Successful Outcome of a Patient with Concomitant Pancreatic and Renal Carcinoma Receiving Secoisolariciresinol Diglucoside Therapy Alone: A Case Report.

Introduction: Pancreatic cancer (PC) is among the deadliest malignancies. Kidney cancer (KC) is a common malignancy globally. Chemo- or radio-therapies are not very effective to control PC or KC, and overdoses often cause severe site reactions to the patients. As a result, novel treatment strategies with high efficacy but without toxic side effects are urgently desired. Secoisolariciresinol diglucoside (SDG) belongs to plant lignans with potential anticancer activities, but clinical evidence is not available in PC or KC treatment. Patient Concerns: We report a rare case of an 83-year-old female patient with pancreatic and kidney occupying lesions that lacked the conditions to receive surgery or chemo- or radiotherapy. Diagnosis: Pancreatic and kidney cancers. Interventions: We gave dietary SDG to the patient as the only therapeutics. Outcomes: SDG effectively halted progression of both PC and KC. All clinical manifestations, including bad insomnia, loss of appetite, stomach symptoms, and skin itching over the whole body, all disappeared. The initial massive macroscopic hematuria became microscopic and infrequent, and other laboratory results also gradually returned to normal. Most of the cancer biomarkers, initially high such as CEA, CA199, CA724, CA125, came down rapidly, among which CA199 changed most radically. This patient has had progression-free survival of one year so far. Conclusion: These results demonstrate the potent inhibitory effects of SDG on PC and KC of this patient and provide promising novel therapeutics for refractory malignant tumors.

The origin of different bending stiffness between double-stranded RNA and DNA revealed by magnetic tweezers and simulations.

The subtle differences in the chemical structures of double-stranded (ds) RNA and DNA lead to significant variations in their biological roles and medical implications, largely due to their distinct biophysical properties, such as bending stiffness. Although it is well known that A-form dsRNA is stiffer than B-form dsDNA under physiological salt conditions, the underlying cause of this difference remains unclear. In this study, we employ high-precision magnetic-tweezer experiments along with molecular dynamics simulations and reveal that the relative bending stiffness between dsRNA and dsDNA is primarily determined by the structure- and salt-concentration-dependent ion distribution around their helical structures. At near-physiological salt conditions, dsRNA shows a sparser ion distribution surrounding its phosphate groups compared to dsDNA, causing its greater stiffness. However, at very high monovalent salt concentrations, phosphate groups in both dsRNA and dsDNA become fully neutralized by excess ions, resulting in a similar intrinsic bending persistence length of approximately 39 nm. This similarity in intrinsic bending stiffness of dsRNA and dsDNA is coupled to the analogous fluctuations in their total groove widths and further coupled to the similar fluctuation of base-pair inclination, despite their distinct A-form and B-form helical structures.

[Dumai moxibustion combined with low-dose tadalafil for erectile dysfunction: Evaluation of therapeutic effect].

OBJECTIVE: To investigate the clinical effect of dumai (governor meridian) moxibustion combined with low-dose tadalafil in the treatment of ED with decline of vital gate fire. METHODS: We enrolled in this study 130 ED patients with decline of vital gate fire who met the inclusion criteria and equally randomized them into a control and an experimental group, the former treated with low-dose tadalafil tablets at 5 mg once a day while the latter by dumai moxibustion once a week in addition, all for 4 weeks. Of the total number of subjects, 62 in the control group and 63 in the experimental group completed the experiment. We recorded the scores on IIEF-5, Erection Quality Scale (EQS), Erection Hardness Scale (EHS), TCM symptoms and Treatment Satisfaction Scale (TSS) as well as the penile hemodynamic parameters peak systolic velocity (PSV), end diastolic velocity (EDV) and resistance index (RI) before and after treatment and compared them between the two groups. RESULTS: The total response rate was significantly higher in the experimental group than in the control (87.30% vs 66.13%, P < 0.05). IIEF-5, EQS, EHS and TSS scores, PSV and RI were markedly increased while TCM symptoms and EDV remarkably decreased in both groups after treatment (P < 0.05), even more significantly in the experimental than in the control group (P < 0.05). CONCLUSION: Dumai moxibustion combined with low-dose tadalafil can improve erectile function, increase penile blood flow velocity and alleviate clinical symptoms in ED patients with decline of vital gate fire, with definite clinical effect and safety.

