semi-quantitative health risk assessment model and the United States Environmental Protection Agency (US EPA) inhalation risk assessment model were applied to assess the occupational exposure. In welding workshops, the levels of 8-h time weighted average (8 h-TWA) calculated for welding fume (range 0.288 ~ 6.281 mg/m3), Mn (range Nd ~ 0.829 mg/m3), and Fe (range 0.027 ~ 2.234 mg/m3) partly exceeded the permissible limits. While, in non-welding workshops, the average of 8 h-TWA for Cu (0.411 mg/m3) was higher than the limit. The risk rates (RR) assessed for Pb (2.4 vs 1.7), Mn (2.0 vs 1.4), and Fe (1.4 vs 1.0) were higher in welding workshops than that in non-welding workshops, but Cu (1.0 vs 2.2) were lower. The mean excess lifetime cancer risks (ELCR) in welding (5.59E - 06 per 1000 people) and non-welding (1.88E - 06 per 1000 people) workshops were acceptable. The mean non-cancer risk (HQ) estimated for Mn was greater than 10 in both welding (HQ = 164) and non-welding (HQ = 11.1) workshops. These results indicate that there was a risk of occupational exposure implication in the electronic manufacturing workshops. Reducing contaminant exposure through engineering controls and management strategies, such as efficient ventilation and reducing exposure hours, is thus suggested.

Discovery of Orally Bioavailable FGFR2/FGFR3 Dual Inhibitors via Structure-Guided Scaffold Repurposing Approach.

Fibroblast growth factor receptors (FGFRs) are transmembrane receptor tyrosine kinases that regulate multiple physiological processes. Aberrant activation of FGFR2 and FGFR3 has been linked to the pathogenesis of many tumor types, including cholangiocarcinoma and bladder cancer. Current therapies targeting the FGFR2/3 pathway exploiting small-molecule kinase inhibitors are associated with adverse events due to undesirable inhibition of FGFR1 and FGFR4. Isoform-specific FGFR2 and FGFR3 inhibitors that spare FGFR1 and FGFR4 could offer a favorable toxicity profile and improved therapeutic window to current treatments. Herein we disclose the discovery of dual FGFR2/FGFR3 inhibitors exploiting scaffold repurposing of a previously reported ALK2 tool compound. Structure-based drug design and structure-activity relationship studies were employed to identify selective and orally bioavailable inhibitors with equipotent activity toward wild-type kinases and a clinically observed gatekeeper mutant.

Discovery of Pyrazolopyridine Derivatives as HPK1 Inhibitors.

In spite of the great success of immune checkpoint inhibitors in immune-oncology therapy, an urgent need still exists to identify alternative approaches to broaden the scope of therapeutic coverage. Hematopoietic progenitor kinase 1 (HPK1), also known as MAP4K1, functions as a negative regulator of activation signals generated by the T cell antigen receptor. Herein we report the discovery of novel pyrazolopyridine derivatives as selective inhibitors of HPK1. The structure-activity relationship campaign led to the discovery of compound 16, which has shown promising enzymatic and cellular potency with encouraging kinome selectivity. The outstanding pharmacokinetic profiles of 16 in rats and monkeys supported further evaluations of its efficacy and safety in preclinical models.