Optimal Treatment Parameters for Ultrasound-Stimulated Microbubbles in Upregulating Proliferation and Stemness of Bone Marrow Mesenchymal Stem Cells.

OBJECTIVES: Ultrasound-targeted microbubble disruption (UTMD) is a widely used technique to improve the differentiation and proliferation capacity of mesenchymal stem cells (MSCs), but the optimal therapeutic parameters for UTMD are unclear. In this study, we aimed to find the appropriate peak negative pressure (PNP), which is a key parameter for enhancing the stemness properties and proliferation of MSCs. METHODS: Experiments were performed in UTMD group, ultrasound (US) group under different PNP exposure conditions (0.5, 1.0, and 1.5 MPa), and control group. Apoptosis safety was analyzed by flow cytometry and MSC proliferation was measured at 12, 24, and 36 hours after irradiation by cell counting kit 8. The expression of the stemness genes NANOG, OCT-4, and SOX-2 were determined by enzyme-linked immunosorbent assay (ELISA) or reverse transcription polymerase chain reaction. RESULTS: The results showed that the 1.5 MPa UTMD-treated group had the highest proliferation capacity of MSCs at 24 hours. ELISA or quantitative reverse transcription polymerase chain reaction results showed that UTMD treatment of the 1.5 MPa group significantly upregulated the expression of the stemness genes NANOG, SOX-2, and OCT-4. CONCLUSIONS: In conclusion, the appropriate peak PNP value of UTMD was 1.5 MPa, and 1.5 MPa-mediated UTMD group obviously promoted MSCs proliferation and maintained stemness by upregulating the expression of stemness genes.

Chloroplast envelope ATPase PGA1/AtFtsH12 is required for chloroplast protein accumulation and cytosol-chloroplast protein homeostasis in Arabidopsis.

The establishment of photosynthetic protein complexes during chloroplast development requires the influx of a large number of chloroplast proteins that are encoded by the nuclear genome, which is critical for cytosol and chloroplast protein homeostasis and chloroplast development. However, the mechanisms regulating this process are still not well understood in higher plants. Here, we report the isolation and characterization of the pale green Arabidopsis pga1-1 mutant, which is defective in chloroplast development and chloroplast protein accumulation. Using genetic and biochemical evidence, we reveal that PGA1 encodes AtFtsH12, a chloroplast envelope-localized protein of the FtsH family proteins. We determined a G703R mutation in the GAD motif of the conserved ATPase domain renders the pga1-1 a viable hypomorphic allele of the essential gene AtFtsH12. In de-etiolation assays, we showed that the accumulation of photosynthetic proteins and the expression of photosynthetic genes were impaired in pga1-1. Using the FNRctp-GFP and pTAC2-GFP reporters, we demonstrated that AtFtsH12 was required for the accumulation of chloroplast proteins in vivo. Interestingly, we identified an increase in expression of the mutant AtFtsH12 gene in pga1-1, suggesting a feedback regulation. Moreover, we found that cytosolic and chloroplast proteostasis responses were triggered in pga1-1. Together, taking advantage of the novel pga1-1 mutant, we demonstrate the function of AtFtsH12 in chloroplast protein homeostasis and chloroplast development.

Feasibility and tolerability of sintilimab plus anlotinib as the second-line therapy for patients with advanced biliary tract cancers: An open-label, single-arm, phase II clinical trial.

Patients with biliary tract cancer (BTC) were associated with poor prognosis and limited therapeutic options after first-line therapy currently. In this study, we sought to evaluate the feasibility and tolerability of sintilimab plus anlotinib as the second-line treatment for patients with advanced BTC. Eligible patients had histologically confirmed locally advanced unresectable or metastatic BTC and failed after the first-line treatment were recruited. The primary endpoint was overall survival (OS). Simultaneously, association between clinical outcomes and genomic profiling and gut microbiome were explored to identify the potential biomarkers for this regimen. Twenty patients were consecutively enrolled and received study therapy. The trail met its primary endpoint with a median OS of 12.3 months (95% CI: 10.1-14.5). Only four (20%) patients were observed of the grade 3 treatment-related adverse events (TRAEs) and no grade 4 or 5 TRAEs were detected. Mutation of AGO2 was correlated with a significantly longer OS. Abundance of Proteobacteria was associated with inferior clinical response. Therefore, sintilimab plus anlotinib demonstrated encouraging anti-tumor activity with a tolerable safety profile and deserved to be investigated in larger randomized trials for patients with advanced BTC subsequently.