A mutation-sensitive, multiplexed and amplification-free detection of nucleic acids by stretching single-molecule tandem hairpin probes.

The detection of nucleic acid sequences in parallel with the discrimination of single nucleotide variations (SNVs) is critical for research and clinical applications. A few limitations make the detection technically challenging, such as too small variation in probe-hybridization energy caused by SNVs, the non-specific amplification of false nucleic acid fragments and the few options of dyes limited by spectral overlaps. To circumvent these limitations, we developed a single-molecule nucleic acid detection assay without amplification or fluorescence termed THREF (hybridization-induced tandem DNA hairpin refolding failure) based on multiplexed magnetic tweezers. THREF can detect DNA and RNA sequences at femtomolar concentrations within 30 min, monitor multiple probes in parallel, quantify the expression level of miR-122 in patient tissues, discriminate SNVs including the hard-to-detect G-U or T-G wobble mutations and reuse the probes to save the cost. In our demonstrative detections using mock clinic samples, we profiled the let-7 family microRNAs in serum and genotyped SARS-CoV-2 strains in saliva. Overall, the THREF assay can discriminate SNVs with the advantages of high sensitivity, ultra-specificity, multiplexing, reusability, sample hands-free and robustness.

Enterolactone and trabectedin suppress epithelial ovarian cancer synergistically via upregulating THBS1.

Epithelial ovarian cancer (EOC) is the most common and fatal subtype of ovarian malignancies, with no effective therapeutics available. Our previous studies have demonstrated extraordinary suppressive efficacy of enterolactone (ENL) on EOC. A chemotherapeutic agent, trabectedin (Trabe), is shown to be effective on ovarian cancer, especially when combined with other therapeutics, such as pegylated liposomal doxorubicin or oxaliplatin. Thrombospondin 1 (THBS1), a kind of matrix glycoprotein, plays important roles against cancer development through inhibiting angiogenesis but whether it is involved in the suppression of EOC by ENL or Trabe remains unknown. To test combined suppressive effects of ENL and Trabe on EOC and possible involvement of THBS1 in the anticancer activities of ENL and Trabe. The EOC cell line ES-2 was transfected with overexpressed THBS1 by lentivirus vector. We employed tube formation assay to evaluate the anti-angiogenesis activity of ENL and of its combined use with Trabe after THBS1 overexpression and established drug intervention and xenograft nude mouse cancer models to assess the in vivo effects of the hypothesized synergistic suppression between the agents and the involvement of THBS1. Mouse fecal samples were collected for 16S rDNA sequencing and microbiota analysis. We detected strong inhibitory activities of ENL and Trabe against the proliferation and migration of cancer cells and observed synergistic effects between ENL and Trabe in suppressing EOC. ENL and Trabe, given either separately or in combination, could suppress the tube formation capability of human microvascular endothelial cells, and this inhibitory effect became even stronger with THBS1 overexpression. In the ENL plus Trabe combination group, the expression of tissue inhibitor of metalloproteinases 3 and cluster of differentiation 36 was both upregulated, whereas matrix metalloproteinase 9, vascular endothelial growth factor, and cluster of differentiation 47 were all decreased. With the overexpression of THBS1, the results became even more pronounced. In animal experiments, combined use of ENL and Trabe showed superior inhibitory effects to either single agent and significantly suppressed tumor growth, and the overexpression of THBS1 further enhanced the anti-cancer activities of the drug combination group. ENL and Trabe synergistically suppress EOC and THBS1 could remarkably facilitate the synergistic anticancer effects of ENL and Trabe.

Genome-wide association analysis for grain moisture content and dehydration rate on maize hybrids.

