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Cancer-derived exosomes are involved in the development of cancer cachexia. Carnosol, which exhibited ameliorating effects on cancer cachexia of C26 tumour-bearing mice in our previous study, alleviated atrophy of C2C12 myotubes induced by exosomes of C26 tumour cells in the present study. MiR-183-5p was found to be rich in C26 cells and C26 exosomes, and miR-183-5p mimic could directly induce atrophy of C2C12 myotubes. Carnosol at 5 to 20 μM could dose-dependently ameliorate the myotube atrophy induced by miR-183-5p. Four and a half LIM domain protein 1 (FHL1) was shown to be the direct target of miR-183-5p. Increase in myostatin, p-Smad3, MuRF-1, Atrogin-1, HIF-1α and p-STAT3 and decrease in mitochondrial respiration were also induced by miR-183-5p mimic in C2C12 myotubes. Carnosol could not affect the decrease in FHL-1 and the activation of STAT3 pathway but could significantly alleviate the increase in myostatin, p-Smad3, MuRF-1, Atrogin-1 and the decrease in mitochondrial respiration induced by miR-183-5p. The protective effects of carnosol on myotubes against atrophy of C2C12 myotubes induced by miR-183-5p, based on both its inhibiting effects on MuRF-1 and Atrogin-1-mediated protein degradation and its ability of keeping the mitochondrial respiration, might contribute to its ameliorating effects on cancer cachexia.

Introduction Genetic landscape, disease characteristics and clinical outcomes of young adults with myeloproliferative neoplasms (MPNs) were reported. However, data on patient-reported outcomes (PROs) in young adults with MPNs were rare. Methods We conducted a multicenter, cross-sectional study to compared the PROs in respondents with thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) by age at survey, including the young group (18-40 years), middle-aged group (41-60 years), and elderly group (> 60 years). Results Of the 1664 respondents with MPNs, 349 (21.0%) were young including 244 (69.9%) with ET, 34 (9.7%) with PV and 71 (20.3%) with MF. In multivariate analyses the young groups with ET and MF were associated with the lowest MPN-10 scores among the 3 age groups; those with MF, highest proportion of reporting negative impact of disease and therapy on their daily life and work. The young groups with MPNs had the highest physical component summary scores, but the lowest mental component summary scores in those with ET. The young groups with MPNs were most concerned about fertility; those with ET, treatment-related adverse events and long-term efficacy of treatment. Conclusions We concluded that young adults with MPNs have different PROs compared with middle-aged and elderly patients.

The neuroendocrine system consists of a heterogeneous collection of neuropeptidergic neurons in the brain, among which hypothalamic KNDy neurons represent an indispensable cell subtype controlling puberty onset. Although neural progenitors and neuronal precursors along the cell lineage hierarchy adopt a cascade diversification strategy to generate hypothalamic neuronal heterogeneity, the cellular logic operating within the lineage to specify a subtype of neuroendocrine neurons remains unclear. As human genetic studies have recently established a link between TBX3 mutations and delayed puberty onset, we systematically studied Tbx3-derived neuronal lineage and Tbx3-dependent neuronal specification and found that Tbx3 hierarchically established and maintained the identity of KNDy neurons for triggering puberty. Apart from the well-established lineage-dependent fate determination, we uncovered rules of interlineage interaction and intralineage retention operating through neuronal differentiation in the absence of Tbx3. Moreover, we revealed that human TBX3 mutations disturbed the phase separation of encoded proteins and impaired transcriptional regulation of key neuropeptides, providing a pathological mechanism underlying TBX3-associated puberty disorders.