Recombinant human bone morphogenetic protein is a valid alternative to autologous bone graft for long bone non-unions: a systematic review and meta-analysis.

OBJECTIVE: To compare the efficacy of recombinant human bone morphogenetic proteins (rhBMPs) and autologous bone graft (ABG) on the healing of long bone non-union. METHODS: A systematic literature search was conducted on PubMed, Web of Science, Cochrane Library, and CNKI up to December 2021. Two authors independently screened the studies, extracted data, and assessed the quality of the trials. A Meta-analysis was performed using state software (version 12.0). RESULTS: A total of 14 studies were included in this meta-analysis. Overall, there was no significant difference between the rhBMPs group and the ABG group in terms of healing rate (RR = 1.04, 95% CI = 0.96-1.12, p = 0.365) and healing time (SMD = -0.31, 95% CI = -0.76-0.14, p = 0.175). Subgroup analysis showed rhBMPs lead to higher healing rates (RR = 1.35, 95% CI = 1.17-1.56, p < 0.001), and shorter healing time (SMD = -0.65, 95% CI = -1.08 to -0.22, p = 0.003) in the subgroup of moderate-quality studies. Sensitivity analysis proved that our conclusions were relatively robust. No significant publication bias was recognized in all studies (Begg's test, p = 0.193; Egger's test, p = 0.307). CONCLUSIONS: RhBMPs or combined with allografts bone, inorganic bone was a valid alternative to ABG for the treatment of long bone non-union.

VAR2/AtFtsH2 and EVR2/BCM1/CBD1 synergistically regulate the accumulation of PSII reaction centre D1 protein during de-etiolation in Arabidopsis.

Thylakoid FtsH complex participates in PSII repair cycle during high light-induced photoinhibition. The Arabidopsis yellow variegated2 (var2) mutants are defective in the VAR2/AtFtsH2 subunit of thylakoid FtsH complex. Taking advantage of the var2 leaf variegation phenotype, dissections of genetic enhancer loci have yielded novel paradigms in understanding functions of thylakoid FtsH complex. Here, we report the isolation of a new var2 enhancer, enhancer of variegation2-1 (evr2-1). We confirmed that EVR2 encodes a chloroplast protein that was known as BALANCE OF CHLOROPHYLL METABOLISM 1 (BCM1), or CHLOROPHYLL BIOSYNTHETIC DEFECT 1 (CBD1). We showed that EVR2/BCM1/CBD1 was involved in the oligomerization of photosystem I complexes. Genetic assays indicated that general defects in chlorophyll biosynthesis and the accumulation of photosynthetic complexes do not necessarily enhance var2 leaf variegation. In addition, we found that VAR2/AtFtsH2 is required for the accumulation of photosynthetic proteins during de-etiolation. Moreover, we identified PSII core proteins D1 and PsbC as potential EVR2-associated proteins using Co-IP/MS. Furthermore, the accumulation of D1 protein was greatly compromised in the var2-5 evr2-1 double mutant during de-etiolation. Together, our findings reveal a functional link between VAR2/AtFtsH2 and EVR2/BCM1/CBD1 in regulating chloroplast development and the accumulation of PSII reaction centre D1 protein during de-etiolation.

Glycogen metabolism reprogramming promotes inflammation in coal dust-exposed lung.