For mechanized maize production, a low grain water content (GWC) at harvest is necessary. However, as a complex quantitative trait, understand the genetic mechanism of GWC remains a large gap, especially in hybrids. In this study, a hybrid population through two environments including 442 F1 was used for genome-wide association analysis of GWC and the grain dehydration rate (GDR), using the area under the dry down curve (AUDDC) as the index. Then, we identified 19 and 17 associated SNPs for GWC and AUDDC, including 10 co-localized SNPs, along with 64 and 77 pairs of epistatic SNPs for GWC and AUDDC, respectively. These loci could explain 11.39-68.2% of the total phenotypic variation for GWC and 41.07-67.02% for AUDDC at different stages, whose major effect was the additive and epistatic effect. By exploring the candidate genes around the significant sites, a total of 398 and 457 possible protein-coding genes were screened, including autophagy pathway and auxin regulation-related genes, and five inbred lines with the potential to reduce GWC in the combined F1 hybrid were identified. Our research not only provides a certain reference for the genetic mechanism analysis of GWC in hybrids but also provides an added reference for breeding low-GWC materials. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-022-01349-x.

Fecal microbiota transplantation inhibits colorectal cancer progression: Reversing intestinal microbial dysbiosis to enhance anti-cancer immune responses.

Many lines of evidence demonstrate the associations of colorectal cancer (CRC) with intestinal microbial dysbiosis. Recent reports have suggested that maintaining the homeostasis of microbiota and host might be beneficial to CRC patients, but the underlying mechanisms remain unclear. In this study, we established a CRC mouse model of microbial dysbiosis and evaluated the effects of fecal microbiota transplantation (FMT) on CRC progression. Azomethane and dextran sodium sulfate were used to induce CRC and microbial dysbiosis in mice. Intestinal microbes from healthy mice were transferred to CRC mice by enema. The vastly disordered gut microbiota of CRC mice was largely reversed by FMT. Intestinal microbiota from normal mice effectively suppressed cancer progression as assessed by measuring the diameter and number of cancerous foci and significantly prolonged survival of the CRC mice. In the intestine of mice that had received FMT, there were massive infiltration of immune cells, including CD8+ T and CD49b+ NK, which is able to directly kill cancer cells. Moreover, the accumulation of immunosuppressive cells, Foxp3+ Treg cells, seen in the CRC mice was much reduced after FMT. Additionally, FMT regulated the expressions of inflammatory cytokines in CRC mice, including down-regulation of IL1a, IL6, IL12a, IL12b, IL17a, and elevation of IL10. These cytokines were positively correlated with Azospirillum_sp._47_25, Clostridium_sensu_stricto_1, the E. coli complex, Akkermansia, Turicibacter, and negatively correlated with Muribaculum, Anaeroplasma, Candidatus_Arthromitus, and Candidatus Saccharimonas. Furthermore, the repressed expressions of TGFb, STAT3 and elevated expressions of TNFa, IFNg, CXCR4 together promoted the anti-cancer efficacy. Their expressions were positively correlated with Odoribacter, Lachnospiraceae-UCG-006, Desulfovibrio, and negatively correlated with Alloprevotella, Ruminococcaceae UCG-014, Ruminiclostridium, Prevotellaceae UCG-001 and Oscillibacter. Our studies indicate that FMT inhibits the development of CRC by reversing gut microbial disorder, ameliorating excessive intestinal inflammation and cooperating with anti-cancer immune responses.

Universality in RNA and DNA deformations induced by salt, temperature change, stretching force, and protein binding.

Nucleic acid deformations play important roles in many biological processes. The physical understanding of nucleic acid deformation by environmental stimuli is limited due to the challenge in the precise measurement of RNA and DNA deformations and the complexity of interactions in RNA and DNA. Magnetic tweezers experiments provide an excellent opportunity to precisely measure DNA and RNA twist changes induced by environmental stimuli. In this work, we applied magnetic tweezers to measure double-stranded RNA twist changes induced by salt and temperature changes. We observed RNA unwinds when lowering salt concentration, or increasing temperature. Our molecular dynamics simulations revealed the mechanism: lowering salt concentration or increasing temperature enlarges RNA major groove width, which causes twist decrease through twist-groove coupling. Combining these results with previous results, we found some universality in RNA and DNA deformations induced by three different stimuli: salt change, temperature, and stretching force. For RNA, these stimuli first modify the major groove width, which is transduced into twist change through twist-groove coupling. For DNA, these stimuli first modify diameter, which is transduced into twist change through twist-diameter coupling. Twist-groove coupling and twist-diameter coupling appear to be utilized by protein binding to reduce DNA and RNA deformation energy cost upon protein binding.

