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IntroductionAlthough allogeneic hematopoietic stem cell transplantation (HCT) can be a curative therapy for hematologic disorders, it is associated with treatment-related complications and losses in cardiorespiratory fitness and physical function. High-intensity interval training (HIIT) may be a practical way to rapidly improve cardiorespiratory fitness and physical function in the weeks prior to HCT. The primary aim of this study was to assess the feasibility of implementing a pre-HCT home-based HIIT intervention. The secondary aim was to evaluate pre to post changes in cardiorespiratory fitness and physical function following the intervention.MethodsThis was a single-arm pilot study with patients who were scheduled to undergo allogeneic HCT within six months. Patients were instructed to complete three 30-minute home-based HIIT sessions/week between the time of study enrollment and sign-off for HCT. Sessions consisted of a 5-minute warm-up, 10 high and low intervals performed for one minute each, and a 5-minute cool-down. Prescribed target heart rates (HR) for the high- and low-intensity intervals were 80-90% and 50-60% of HR reserve, respectively. Heart rates during HIIT were captured via an Apple Watch and were remotely monitored. Feasibility was assessed via retention, session adherence, and adherence to prescribed interval number and intensities. Paired t-tests were used to compare changes in fitness (VO2peak) and physical function [Short Physical Performance Battery (SPPB), 30-second sit to stand, and six-minute walk test (6MWT)] between baseline and sign-off. Pearson correlations were used to determine the relationship between intervention length and changes in cardiorespiratory fitness or functional measures.ResultsThirteen patients (58.8±11.6 years) participated in the study, and nine (69.2%) recorded their training sessions throughout the study. Median session adherence for those nine participants was 100% (IQR: 87-107). Adherence to intervals was 92% and participants met or exceeded prescribed high-intensity HR on 68.8±34.8% of intervals. VO2peak improved from baseline to sign-off (14.6±3.1 mL/kg/min to 17.9±3.3 mL/kg/min; pConclusionsFindings demonstrate that implementing a pre-HCT home-based remotely monitored HIIT program is feasible and may provide benefits to cardiorespiratory fitness and physical function.

Chronic low-grade inflammation is regarded to an important signature of atherosclerosis (AS). Macrophage (Mψ) and related polarization have been demonstrated to play a crucial role in the occurrence and development of AS inflammation. Butyrate, a bioactive molecule produced by the intestinal flora, has been increasingly demonstrated to exhibit a vital role for regulating the inflammation in chronic metabolic diseases. However, the effectiveness and multiple anti-inflammation mechanisms of butyrate on AS still need to be further understood. ApoE-/- mice fed with high-fat diet as AS model were administered with sodium butyrate (NaB) for 14 weeks of treatment. Our results showed that the atherosclerotic lesion in the AS group was dramatically reduced after NaB intervention. Moreover, deteriorated routine parameters of AS including body weights (BWs), low-density lipoprotein (LDL-C), triglyceride (TG), total cholesterol (TC) were significantly reversed by NaB administration. Abnormal elevated plasma and aorta pro-inflammatory indicators including interleukin (IL)-1β, IL-6, IL-17A, tumor necrosis factor (TNF)-α and lipopolysaccharide (LPS), as well as reduced anti-inflammatory IL-10 in plasma were respectively rectified after NaB administration. Consistently, accumulated Mψ and associated imbalance of polarization in the arota were attenuated with NaB treatment. Importantly, we demonstrated that the suppression of Mψ and associated polarization of NaB was dependent on binding G-protein coupled receptor (GPR) and inhibiting histone deacetylase HDAC3. Moreover, we found that intestinal butyrate-producing bacteria, anti-inflammatory bacteria and intestinal tight junction protein zonula occludens-1 (ZO)-1 may contribute to this effectiveness. Intriguingly, according to transcriptome sequencing of atherosclerotic aorta, 29 elevated and 24 reduced miRNAs were found after NaB treatment, especially miR-7a-5p, suggesting that non-coding RNA may possess a potential role in the protection of NaB against AS. Correlation analysis showed that there were close complicated interactions among gut microbiota, inflammation and differential miRNAs. Collectively, this study revealed that dietary NaB may ameliorate atherosclerotic inflammation by regulating Mψ polarization via GPR43/HDAC-miRNAs axis in ApoE-/- mice.