Long-term coal dust exposure triggers complex inflammatory processes in the coal workers' pneumoconiosis (CWP) lungs. The progress of the inflammation is reported to be affected by disordered cell metabolism. However, the changes in the metabolic reprogramming associated with the pulmonary inflammation induced by the coal dust particles are unknown. Herein, we show that coal dust exposure causes glycogen accumulation and the reprogramming of glucose metabolism in the CWP lung. The glycogen accumulation caused by coal dust is mainly due to macrophages, which reprogram glycogen metabolism and trigger an inflammatory response. In addition, 2-deoxy-D-glucose (2-DG) reduced glycogen content in macrophages, which was accompanied by mitigated inflammation and restrained NF-κB activation. Accordingly, we have pinpointed a novel and crucial metabolic pathway that is an essential regulator of the inflammatory phenotype of coal dust-exposed macrophages. These results shed light on new ways to regulate CWP inflammation.

Five New Polyoxypregnane Glycosides from the Vines of Aspidopterysobcordata and Their Antinephrolithiasis Activity.

From the dried vines of Aspidopterys obcordata Hemsl, five new polyoxypregnane glycosides, named obcordatas J-N (1-5), were obtained. Their structures were fully elucidated and characterized by HRESIMS and extensive spectroscopic data. In addition, all of the new compounds were screened for their antinephrolithiasis activity in vitro. The results showed that compounds 1-3 have prominent protective effects on calcium oxalate crystal-induced human kidney 2 (HK-2) cells, with EC50 values ranging from 6.72 to 14.00 µM, which is consistent with the application value of A. obcordata in folk medicine for kidney stones.

Occupational Commitment of Chinese Kindergarten Teachers During the COVID-19 Pandemic: Predictions of Anti-Epidemic Action, Income Reduction, and Career Confidence.

This study highlights a survey on 5783 kindergarten teachers' occupational commitment and its influencing factors in the socioeconomic context of China during the COVID-19 pandemic. Data were collected through the WenJuanXing public online platform. Quantitative analysis results showed that kindergarten teachers' occupational commitment was optimistic on the whole during this period, among which the affective commitment and the normative commitment were satisfactory, but the continuing commitment needed to be strengthened. The type of kindergartens, the personnel affiliation, the educational background, and the professional post of kindergarten teachers had significant impacts on their occupational commitment. The income reduction was negatively correlated with and predictive of kindergarten teachers' occupational commitment. Anti-epidemic action and career confidence were positively correlated with and predictive of kindergarten teachers' occupational commitment. Furthermore, anti-epidemic action, income reduction, and career confidence had joint predictive effects on kindergarten teachers' occupational commitment. More related backgrounds and suggestions have been discussed.

Correction to: Ready player one? Autophagy shapes resistance to photodynamic therapy in cancers.

The below funding information was not submitted and hence not included in the original publication. The funding information is given below.

Comparison of clinical outcomes of laparoscopic versus open surgery for recurrent hepatocellular carcinoma: a meta-analysis.

BACKGROUND: The purpose of this study is to compare the clinical outcomes of laparoscopic liver resection versus open liver resection for recurrent hepatocellular carcinoma (RHCC). METHODS: Published studies which investigated laparoscopic versus open liver resection for RHCC were identified, and meta-analysis was used for statistical analysis. RESULTS: Six studies were analyzed by meta-analysis method, and cumulative 335 cases were included in this study. Laparoscopic liver resection was performed in 145 cases, and open liver resection was performed in 190 cases. Meta-analysis showed that there was no difference in operative time and 90-day mortality between the laparoscopic group and the open group (p = 0.06 and p = 0.06 respectively); Nevertheless, compared with the open group, the laparoscopic group resulted in significantly lower rate of in-hospital complication (p < 0.0001), much less blood loss (p < 0.0001) and shorter postoperative hospital stay (p = 0.002). CONCLUSION: Laparoscopic liver resection for RHCC offers a benefit of lower in-hospital complication rate, less blood loss, shorter postoperative hospital stay, while similar operative time and 90-day mortality as the open liver resection. Laparoscopic liver resection is feasible with satisfactory postoperative outcomes and can be a safe alternative treatment strategy to open procedure for RHCC.