Background The COVID-19 pandemic has posed significant threats to both the physical and psychological health of healthcare workers working in the front-line combating COVID-19. However, studies regarding the medium to long term impact of COVID-19 on mental health among healthcare workers are limited. Therefore, we conducted this cross-sectional survey to investigate the prevalence, factors and impact of post-traumatic stress disorder (PTSD) in healthcare workers exposed to COVID-19 8 months after the end of the outbreak in Wuhan, China. Methods A web-based questionnaire was delivered as a link via the communication application WeChat to those healthcare workers who worked at several COVID-19 units during the outbreak (from December 2019 to April 2020) in Wuhan, China. The questionnaire included questions on social-demographic data, the post-traumatic stress disorder checklist-5 (PCL-5), the family care index questionnaire (Adaptation, Partnership, Growth, Affection and Resolve, APGAR), and the quality-of-life scale (QOL). The prevalence, risk and protective factors, and impact of PTSD on healthcare workers were subsequently analyzed. Results Among the 659 participants, 90 healthcare workers were still suffering from PTSD 8 months after the end of the outbreak of COVID-19 in Wuhan, in which avoidance and negative impact were the most affected dimensions. Suffering from chronic disease, experiencing social isolation, and job dissatisfaction came up as independent risk factors for PTSD, while obtaining COVID-19 related information at an appropriate frequency, good family function, and working in well-prepared mobile cabin hospitals served as protective factors. The impact of PTSD on COVID-19 exposed healthcare workers was apparent by shortened sleeping time, feeling of loneliness, poorer quality of life and intention to resign. Conclusions Eight months after the end of the COVID-19 outbreak in Wuhan, the level of PTSD in healthcare workers exposed to COVID-19 was still high. Apart from the commonly recognized risk factors, comorbid chronic disease was identified as a new independent risk factor for developing PTSD. For countries where the pandemic is still ongoing or in case of future outbreaks of new communicable diseases, this study may contribute to preventing cases of PTSD in healthcare workers exposed to infectious diseases under such circumstances.

We explored variables associated with patient-reported outcomes (PROs) including symptom burden, impact on daily life and work, obstacles during therapy, satisfaction level with therapy, and health-related quality of life in 1500 respondents with myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) in a multicenter, cross-sectional study across China, a representative of the developing countries. In multivariate analyses, urban household registration and higher education level were significantly-associated with no symptoms at diagnosis in respondents with ET or MF. CALR mutation was significantly-associated with lower MPN-10 scores in respondents with MF. Higher MPN-10 scores were significantly-associated with negative impact on daily life and work as well as lower satisfaction level in respondents with ET, PV and MF. Receiving ruxolitinib was significantly-associated with high satisfaction and satisfaction in respondents with MF. In addition, other demographics and clinical variables were also impacting PROs.

Background Cancer cachexia is a serious metabolic disorder syndrome that is responsible for the deaths of approximately 30% of patients with cancer, but effective drugs for cancer cachexia are still lacking. Inflammatory cytokines such as TNF-α or IL-6 are involved in the induction of skeletal muscle atrophy and fat depletion in patients with cancer cachexia. Purpose In this study, we assessed the therapeutic effects of the natural compound alantolactone (AL) on cancer cachexia and tried to clarify the mechanisms by which it ameliorates muscle atrophy. Methods The C26 tumor-bearing cancer cachexia mouse model was used to evaluate the efficacy of AL in alleviating cancer cachexia in vivo. The levels of IL-6 or TNF-α in mouse serum were detected using ELISA kits. Cultured C2C12 myotubes and 3T3-L1 adipocytes treated with conditioned medium of C26 tumor cells, IL-6 or TNF-α were employed as in vitro cancer cachexia models to examine the effects of AL in vitro. Results AL (5 or 10 mg/kg, qd, i.p.) protected mice with C26 tumors and cachexia from a loss of body weight and muscle wasting but only slightly ameliorated fat loss. The circulating level of IL-6 but not TNF-α was significantly decreased by AL. AL treatment significantly inhibited STAT3 activation in the gastrocnemius (GAS) muscle of cancer cachexia mice. AL (0.125, 0.25, 0.5 and 1 µM) dose-dependently ameliorated myotube atrophy and STAT3 activation in cultured C2C12 myotubes induced by conditioned medium from C26 tumor cells. AL also ameliorated C2C12 myotube atrophy induced by IL-6 and inhibited IL-6-mediated STAT3 activation. AL exhibited weak effects on ameliorating TNF-α-mediated myotube atrophy and NF-κB activation. Only AL at high doses of more than 5 µM ameliorated lipolysis and STAT3 activation induced in mature 3T3-L1 adipocytes by conditioned medium from C26 tumor cells. Conclusions AL significantly ameliorated muscle atrophy in a cancer cachexia model mainly through the inhibition of the STAT3 pathway. AL might be a promising lead compound in the development of drug candidates for cancer cachexia therapy.