BackgroundThe latest guidance on chronic fatigue syndrome (CFS) recommends exercise therapy. Tai Chi, an exercise method in traditional Chinese medicine, is reportedly helpful for CFS. However, the mechanism remains unclear. The present longitudinal study aimed to detect the influence of Tai Chi on functional brain connectivity in CFS.MethodsThe study recruited 20 CFS patients and 20 healthy controls to receive eight sessions of Tai Chi exercise over a period of one month. Before the Tai Chi exercise, an abnormal functional brain connectivity for recognizing CFS was generated by a linear support vector model. The prediction ability of the structure was validated with a random forest classification under a permutation test. Then, the functional connections (FCs) of the structure were analyzed in the large-scale brain network after Tai Chi exercise while taking the changes in the Fatigue Scale-14, Pittsburgh Sleep Quality Index (PSQI), and the 36-item short-form health survey (SF-36) as clinical effectiveness evaluation. The registration number is ChiCTR2000032577 in the Chinese Clinical Trial Registry.Results1) The score of the Fatigue Scale-14 decreased significantly in the CFS patients, and the scores of the PSQI and SF-36 changed significantly both in CFS patients and healthy controls. 2) Sixty FCs were considered significant to discriminate CFS (P = 0.000, best accuracy 90%), with 80.5% ± 9% average accuracy. 3) The FCs that were majorly related to the left frontoparietal network (FPN) and default mode network (DMN) significantly increased (P = 0.0032 and P = 0.001) in CFS patients after Tai Chi exercise. 4) The change of FCs in the left FPN and DMN were positively correlated (r = 0.40, P = 0.012).ConclusionThese results demonstrated that the 60 FCs we found using machine learning could be neural biomarkers to discriminate between CFS patients and healthy controls. Tai Chi exercise may improve CFS patients' fatigue syndrome, sleep quality, and body health statement by strengthening the functional connectivity of the left FPN and DMN under these FCs. The findings promote our understanding of Tai Chi exercise's value in treating CFS.

Although hematopoietic stem cell transplantation (HCT) is the only curative treatment for acute myeloid leukemia (AML), it is associated with significant treatment related morbidity and mortality. There is great need for predictive biomarkers associated with overall survival (OS) and clinical outcomes. We hypothesized that circulating metabolic, inflammatory, and immune molecules have potential as predictive biomarkers for AML patients who receive HCT treatment. This retrospective study was designed with an exploratory approach to comprehensively characterize immune, inflammatory, and metabolomic biomarkers. We identified patients with AML who underwent HCT and had existing baseline plasma samples. Using those samples (n = 34), we studied 65 blood based metabolomic and 61 immune/inflammatory related biomarkers, comparing patients with either long-term OS (≥ 3 years) or short-term OS (OS ≤ 1 years). We also compared the immune/inflammatory response and metabolomic biomarkers in younger vs. older AML patients (≤30 years vs. ≥ 55 years old). In addition, the biomarker profiles were analyzed for their association with clinical outcomes, namely OS, chronic graft versus host disease (cGVHD), acute graft versus host disease (aGVHD), infection and relapse. Several baseline biomarkers were elevated in older versus younger patients, and baseline levels were lower for three markers (IL13, SAA, CRP) in patients with OS ≥ 3 years. We also identified immune/inflammatory response markers associated with aGVHD (IL-9, Eotaxin-3), cGVHD (Flt-1), infection (D-dimer), or relapse (IL-17D, bFGF, Eotaxin-3). Evaluation of metabolic markers demonstrated higher baseline levels of medium- and long-chain acylcarnitines (AC) in older patients, association with aGVHD (lactate, long-chain AC), and cGVHD (medium-chain AC). These differentially expressed profiles merit further evaluation as predictive biomarkers.

IntroductionIn order to study the role of the microbiome in hematopoietic stem cell transplantation (HCT), researchers collect stool samples from patients at various time points throughout HCT. However, stool collection requires active subject participation and may be limited by patient reluctance to handling stool.MethodsWe performed a prospective study on the impact of financial incentives on stool collection rates. The intervention group consisted of allogeneic HCT patients from 05/2017-05/2018 who were compensated with a $10 gas gift card for each stool sample. The intervention group was compared to a historical control group of allogeneic HCT patients from 11/2016-05/2017 who provided stool samples before the incentive was implemented. To control for possible changes in collections over time, we also compared a contemporaneous control group of autologous HCT patients from 05/2017-05/2018 with a historical control group of autologous HCT patients from 11/2016-05/2017; neither autologous HCT group was compensated. The collection rate was defined as the number of samples provided divided by the number of time points we attempted to obtain stool.ResultsThere were 35 allogeneic HCT patients in the intervention group, 19 allogeneic HCT patients in the historical control group, 142 autologous HCT patients in the contemporaneous control group (that did not receive a financial incentive), and 75 autologous HCT patients in the historical control group. Allogeneic HCT patients in the intervention group had significantly higher average overall collection rates when compared to the historical control group allogeneic HCT patients (80% vs 37%, pConclusionOur results demonstrate that a modest incentive can significantly increase collection rates. These results may help to inform the design of future studies involving stool collection.