ZYG11B potentiates the antiviral innate immune response by enhancing cGAS-DNA binding and condensation.

As a key dsDNA recognition receptor, cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) plays a vital role in innate immune responses. Activated cGAS, by sensing DNA, catalyzes the synthesis of the secondary messenger cyclic GMP-AMP (cGAMP), which subsequently activates downstream signaling to induce production of interferons and inflammatory cytokines. Here, we report Zyg-11 family member B (ZYG11B) as a potent amplifier in cGAS-mediated immune responses. Knockdown of ZYG11B impairs production of cGAMP and subsequent transcription of interferon and inflammatory cytokines. Mechanistically, ZYG11B enhances cGAS-DNA binding affinity, potentiates cGAS-DNA condensation, and stabilizes the cGAS-DNA condensed complex. Moreover, herpes simplex virus 1 (HSV-1) infection induces ZYG11B degradation in a cGAS-unrelated manner. Our findings not only reveal an important role of ZYG11B in the early stage of DNA-induced cGAS activation but also indicate a viral strategy to dampen the innate immune response.

[Effects of heat-reinforcing needling on synovial inflammation and miR-155/TLR4/NF-κB signaling axis in rheumatoid arthritis rabbits with cold syndrome].

OBJECTIVE: To observe the effects of heat-reinforcing needling on synovial inflammation and microRNA-155 (miR-155)/Toll-like receptor 4 (TLR4)/nuclear transcription factor-κB (NF-κB) signaling axis, so as to investigate its anti-inflammatory mechanism in rabbits with cold syndrome of rheumatoid arthritis (RA). METHODS: A total of 36 rabbits were randomly divided into normal, model, agonist, inhibitor, heat-reinforcing needling (HRN) and agonist+heat-reinforcing needling (A+HRN) groups, with 6 rabbits in each group. The RA with cold syndrome model was induced by injecting ovalbumin dry powder and Freund's complete adjuvant combined with cold freezing. Rabbits in agonist group were intraperitoneally injected with miR-155 agomir 4.5 OD; rabbits in the inhibitor group were intraperitoneally injected with miR-155 antagomir 6.1 OD; rabbits in HRN group received heat-reinforcing needling at bilateral "Zusanli" (ST36) for 30 min；rabbits in A+HRN group received the same treatment as agonist group, and 30 min later, received the same treatment as the HRN group; rabbits in the normal and model groups were grasped and fixed in the same way, all groups received continuous treatment once a day for 7 d. After modeling, the knee joints of rabbits were examined by ultrasound, the pain threshold and the circumference were determined. After the interventions, the pain threshold and knee circumference were measured; the pathological morphology of synovial tissue of the knee joints were observed by HE staining; the mRNA levels of miR-155 and suppressor of cytokine signaling protein 1 (SOCS1), the expression levels of SOCS1, TLR4, NF-κB p65, interleukin (IL)-1ß and IL-17A proteins in synovial tissue of knee joints were detected by real-time PCR and Western blot respectively. RESULTS: Compared with the normal group, the pain threshold was significantly decreased (P<0.05), and the knee circumference was significantly increased (P<0.05); the synovial tissue of knee joints showed significant hyperplasia, abundant blood flow signal, joint cavity effusion and obvious inflammatory invasion, the pathological score was significantly increased (P<0.05), the expressions of miR-155 mRNA and IL-1ß, IL-17A, TLR4, NF-κB p65 proteins were significantly increased (P<0.05), the expressions of SOCS1 mRNA and protein were significantly decreased (P<0.05) in the model group. Compared with model group, the pain threshold was significantly increased (P<0.05), the circumference of knee joint was significantly decreased (P<0.05); in synovial tissue, the pathological score was decreased (P<0.05), the expression levels of miR-155 mRNA and IL-1ß, IL-17A, TLR4, NF-κB p65 proteins were significantly decreased (P<0.05), and the expressions of SOCS1 mRNA and protein were significantly increased (P<0.05) in inhibitor group and HRN group, while the above changes in agonist group were reversed (P<0.05). Compared with the agonist group, the pain threshold was significantly increased (P<0.05), the knee circumference was significantly decreased (P<0.05), the synovial pathological score was significantly decreased (P<0.05), the expressions of miR-155 mRNA and IL-1ß, IL-17A, TLR4, NF-κB proteins in synovial tissue were significantly decreased (P<0.05), and the expression levels of SOCS1 mRNA and protein were significantly increased (P<0.05) in A+HRN group. CONCLUSION: The heat-reinforcing needling can increase the pain threshold, reduce the knee circumference and inhibit the inflammatory response in rabbits with RA cold syndrome. The possible mechanism is related to the regulation of miR-155/TLR4/NF-κB signaling axis.