The liver kinase B1 (LKB1) is encoded by tumor suppressor gene STK11, which is mutated in Peutz–Jeghers syndrome patients. Lkb1 plays indispensable roles in energy homeostasis. However, how Lkb1 regulates energy homeostasis in vivo remains to be fully understood. We found that inactivation of zebrafish Lkb1 upregulates pyruvate dehydrogenase kinase 2 expression and inactivates pyruvate dehydrogenase complex by increasing phosphorylation of pyruvate dehydrogenase. As a result, glycolysis is significantly enhanced as indicated by increased lactate production, which resembles the Warburg effect in cancer cells. Inhibition of Pdk2 in lkb1 mutants with dichloroacetate, a promising anticancer drug, rescued the lactate production to wild-type level, suggesting the lkb1 mutant may be used to screen compounds targeting aerobic glycolysis in cancer therapy.

Fully grown oocytes of most vertebrates are arrested at prophase I of meiosis (G2 arrest). Upon exposure to steroid hormones, oocytes resume meiotic process, also called G2/M transition. The G protein-signaling pathway has been shown to play essential roles in the meiotic arrest at G2 phase. Previously, we showed that long chain fatty acyl-coenzyme A synthetase acsl1b was required for maintaining the meiotic arrest in Xenopus Acsl1b presumably synthesizes palmitoyl-coenzyme A that can be utilized by acyltransferases to modify proteins essential for the G2 arrest. In the present study, we report that protein acyltransferase ZDHHC3 functions downstream of acsl1b to maintain oocyte meiotic arrest. Depletion of maternal ZDHHC3 RNA in oocytes reduces the progesterone threshold to promote G2/M transition from 2 to 0.01 μM. As expected, Gs alpha palmitoylation level is greatly decreased in ZDHHC3-depleted oocytes. Furthermore, we mapped ZDHHC3 palmitoylation sites in Gs alpha and showed that palmitoylat...

To analysis the early complications of tibial fracture and its related factors, and propose a solution.From December 2003 to December 2013,38 patients with early complications of tibial plateau fracture after operation were retrospectively analyzed. There were 35 males and 3 females, aged from 37 to 69 years old (averaged 42.3 years). According to Schatzker classification, 3 cases were classified as type II, 2 cases as type III, 2 cases as type IV, 19 cases as type V, 12 cases as type VI. The intervals between injury and operation ranged from 9 hours to 9 days, 26 cases within 3 days. Fifteen cases were treated with internal fixation of plates and 23 were treated by plate fixation and bone transplantation. Early complications included skin necrosis in 15 cases, infection in 6 cases, osteofascial compartment syndrome in 3 cases, common peroneal nerve injury in 2 cases, the superficial peroneal nerve injury in 3 cases, popliteal artery injury in 2 cases, loss of reduction in 7 cases.The wound of 14 cases healed at the first stage and 24 cases healed delay. Hospitalization days ranged from 7 to 67 days (averaged 25.6 days). All patients were followed up for 12 to 36 months with an average of 16.4 months. The fracture healing time ranged from 3 to 9 months (averaged 6.9 months). According to Merchant knee function evaluation criteria, the results were excellent in 19 cases, good in 12, fair in 5 and poor in 2.Early complications of tibial fracture after operation is closely associated with the severe fracture complexity and related with preoperative preparation, surgical timing, operation incision selection and surgical technique. Early detection and timely processing reduce damage.