BackgroundAllogeneic hematopoietic stem cell transplantation (HCT) is an often curative intent treatment, however it is associated with significant gastrointestinal (GI) toxicity and treatment related mortality. Graft-versus-host disease is a significant contributor to transplant-related mortality. We performed a phase 2 trial of the somatostatin analog pasireotide to prevent gastrointestinal toxicity and GVHD after myeloablative allogeneic HCT.MethodsPatients received 0.9mg pasireotide every 12 hours from the day prior to conditioning through day +4 after HCT (or a maximum of 14 days). The primary outcomes were grade 3-4 gastrointestinal toxicity through day 30 and acute GVHD. Secondary outcomes were chronic GVHD, overall survival and relapse free survival at one year. Stool and blood samples were collected from before and after HCT for analyses of stool microbiome, local inflammatory markers, and systemic inflammatory and metabolic markers. Results were compared with matched controls.ResultsTwenty-six patients received pasireotide and were compared to 52 matched contemporaneous controls using a 1-2 match. Grade 3-4 GI toxicity occurred in 21 (81%) patients who received pasireotide and 35 (67%) controls (p = 0.33). Acute GVHD occurred in 15 (58%) patients in the pasireotide group and 28 (54%) controls (p = 0.94). Chronic GVHD occurred in 16 patients in the pasireotide group (64%) versus 22 patients in the control group (42%) (p = 0.12). Overall survival at 1 year in the pasireotide group was 63% (95% CI: 47%,86%) versus 82% (95% CI: 72%, 93%) in controls (log-rank p = 0.006). Relapse-free survival rate at one year was 40% (95% CI: 25%, 65%) in the pasireotide group versus 78% (95% CI: 68%, 91%) in controls (log-rank p = 0.002). After controlling for the effect of relevant covariates, patients in the pasireotide group had attenuated post-HCT loss of microbial diversity. Analysis of systemic inflammatory markers and metabolomics demonstrated feasibility of such analyses in patients undergoing allogeneic HCT. Baseline level and pre-to-post transplant changes in several inflammatory markers (including MIP1a, MIP1b, TNFa, IL8Pro, and IL6) correlated with likelihood of survival.ConclusionsPasireotide did not prevent gastrointestinal toxicity or acute GVHD compared to contemporaneous controls. Pasireotide was associated with numerically higher chronic GVHD and significantly decreased OS and RFS compared to contemporaneous controls. Pasireotide may provide a locally protective effect in the stool microbiome and in local inflammation as measured by stool calprotectin, stool beta-defensin, and stool diversity index.

Allogeneic-HCT (allo-HCT), while potentially curative, can result in significant complications including graft versus host disease (GVHD). Prior studies suggest that metabolic syndrome may be one risk factor for GVHD. We hypothesized that hepatic steatosis on pre-HCT computed tomography (CT) scans may be a marker for development of GVHD and poor outcomes in allo-HCT. In this retrospective study, we reviewed the pre-HCT CT scans and transplant outcome data of patients who underwent allo-HCT at Duke University Medical Center from 2009 to 2017. The presence of steatosis was confirmed using CT attenuation measurements. We then assessed the association between pre-HCT hepatic steatosis and HCT-related outcomes including GVHD. 80 patients who had pre-HCT CT scans were included in the study. Pre-transplant hepatic steatosis was associated with the development of chronic GVHD (OR 4.2, p = 0.02), but was not associated with acute GVHD (OR 1.3, p = 0.7), non-relapse mortality (p = 0.81) or overall survival (p = 0.74). Based on this single center retrospective study, pre-transplant hepatic steatosis is associated with development of chronic GVHD. Further, prospective study with other imaging modalities including non-contrasted CT scans is needed to determine if this association is reproducible.