Relationship of Microvascular Obstruction with Global and Regional Myocardial Function Determined by Cardiac Magnetic Resonance after ST-Segment Elevation Myocardial Infarction.

Objective To investigate the impact of microvascular obstruction (MVO) on the global and regional myocardial function by cardiac magnetic resonance feature-tracking (CMR-FT) in ST-segment-elevation myocardial infarction (STEMI) patients after percutaneous coronary intervention.Methods Consecutive acute STEMI patients who underwent cardiac magnetic resonance imaging 1 - 7 days after successful reperfusion by percutaneous coronary intervention treatment were included in this retrospective study. Based on the presence or absence of MVO on late gadolinium enhancement images, patients were divided into groups with MVO and without MVO. The infarct zone, adjacent zone, and remote zone were determined based on a myocardial 16-segment model. The radial strain (RS), circumferential strain (CS), and longitudinal strain (LS) of the global left ventricle (LV) and the infarct, adjacent, and remote zones were measured by CMR-FT from cine images and compared between patients with and without MVO using independent-samples t-test. Logistic regression analysis was used to assess the association of MVO with the impaired LV function.Results A total of 157 STEMI patients (mean age 56.66 ± 11.38 years) were enrolled. MVO was detected in 37.58% (59/157) of STEMI patients, and the mean size of MVO was 3.00 ±3.76 mL. Compared with patients without MVO (n =98 ), the MVO group had significantly reduced LV global RS (t= -4.30, P < 0.001), global CS (t= 4.99, P < 0.001), and global LS ( t= 3.51, P = 0.001). The RS and CS of the infarct zone in patients with MVO were significantly reduced (t= -3.38, P = 0.001; t= 2.64, P = 0.01; respectively) and the infarct size was significantly larger (t= 8.37, P < 0.001) than that of patients without MVO. The presence of LV MVO [OR= 4.10, 95%CI: 2.05 - 8.19, P<0.001) and its size [OR=1.38, 95%CI: 1.10-1.72, P=0.01], along with the heart rate and LV infarct size were significantly associated with impaired LV global CS in univariable Logistic regression analysis, while only heart rate (OR=1.08, 95%CI: 1.03 - 1.13, P=0.001) and LV infarct size (OR=1.10, 95%CI: 1.03 - 1.16, P=0.003) were independent influencing factors for the impaired LV global CS in multivariable Logistic regression analysis.Conclusion The infarct size was larger in STEMI patients with MVO, and MVO deteriorates the global and regional LV myocardial function.

[To evaluate the efficacy of Yishen Tongluo decoction combined with low-dose tadalafil in the treatment of diabetic erectile dysfunction with kidney deficiency and blood stasis syndrome].