Nogo-A is a major myelin associated inhibitor that blocks regeneration of injured axons in the central nervous system (CNS). Nogo-66 (a 66-residue domain of Nogo-A) expressed on the surface of oligodendrocytes has been shown to directly interact with Nogo-66 receptor 1 (NgR1). A number of additional components of NgR1 receptor complex essential for its signaling have been uncovered. However, detailed composition of the complex and its signaling mechanisms remain to be fully elucidated. In this study, we show that Nogo receptor 3 (NgR3), a paralog of NgR1, is a binding protein for NgR1. The interaction is highly specific because other members of the reticulin family, to which Nogo-A belongs, do not bind to NgR3. Neither does NgR3 show any binding activity with Nogo receptor 2 (NgR2), another NgR1 paralog. Majority of NgR3 domains are required for its binding to NgR1. Moreover, a truncated NgR3 with the membrane anchoring domain deleted can function as a decoy receptor to reverse neurite outgrowth inhibition caused by Nogo-66 in culture. These in vitro results, together with previously reported overlapping expression profile between NgR1 and NgR3, suggest that NgR3 may be associated with NgR1 in vivo and that their binding interface may be targeted for treating neuronal injuries.

Shunt active power filter with LCL output filter involves the tracking of transient current with high frequency harmonic components. The current control brings some complexity. This paper presents a kind of current control algorithm, which combines the triangle carrier comparison method with hysteresis control method. At the same time, the automatic self-correction of the grid-side disturbance while controlling current is discussed. The proposed algorithm is characterized by fast tracking of harmonic current, small computation capacity and easy implementation for engineering applications. Simulation and experiment verify the effectiveness of the proposed method.

In most vertebrates, fully grown oocytes are arrested in meiotic prophase I and only resume the cell cycle upon external stimuli, such as hormones. The proper arrest and resumption of the meiotic cycle is critical for reproduction. A Galpha(S) signaling pathway essential for the arrest is conserved in organisms from Xenopus to mouse and human. A previous gene association study implicated that mutations of human ACSL6 may be related to premature ovarian failure. However, functional roles of ACSL6 in human infertility have yet to be reported. In the present study, we found that triacsin C, a potent and specific inhibitor for ACSL, triggers maturation in Xenopus and mouse oocytes in the absence of hormone, suggesting ACSL activity is required for the oocyte arrest. In Xenopus, acsl1b may fulfill a major role in the process, because inhibition of acsl1b by knocking down its RNA results in abnormal acceleration of oocyte maturation. Such abnormally matured eggs cannot support early embryonic development. Moreover, direct inhibition of protein palmitoylation, which lies downstream of ACSLs, also causes oocyte maturation. Furthermore, palmitoylation of Galpha(s), which is essential for its function, is inhibited when the ACSL activity is blocked by triacsin C in Xenopus. Thus, disruption of ACSL activity causes inhibition of the Galpha(s) signaling pathway in the oocytes, which may result in premature ovarian failure in human.

In most vertebrates, fully grown oocytes are arrested in meiotic prophase I and only resume the cell cycle upon external stimuli, such as hormones. The proper arrest and resumption of the meiotic cycle is critical for reproduction. A Galpha(S) signaling pathway essential for the arrest is conserved in organisms from Xenopus to mouse and human. A previous gene association study implicated that mutations of human ACSL6 may be related to premature ovarian failure. However, functional roles of ACSL6 in human infertility have yet to be reported. In the present study, we found that triacsin C, a potent and specific inhibitor for ACSL, triggers maturation in Xenopus and mouse oocytes in the absence of hormone, suggesting ACSL activity is required for the oocyte arrest. In Xenopus, acsl1b may fulfill a major role in the process, because inhibition of acsl1b by knocking down its RNA results in abnormal acceleration of oocyte maturation. Such abnormally matured eggs cannot support early embryonic development. Moreover, direct inhibition of protein palmitoylation, which lies downstream of ACSLs, also causes oocyte maturation. Furthermore, palmitoylation of Galpha(s), which is essential for its function, is inhibited when the ACSL activity is blocked by triacsin C in Xenopus. Thus, disruption of ACSL activity causes inhibition of the Galpha(s) signaling pathway in the oocytes, which may result in premature ovarian failure in human.