Predicting the socio-economic level of an urban region is of great significance for governments and city managers when allocating resources and making decisions. However, the current approaches for estimating regional socio-economic levels heavily rely on census data, which demands significant effort in terms of time and money. With the ubiquitous usage of smart phones and the prevalence of mobile applications, massive amounts of data are generated by mobile networks that record people's behaviors. In this paper, we propose a low-cost approach of using humans' online and offline indicators to predict the socio-economic levels of urban regions. The results show that the socio-economic prediction model that is trained using online and offline features extracted from these data achieves a high accuracy over 85%. Notably, online features are showed to be tightly linked with socio-economic development. In environments where censuses are rarely held, our method provides an option for timely and accurate prediction of the economic status of urban regions.

PURPOSE:To distinguish clinical factors that have time-varying (as opposed to constant) impact upon patient and graft survival among pediatric liver transplant recipients. METHODS:Using national data from 2002 through 2013, we examined potential clinical and demographic covariates using Gray's piecewise constant time-varying coefficients (TVC) models. For both patient and graft survival, we estimated univariable and multivariable Gray's TVC, retaining significant covariates based on backward selection. We then estimated the same specification using traditional Cox proportional hazards (PH) models and compared our findings. RESULTS:For patient survival, covariates included recipient diagnosis, age, race/ethnicity, ventilator support, encephalopathy, creatinine levels, use of living donor, and donor age. Only the effects of recipient diagnosis and donor age were constant; effects of other covariates varied over time. We retained identical covariates in the graft survival model but found several differences in their impact. CONCLUSION:The flexibility afforded by Gray's TVC estimation methods identify several covariates that do not satisfy constant proportionality assumptions of the Cox PH model. Incorporating better survival estimates is critical for improving risk prediction tools used by the transplant community to inform organ allocation decisions.

Watermelon (Citrullus lanatus (Thunb.) Matsum. & Nakai) is a non-climacteric fruit. The modern sweet-dessert watermelon is the result of years of cultivation and selection for fruits with desirable qualities. To date, the mechanisms of watermelon fruit ripening, and the role of abscisic acid (ABA) in this process, has not been well understood. We quantified levels of free and conjugated ABA contents in the fruits of cultivated watermelon (97103; C. lanatus subsp. vulgaris), semi-wild germplasm (PI179878; C. lanatus subsp. mucosospermus), and wild germplasm (PI296341-FR; C. lanatus subsp. lanatus). Results showed that ABA content in the fruits of 97103 and PI179878 increased during fruit development and ripening, but maintained a low steady state in the center flesh of PI296341-FR fruits. ABA levels in fruits were highest in 97103 and lowest in PI296341-FR, but no obvious differences in ABA levels were observed in seeds of these lines. Examination of 31 representative watermelon accessions, including different C. lanatus subspecies and ancestral species, showed a correlation between soluble solids content (SSC) and ABA levels in ripening fruits. Furthermore, injection of exogenous ABA or nordihydroguaiaretic acid (NDGA) into 97103 fruits promoted or inhibited ripening, respectively. Transcriptomic analyses showed that the expression levels of several genes involved in ABA metabolism and signaling, including Cla009779 (NCED), Cla005404 (NCED), Cla020673 (CYP707A), Cla006655 (UGT) and Cla020180 (SnRK2), varied significantly in cultivated and wild watermelon center flesh. Three SNPs (-738, C/A; -1681, C/T; -1832, G/T) in the promoter region of Cla020673 (CYP707A) and one single SNP (-701, G/A) in the promoter of Cla020180 (SnRK2) exhibited a high level of correlation with SSC variation in the 100 tested accessions. Our results not only demonstrate for the first time that ABA is involved in the regulation of watermelon fruit ripening, but also provide insights into the evolutionary mechanisms of this phenomenon.

Privacy-aware intersection set computation (PISC) can be modeled as secure multi-party computation. The basic idea is to compute the intersection of input sets without leaking privacy. Furthermore, PISC should be sufficiently flexible to recommend approximate intersection items. In this paper, we reveal two previously unpublished attacks against PISC, which can be used to reveal and link one input set to another input set, resulting in privacy leakage. We coin these as Set Linkage Attack and Set Reveal Attack. We then present a lightweight and flexible PISC scheme (LiPISC) and prove its security (including against Set Linkage Attack and Set Reveal Attack).