OBJECTIVE: To observe the clinical efficacy of the combined treatment of Yishen Tongluo formula and low-dose tadalafil in diabetic erectile dysfunction. METHODS: A total of 80 patients with diabetic erectile dysfunction were randomly divided into two groups. The control group given tadalafil treatment, observation group in the control group given Yishen Tongluo Formula on the basis of treatment. The treatment period was 8 weeks. Erectile function were observed before and after treatment in the two groups patients-5 international questionnaire (IIEF - 5) score, erection quality scale (EQS) score, erectile hardness (EHS) score, TCM syndrome integral, content of serum homocysteine (HCY), endothelial function index ï¼»serum levels of prostaglandin I2 (PGI2)ï¼½ and endothelin (ET) content, a The changes of nitrogen oxide (NO), glucose and lipid metabolism indexes ï¼»triglyceride (TC), total cholesterol (TG)ï¼½ and oxidative stress related factors ï¼»total antioxidant capacity (T-AOC), glutathione peroxidase (GSH-Px)ï¼½ were evaluated, and the clinical efficacy of the two groups was evaluated. RESULTS: In terms of overall efficacy rate, the observation group (79.4%) outperformed that of the control (48.7%, P< 0.01).After treatment, the IIEF-5 score, EQS score, EHS score, and serum levels of PGI2, NO, T-AOC and GSH-Px were higher than those before treatment in the two groups (P< 0.05). The TCM syndrome score and serum HCY, ET-1, TC and TG were lower than those before treatment (P< 0.05), and the comparison group's consequence was comparatively worse than the group under observation (P< 0.01). CONCLUSIONS: Yishen Tongluo Formula can dramatically enhance the erectile dysfunction andimprovement of glucose-lipid metabolism when adopted in together with low-dose tadalafil.

[Effect of heat-reinforcing needling on expression of P2X7R, NLRP3 and Caspase-1 in synovial tissues of knee joint in rabbits with cold syndrome rheumatoid arthritis].

OBJECTIVE: To observe the effects of heat-reinforcing needling on the expression of purinergic ligand-gated ion channel 7 receptor(P2X7R)，Nodlike receptor protein 3(NLRP3) and Caspase-1 in synovium tissues of knee joint of rabbits with cold syndrome rheumatoid arthritis(RA)，so as to explore the anti-inflammatory mechanism of heat reinforcing needling in the treatment of RA. METHODS: Thirty male New Zealand white rabbits were randomly divided into normal group, model group, reinforcing-reducing needling group(RRG), heat-reinforcing needling group(HRG), and antagonist group(AG), with 6 rabbits in each group.The model of cold syndrome RA was established by ovalbumin combined with Freund's adjuvant and cryogenic freezing. Rabbits of RRG and HRG were treated with corresponding acupuncture techniques on both sides of "Zusanli"(ST36) for 30 min, once a day for 7 days; Rabbits of the AG was intraperitoneally injected with A438079(2.5 mg/kg), once a day for 7 days. After intervention, color Doppler ultrasound was used to observe the joint cavity effusion, synovial thickness and internal blood flow signal.The histomorphological changes of synovial tissues were observed by HE staining. Quantitative real-time PCR method was used to detect the mRNA expression levels of P2X7R, NLRP3, and Caspase-1 in synovial tissues. Western blot was used to detect the protein expression of interleukin(IL)-1ß, IL-6 and tumor necrosis factor(TNF)-α in synovial tissues. RESULTS: Compared with the normal group, the synovial tissues in the model group was thickened, linear and punctate blood flow signals were increased, joint effusion was obvious, synovial coating cells were enlarged, the synovial matrix was severely hyperplasia, inflammatory cells infiltration was obvious.The mRNAs expression levels of P2X7R, NLRP3, Caspase-1 and IL-1ß, IL-6, TNF-α proteins in synovial tissues were significantly increased(P<0.01). Compared with model group, abnormal blood flow signals, synovial thickness, joint effusion, proliferation of synovial matrix, inflammatory cell infiltration and synovial coating cells in the RRG, HRG and AG were improved. The mRNAs expression levels of P2X7R, NLRP3, Caspase-1 and IL-1ß, IL-6, TNF-α proteins in synovial tissues were decreased in the RRG, HRG and AG (P<0.05, P<0.01). Compared with the RRG, the above indexes were lower in the HRG and AG (P<0.05, P<0.01).There was no significant difference in all indexes above between the HRG and AG (P<0.01, P<0.05). CONCLUSION: Heat reinforcing needling can improve synovial inflammation of RA, which may be related to regulating the expressions of P2X7R/NLRP3/Caspase-1 signaling pathway.

5-Methyl-cytosine stabilizes DNA but hinders DNA hybridization revealed by magnetic tweezers and simulations.