[Research progress in endoscopic retrograde cholangiopancreatography-mediated photodynamic therapy for cholangiocarcinoma].

The malignant degree of cholangiocarcinoma is high, and the early diagnosis is difficult. The vast majority of patients are unresectable when they are diagnosed. The patients have low quality of life and short survival cycle. Traditional radiotherapy and chemotherapy have poor efficacy and lead to side effects, and thus lack effective control measures for cholangiocarcinoma. Endoscopic retrograde cholangiopancreatography (ERCP) is an important method for diagnosing and treating biliary tract diseases. Photodynamic therapy (PDT) is a new local treatment for cholangiocarcinoma. In recent years, ERCP-mediated PDT treatment of cholangiocarcinoma has gradually emerged. ERCP-mediated PDT can effectively relieve the symptoms of patients with cholangiocarcinoma, improve the patients' quality of life, prolong the survival cycle, and is expected to become a new treatment for cholangiocarcinoma.

Ready player one? Autophagy shapes resistance to photodynamic therapy in cancers.

Photodynamic therapy (PDT) is a procedure used in cancer therapy that has been shown to be useful for certain indications. Considerable evidence suggests that PDT might be superior to conventional modalities for some indications. In this report, we examine the relationship between PDT responsiveness and autophagy, which can exert a cytoprotective effect. Autophagy is an essential physiological process that maintains cellular homeostasis by degrading dysfunctional or impaired cellular components and organelles via a lysosome-based pathway. Autophagy, which includes macroautophagy and microautophagy, can be a factor that decreases or abolishes responses to various therapeutic protocols. We systematically discuss the mechanisms underlying cell-fate decisions elicited by PDT; analyse the principles of PDT-induced autophagy, macroautophagy and microautophagy; and present evidence to support the notion that autophagy is a critical mechanism in resistance to PDT. A combined strategy involving autophagy inhibitors may be able to further enhance PDT efficacy. Finally, we provide suggestions for future studies, note where our understanding of the relevant molecular regulators is deficient, and discuss the correlations among PDT-induced resistance and autophagy, especially microautophagy.

Segmented waveguide photodetector with 90% quantum efficiency.

We demonstrate a novel InGaAsP/InP segmented waveguide photodetector based on directional couplers. By matching the imaginary parts of the propagation constants of the even and odd modes, we designed a photodetector with 6 elements, each with an absorber volume of only 19 µm3 and a bandwidth of 15 GHz, that has an internal quantum efficiency (QE) of 90% at 1550 nm wavelength corresponding to 1.13 A/W.

Low dark current III-V on silicon photodiodes by heteroepitaxy.

Top-illuminated PIN and modified uni-traveling carrier (MUTC) photodiodes based on InGaAs/InAlAs/InP were epitaxially grown on Si templates. Photodiodes with 30-µm diameter have dark currents as low as 10 nA at 3 V corresponding to a dark current density of only 0.8 mA/cm2. The responsivity, 3-dB bandwidth, output power and third-order output intercept point (OIP3) were 0.79 A/W, 9 GHz, 2.6 dBm and 15 dBm, respectively.

A Comparative Study of Albumin-Bilirubin Score with Child-Pugh Score, Model for End-Stage Liver Disease Score and Indocyanine Green R15 in Predicting Posthepatectomy Liver Failure for Hepatocellular Carcinoma Patients.