Reprogramming somatic cells to become induced pluripotent stem cells (iPSCs) by using defined factors represents an important breakthrough in biology and medicine, yet remains inefficient and poorly understood. We therefore devised synthetic factors by fusing the VP16 transactivation domain to OCT4 (also known as Pou5f1), NANOG and SOX2, respectively. These synthetic factors could reprogramme both mouse and human fibroblasts with enhanced efficiency and accelerated kinetics. Remarkably, Oct4–VP16 alone could efficiently reprogramme mouse embryonic fibroblasts (MEFs) into germline-competent iPSCs. Furthermore, episomally delivered synthetic factors could reproducibly generate integration-free iPSCs from MEFs with enhanced efficiency. Our results not only demonstrate the feasibility of engineering more potent reprogramming factors, but also suggest that transcriptional reactivation of OCT4 target genes might be a rate-limiting step in the conversion of somatic cells to pluripotent cells. Synthetic factor-based reprogramming might lead to a paradigm shift in reprogramming research.

To evaluate the design principles, clinical results and significance of hatchet skin flaps for repairing tissue defects in different parts of cheek.The area of cheek was divided into three parts, P(I), P(II) and P(III), with vertical lines through the medial canthus and lateral canthus. Different kinds of hatchet skin flaps were designed to repair tissue defects in different part of cheek. The hatchet skin flaps were performed in 29 cases with tissue defects in different part of cheek from August 2005 to August 2009. There were 17 male and 12 female, aged from 19 to 81 years, with a mean age of (45 ± 16) years. The size of tissue defect ranged from 1.5 cm × 1.5 cm to 2.5 cm × 3.5 cm. Patients' satisfactions were evaluated with a questionnaire in 5 aspects:color and texture match, scar, morbidity, and function after 6 months operatively.All the flaps survived completely with good color and tissue match. The facial contour was not altered obviously. Six to eighteen months later, all scars were almost invisible. All 29 patients were satisfied with their results.The hatchet skin flap is one of the versatile reconstructive methods for repairing of medium and small defects in the three parts of cheek. Defects in different part of cheek should be repaired individually with hatchet flap based on characters of natural lines.

To evaluate the effect of tumescent infiltration solution temperature on core body temperature after liposuction.15 healthy female subjects were randomly divided into 2 groups to receive tumescent infiltration solution at 25 degrees C as group A, or at 37 degrees C as group B. All subjects were under epidural anesthesia. Vital signs, including core temperature, heart rate, respiratory rate and blood pressure, were monitored immediately, 1 hour, 2 hours, 3 hours, 4 hours and 8 hours after operation.The core body temperature immediately, 1 hour, 2 hours and 3 hours after operation were (35.8 +/- 0.5) degrees C, (35.8 +/- 0.5) degrees C, (36.0 +/- 0.5) degrees C, (36.1 +/- 0.5) degrees C in group A, and (36.5 +/- 0.4) degrees C, (36.5 +/- 0.3) degrees C, (36.5 +/- 0.3) degrees C, (36.6 +/- 0.4) degrees C in group B, showing a significant difference between the two groups (P = 0.008, P = 0.008, P = 0.03, P = 0.033, respectively). There was no difference in body temperature 4 hours and 8 hours after operation and in heart rate, respiratory rate and blood pressure between the two groups (P0. 05).The tumescent infiltration solutions at room temperature (25 degrees C) can decrease the core body temperature and increase surgical risk. It might not be good for rehabilitation. It is recommended to use tumescent infiltration solution at body temperature (37 degrees C) in liposuction.