5-Methyl-cytosine (5mC) is one of the most important DNA modifications and plays versatile biological roles. It is well known that 5mC stabilizes DNA duplexes. However, it remains unclear how 5mC affects the kinetics of DNA melting and hybridization. Here, we studied the kinetics of unzipping and rezipping using a 502-bp DNA hairpin by single-molecule magnetic tweezers. Under constant loading rates, 5mC increases the unzipping force but counterintuitively decreases the rezipping force at various salt and temperature conditions. Under constant forces, the non-methylated DNA hops between metastable states during unzipping and rezipping, which implies low energy barriers. Surprisingly, the 5mC DNA can't rezip after fully unzipping unless much lower forces are applied, where it rezips stochastically in a one-step manner, which implies 5mC kinetically hinders DNA hybridization and high energy barriers in DNA hybridization. All-atom molecular dynamics simulations reveal that the 5mC kinetically hinders DNA hybridization due to steric effects rather than electrostatic effects caused by the additional methyl groups of cytosines. Considering the possible high speed of DNA unzipping and zipping during replication and transcription, our findings provide new insights into the biological roles of 5mC.

The Application of Two-Stage Operation for High-Risk Patients with Oesophageal Cancer Following Gastrectomy.

BACKGROUND: Oesophageal replacement by colonic interposition remains a major challenge due to its complexity and high incidence of complications; here we applied the two-stage operation strategy to oesophageal replacement by colonic interposition in high-risk oesophageal cancer patients following gastrectomy. METHODS: We performed a retrospective analysis on the data of patients with a history of distal gastrectomy who underwent one-stage and two-stage oesophageal replacement by colonic interposition from February 2012 to February 2020, and explored the relationship between the staging strategy and postoperative outcomes. RESULTS: The clinical data of 93 patients were collected and analysed. There were no significant differences in the patients' characteristics between the two groups (all p > 0.05), except for comorbidities and Charlson Comorbidity Index (all p < 0.05). The Clavien-Dindo score between the two groups was also not significantly different (p > 0.05). The logistic regression models revealed that patients who had received preoperative therapy had a higher Clavien-Dindo score (p < 0.05), but the stage strategy did not (p > 0.05). CONCLUSIONS: The two-stage operation is feasible in high-risk patients who need to undergo colonic interposition for oesophageal replacement. At the same time, it lowers the technical threshold of colonic interposition for oesophageal replacement, increasing this surgical technique's acceptability.

Liver Transplantation in Acute-on-Chronic Liver Failure: Excellent Outcome and Difficult Posttransplant Course.

Background: Acute-on-chronic liver failure (ACLF) patients have high mortality in a short period of time. This study aimed to compare the prognosis of transplanted ACLF patients to that of nontransplanted ACLF patients and decompensated cirrhosis recipients. Methods: Clinical data of 29 transplanted ACLF patients, 312 nontransplanted ACLF patients, and 60 transplanted decompensated cirrhosis patients were retrospectively collected. Propensity score matching (PSM) analysis was used to match patients between different groups. Results: After PSM, the 90-day and 1-year survival of transplanted ACLF patients was significantly longer than that of nontransplant controls. Although the 90-day survival and 1-year survival of ACLF recipients was similar to that of decompensated cirrhosis controls, ACLF recipients were found to have longer mechanical ventilation, longer intensive care unit (ICU) stay, longer hospital stay, higher incidence of tracheotomy, higher expense, and higher morbidity of complication than matched decompensated cirrhosis controls. The 90-day and 1-year survival of transplanted ACLF grade 2-3 patients was also significantly longer than that of nontransplanted controls. Conclusions: Liver transplantation can strongly improve the prognosis of ACLF patients. Despite having more burdens (including longer mechanical ventilation, longer ICU stay, higher incidence of tracheotomy, longer hospital stay, higher hospitalization expense, and higher complication morbidity), ACLF recipients can obtain similar short-term and long-term survival to decompensated cirrhosis recipients. For severe ACLF patients, liver transplantation can also significantly improve their short-term and long-term survival.

Genetic substructure analysis of three isolated populations in southwest China.