BACKGROUND: The albumin-bilirubin (ALBI) grade is a newly proposed model for assessing the hepatic function. This study aimed to compare the value of the ALBI score with Child-Pugh score, model for end-stage liver disease (MELD) score and indocyanine green (ICG) R15 in predicting posthepatectomy liver failure (PHLF). METHODS: Patients undergoing curative resection for hepatocellular carcinoma (HCC) between January 2014 and June 2017 were enrolled. The values of the Child-Pugh score, MELD score, ICG R15 and ALBI score in predicting PHLF were evaluated. RESULTS: A total of 473 HCC patients were enrolled. The ALBI score was identified as an independent predictor of PHLF. The AUCs for the Child-Pugh score, MELD score, ICG R15 and ALBI score in predicting PHLF were 0.665, 0.649, 0.668, and 0.745 respectively. Multivariable analyses revealed that the ALBI score was an independent predictor of PHLF regardless of the hepatectomy subgroups, but the Child-Pugh score and MELD score were not significant predictors of PHLF both in major and minor hepatectomy subgroups, and ICG R15 was only a significant predictor of PHLF in minor hepatectomy subgroup. CONCLUSION: The ALBI score showed superior predictive value of PHLF over Child-Pugh score, MELD score and ICG R15. We propose to use the ALBI score to evaluate surgical risk for HCC patients undergoing hepatic resection.

Ability of the ALBI grade to predict posthepatectomy liver failure and long-term survival after liver resection for different BCLC stages of HCC.

BACKGROUND: Underlying liver function is a major concern when applying surgical resection for hepatocellular carcinoma (HCC). We aimed to explore the capability of the albumin-bilirubin (ALBI) grade to predict post-hepatectomy liver failure (PHLF) and long-term survival after hepatectomy for HCC patients with different Barcelona Clinic Liver Cancer (BCLC) stages. METHODS: Between January 2010 and December 2014, 338 HCC patients who were treated with liver resection were enrolled. The predictive accuracy of ALBI grade system for PHLF and long-term survival across different BCLC stages was examined. RESULTS: A total of 26 (7.7%) patients developed PHLF. Patients were divided into BCLC 0/A and BCLC B/C categories. ALBI score was found to be a strong independent predictor of PHLF across different BCLC stages by multivariate analysis. In terms of overall survival (OS), it exhibited high discriminative power in the total cohort and in BCLC 0/A subgroup. However, differences in OS between ALBI grade 1 and 2 patients in BCLC B/C subgroup were not significant (P = 0.222). CONCLUSION: The ALBI grade showed good predictive ability for PHLF in HCC patients across different BCLC stages. However, the ALBI grade was only a significant predictor of OS in BCLC stage 0/A patients and failed to predict OS in BCLC stage B/C patients.

PAI1: a novel PP1-interacting protein that mediates human plasma's anti-apoptotic effect in endothelial cells.

Activation of apoptotic signalling in endothelial cells contributes to the detrimental effects of a variety of pathological stimuli. In investigating the molecular events underlying the anti-apoptotic effect of human plasma in cultured human endothelial cells, we unexpectedly uncovered a novel mechanism of apoptosis suppression by human plasma through an interaction between two previously unrelated proteins. Human plasma inhibited hypoxia-serum deprivation-induced apoptosis and stimulated BADS136 and AktS473 phosphorylation. Akt1 silencing reversed part (~52%) of the anti-apoptotic effect of human plasma, suggesting the existence of additional mechanisms mediating the anti-apoptotic effect other than Akt signalling. Human plasma disrupted the interaction of BAD with protein phosphatase 1 (PP1). Mass spectrometry identified fourteen PP1-interacting proteins induced by human plasma. Notably, a group of serine protease inhibitors including plasminogen activator inhibitor 1 (PAI1), a major inhibitor of fibrinolysis, were involved. Silencing of PAI1 attenuated the anti-apoptotic effect of human plasma. Furthermore, combined Akt1 and PAI1 silencing attenuated the majority of the anti-apoptotic effect of human plasma. We conclude that human plasma protects against endothelial cell apoptosis through sustained BAD phosphorylation, which is achieved by, at least in part, a novel interaction between PP1 with PAI1.

[Role of PpIX-based photodynamic therapy in promoting the damage and apoptosis of colorectal cancer cell and its mechanisms].