To evaluate the therapeutic effect of hatchet flap for buccal tissue defect.The hatchet flap was designed beside the tissue defect and advanced to cover the defect.Since 2006, 13 cases were treated with primary healing and no flap loss. The size of the flaps ranged from 1.8 cm x 2.0 cm to 2.5 cm x 3.5 cm. All the cases were followed up for 3 months to 1.5 years. The postoperative appearance was satisfactory with inconspicuous scar.Hatchet flap is very suitable for the buccal tissue defect with satisfactory cosmetic result. The facial natural figure is protected very well.

Two experiments were conducted to determine whether heart manganese-containing superoxide dismutase (MnSOD) gene expression could detect the differences in bioavailabilities of Mn sources more quickly, sensitively and constantly than other indices.In experiment 1, a total of 546 day-old commercial male Arbor Acres (AA) broilers were randomly assign to each of thirteen treatments with six cage replicates according to a completely randomized design involving a 4 x 4 factorial arrangement. Each group of birds was fed Mn-unsupplemented corn-soybean meal basal diets (Control) or basal diets supplemented with 60, 120 or 180 mg/kg Mn as either Mn sulfate, Mn-Met E, Mn-AA B or Mn-AA C for 21 days. At 21 days of age, three birds from each cage were selected according to average bodyweight of the cage and killed. Heart and left leg were excised immediately. Mn concentrations in tissues, MnSOD activity and gene expression of MnSOD in heart were analyzed. In experiment 2, two hundred and seventy day-old AA commercial male broilers were randomly allotted to one of five treatments with six cage replicates in a completely randomized design, and fed a Mn-unsupplemented corn-soybean meal basal diet (Control) or the basal diet supplemented with 120 mg/kg Mn as each of the four Mn sources in experiment 1 for 21 days. The methods in experiment 1 were used to select and slaughter birds from each cage on the 7th, 14th or 21st day. The tissues were collected and analyzed as well.(1) In experiment 1, ash Mn content, heart Mn content, and MnSOD activity in heart mitochondria on the 21st day were affected (P = 0.0001) by dietary added Mn level. Based on slope ratios from multiple linear regressions of these three indices on dietary added Mn intake, the relative bioavailabilities of organic Mn sources did not differ from that of MnSO4 (P0.14). Heart MoSOD mRNA level on the 21st day was affected by both Mn source (P0.10) and Mn level (P = 0.0001). Based on slope ratios from the multiple linear regression of heart MnSOD mRNA level on dietary added Mn intake, if 100% was set for Mn sulfate, the relative bioavailabilities of organic Mn sources with weak, moderate, and strong chelation strengths were 99.0%, 132.3% and 112.7%, respectively. The organic Mn source with the moderate chelation strength was more available (P0.05) than Mn sulfate and organic Mn sources with the weak or strong chelation strengths; (2) In experiment 2, the seven day-old chicks fed on the diet supplemented with the organic Mn source with the moderate chelation strength showed a higher (P0.02) MnSOD mRNA level than those fed on the diets supplemented with Mn sulfate and the organic Mn source with the weak chelation strength, and the same tendency was observed on the 14th day or 21st day (P0.05). Ash Mn content and heart MnSOD activity were less sensitive in detecting the differences among Mn sources in bioavailability than MnSOD mRNA level.The results indicate that dietary Mn significantly affected heart MnSOD gene expression pretranslationally, and heart MnSOD mRNA level as early as on the 7th day could detect differences in bioavailabilities of Mn sources more quickly, sensitively and constantly than all other indices. There was a close correlativity between chelation strengths of these organic Mn sources and their relative bioavailabilities for broilers, in which the organic Mn source with the moderate chelation strength was the most available. The estimation of relative bioavailabilities of Mn sources based on heart MnSOD mRNA level could request a shorter time of experimental period and smaller number of animals, and thus could be a new method for a quick and effective assessment in bioassays of Mn sources for broilers.