Southwest China is home to numerous ethnic minorities, as well as many geographically and genetically isolated groups. However, the genetic substructure of these ethnic groups, especially the paternal genetic structure between groups, has not been comprehensively analyzed. In this study, we used Y chromosome capture and Illumina sequencing technologies to investigate the paternal genetic structure of three isolated groups of male unrelated individuals, including Baima in Pingwu, Sichuan Province, Muya in Shimian, Sichuan Province, and Kongge in Jinghong, Yunnan Province. We calculated the frequencies of related haplogroups by the fixed-point compound amplification method and direct counting method, and used the Past3.0 software to perform principal component analysis to draw a population clustering tree. we observed that Kongge had 3 Y chromosome haplogroups, Baima had 4 Y chromosome haplogroups, and Muya had 5 Y chromosome haplogroups. The results showed that Kongge was most closely related to the Wa, and the Y chromosome types of the Baima and Muya were mainly concentrated in the D haplogroup and its lower reaches. It has the closest relationship with the Tibetans in Qamdo and Nyingchi. The study on the genetic structure of different ethnic groups has enriched the genetic relationship of isolated populations and provided a new perspective for understanding Chinese ethnic groups.

Multivalent Cations Reverse the Twist-Stretch Coupling of RNA.

When stretched, both DNA and RNA duplexes change their twist angles through twist-stretch coupling. The coupling is negative for DNA but positive for RNA, which is not yet completely understood. Here, our magnetic tweezers experiments show that the coupling of RNA reverses from positive to negative by multivalent cations. Combining with the previously reported tension-induced negative-to-positive coupling reversal of DNA, we propose a unified mechanism of the couplings of both RNA and DNA based on molecular dynamics simulations. Two deformation pathways are competing when stretched: shrinking the radius causes positive couplings but widening the major groove causes negative couplings. For RNA whose major groove is clamped by multivalent cations and canonical DNA, their radii shrink when stretched, thus exhibiting positive couplings. For elongated DNA whose radius already shrinks to the minimum and canonical RNA, their major grooves are widened when stretched, thus exhibiting negative couplings.

Twist-diameter coupling drives DNA twist changes with salt and temperature.

DNA deformations upon environmental changes, e.g., salt and temperature, play crucial roles in many biological processes and material applications. Here, our magnetic tweezers experiments observed that the increase in NaCl, KCl, or RbCl concentration leads to substantial DNA overwinding. Our simulations and theoretical calculation quantitatively explain the salt-induced twist change through the mechanism: More salt enhances the screening of interstrand electrostatic repulsion and hence reduces DNA diameter, which is transduced to twist increase through twist-diameter coupling. We determined that the coupling constant is 4.5 ± 0.8 kBT/(degrees∙nm) for one base pair. The coupling comes from the restraint of the contour length of DNA backbone. On the basis of this coupling constant and diameter-dependent DNA conformational entropy, we predict the temperature dependence of DNA twist Δωbp/ΔT ≈ -0.01 degree/°C, which agrees with our and previous experimental results. Our analysis suggests that twist-diameter coupling is a common driving force for salt- and temperature-induced DNA twist changes.

Dissection of the Functional Mechanism of Human Gut Bacterial Strain AD16 by Secondary Metabolites' Identification, Network Pharmacology, and Experimental Validation.

Gut microbiota plays important roles in several metabolic processes, such as appetite and food intake and absorption of nutrients from the gut. It is also of great importance in the maintenance of the health of the host. However, much remains unknown about the functional mechanisms of human gut microbiota itself. Here, we report the identification of one anticancer gut bacterial strain AD16, which exhibited potent suppressive effects on a broad range of solid and blood malignancies. The secondary metabolites of the strain were isolated and characterized by a bioactivity-guided isolation strategy. Five new compounds, streptonaphthalenes A and B (1-2), pestaloficins F and G (3-4), and eudesmanetetraiol A (5), together with nine previously known compounds, were isolated from the effective fractions of AD16. Structures of the new compounds were established by 1D and 2D NMR and MS analysis, and the absolute configurations were determined by the CD method. The analysis of network pharmacology suggested that 3, 2, and 13 could be the key components for the anti-NSCLC activity of AD16. In addition to the PI3K-Akt signaling pathway, the proteoglycans in cancer pathway could be involved in the anti-NSCLC action of AD16.