OBJECTIVE: To explore the effects of protoporphyrin IX (PpIX)-mediated photodynamic therapy (PDT) on induction of apoptosis and death in colon cancer cell and the underlying mechanisms.
 Methods: The cell killing effect of PDT on HCT116 cell was determined by cell counting kit (CCK). The cells were divided into a control group, a single light group, a single PpIX group, and a PDT group. Hoechst 33342 and flow cytometry was used to assess the cell apoptosis. Western blot was employed to analyze the expressions of bcl-2, bax, and caspase-3. Reactive oxygen species (ROS) was detected by flow cytometry.
 Results: The viability of HCT116 cell was decreased gradually with the increase of irradiation dose (P<0.05). Compared to the other 3 groups, ROS production, the number of apoptotic cells and the protein expressions of bax and caspase-3 in PDT group increased, while bcl-2 expression was decreased (P<0.05).
 Conclusion: PpIX-mediated PDT can enhance the apoptosis in HCT116 cell, which may be related to mitochondrial apoptosis pathway.

Interferon-α and cyclooxygenase-2 inhibitor cooperatively mediates TRAIL-induced apoptosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Interferon-alpha (IFN-α) has recently been recognized to harbor therapeutic potential in the prevention and treatment of HCC, but it remains controversial as to whether IFN-α exerts direct cytotoxicity against HCC. Cyclooxygenase-2 (COX-2) is overexpressed in HCC and is considered to play a role in hepatocarcinogenesis. Therefore, we aimed to elucidate the combined effect of a COX-2 inhibitor, celecoxib, and IFN-α on in vitro growth suppression of HCC using the hepatoma cell line HLCZ01 and the in vivo nude mouse xenotransplantation model using HLCZ01 cells. Treatment with celecoxib and IFN-α synergistically inhibited cell proliferation in a dose- and time-dependent manner. Apoptosis was identified by 4׳,6-diamidino-2-phenylindole dihydrochloride and fluorescent staining. IFN-α upregulated the expression of TRAIL, while celecoxib increased the expression of TRAIL receptors. The combined regimen with celecoxib and IFN-α reduced the growth of xenotransplanted HCCs in nude mice. The regulation of IFN-α- and COX-2 inhibitor-induced cell death is impaired in a subset of TRAIL-resistant cells. The molecular mechanisms of HCC cells resistant to TRAIL-induced apoptosis were explored using molecular biological and immunological methods. Interferon-α and the COX-2 inhibitor celecoxib synergistically increased TRAIL-induced apoptosis in hepatocellular carcinoma. These data suggest that IFN-α and celecoxib may offer a novel role with important implications in designing new therapeutics for TRAIL-resistant tumors.

The location of Modic changes in the lumbar spine: a meta-analysis.

PURPOSE: This meta-analysis was to study the location of Modic changes in the lumbar spine. METHODS: The electronic databases including MEDLINE, Web of science, Cochrane Central Register of Controlled Trials, OVID, CBM were searched. Relevant studies that described the patients with Modic Changes were included. Data were extracted and analysed using the version 12.0 STATA software. RESULTS: Thirty-one studies were selected and analyzed (2346 total patients). No significant differences of the incidence of MC were identified between superior and the inferior end plates adjacent to discs [RR = 1.04, 95 % CI (0.74, 1.53)], the same result was detected for the distribution of MC type I between L4/5 and L5/S1 [RR = 0.80, 95 % CI (0.64, 1.02)]. While lower lumbar spine (L4/5, L5/S1) had significant greater incidence of MC [RR = 0.20, 95 % CI (0.15, 0.25)], especially in L5/S1 [RR = 0.82, 95 % CI (0.72, 0.92)]. For MC type II, it also significantly appeared in L5/S1 [RR = 0.80, 95 % CI (0.67, 0.95), P = 0.010]. CONCLUSIONS: In this study, Modic Changes was more common in the lowest two levels, especially in L5/S1. Additionally, the sub-types (type I and type II) were also more likely to appear in L5/S1. It appeared that there existed a correlation between MC and biomechanics. And it seemed that local biomechanical stress might contributed to the distribution of MC and the conversion of type I to type II for the patients treated conservatively.