The factors driving the composition of gut microbiota are still only partly understood but appear to include environmental, cultural, and genetic factors. In order to obtain more insight into the relative importance of these factors, we analyzed the microbiome composition in subjects of Tibetan or Han descent living at different altitudes. DNA was isolated from stool samples. Using polymerase chain reaction methodology, the 16S rRNA V1-V3 regions were amplified and the sequence information was analyzed by principal coordinates analysis and Lefse analyses. Contrasting the Tibetan and Han populations both living at the 3600 m altitude, we found that the Tibetan microbiome is characterized by a relative abundance of Prevotella whereas the Han stool was enriched in Bacteroides. Comparing the microbiome of Han stool obtained from populations living at different altitudes revealed a more energy efficient flora in samples from those living at higher altitude relative to their lower-altitude counterparts. Comparison of the stool microbiome of Tibetan herders living at 4800 m to rural Tibetans living at 3600 m altitude shows that the former have a flora enriched in butyrate-producing bacteria, possibly in response to the harsher environment that these herders face. Thus, the study shows that both altitude and genetic/cultural background have a significant influence on microbiome composition, and it represents the first attempt to compare stool microbiota of Tibetan and Han populations in relation to altitude.

Watermelon [Citrullus lanatus (Thunb.) Matsum. & Nakai] is an important vegetable crop world-wide. Watermelon fruit quality is a complex trait determined by various factors such as sugar content, flesh color and flesh texture. Fruit quality and developmental process of cultivated and wild watermelon are highly different. To systematically understand the molecular basis of these differences, we compared transcriptome profiles of fruit tissues of cultivated watermelon 97103 and wild watermelon PI296341-FR. We identified 2,452, 826 and 322 differentially expressed genes in cultivated flesh, cultivated mesocarp and wild flesh, respectively, during fruit development. Gene ontology enrichment analysis of these genes indicated that biological processes and metabolic pathways related to fruit quality such as sweetness and flavor were significantly changed only in the flesh of 97103 during fruit development, while those related to abiotic stress response were changed mainly in the flesh of PI296341-FR. Our comparative transcriptome profiling analysis identified critical genes potentially involved in controlling fruit quality traits including α-galactosidase, invertase, UDP-galactose/glucose pyrophosphorylase and sugar transporter genes involved in the determination of fruit sugar content, phytoene synthase, β-carotene hydroxylase, 9-cis-epoxycarotenoid dioxygenase and carotenoid cleavage dioxygenase genes involved in carotenoid metabolism, and 4-coumarate:coenzyme A ligase, cellulose synthase, pectinesterase, pectinesterase inhibitor, polygalacturonase inhibitor and α-mannosidase genes involved in the regulation of flesh texture. In addition, we found that genes in the ethylene biosynthesis and signaling pathway including ACC oxidase, ethylene receptor and ethylene responsive factor showed highly ripening-associated expression patterns, indicating a possible role of ethylene in fruit development and ripening of watermelon, a non-climacteric fruit. Our analysis provides novel insights into watermelon fruit quality and ripening biology. Furthermore, the comparative expression profile data we developed provides a valuable resource to accelerate functional studies in watermelon and facilitate watermelon crop improvement.

The central nervous system (CNS) insults may cause massive demyelination and lead to the release of myelin-associated proteins including its major component myelin basic protein (MBP). MBP is reported to induce glial activation but its effect on neurons is still little known. Here we found that MBP specifically bound to the extracellular surface of the neuronal plasma membrane and induced neurotoxicity in vitro. This effect of MBP on neurons was basicity-dependent because the binding was blocked by acidic lipids and competed by other basic proteins. Further studies revealed that MBP induced damage to neuronal membrane integrity and function by depolarizing the resting membrane potential, increasing the permeability to cations and other molecules, and decreasing the membrane fluidity. At last, artificial liposome vesicle assay showed that MBP directly disturbed acidic lipid bilayer and resulted in increased membrane permeability. These results revealed that MBP induces neurotoxicity through its direct interaction with acidic components on the extracellular surface of neuronal membrane, which may suggest a possible contribution of MBP to the pathogenesis in the CNS disorders with myelin damage.

AIMS: Fargesia decurvata is closely allied with F. dracocephala and differs in 5 major characters (i.e. the culm sheath blade base shape, the width of the culm sheath blade base, the auricle shape, and the lower surface of leaf blade) in Fargesia. It is difficult to distinguish these two species because of existing of transitional statements of characters. The aims of this paper are to (i) investigate whether the variation of the characters is continuous or not; (ii) reveal whether the publishment of F. dracocephala was the result of discontinuous sampling of F. decurvata or not. METHODS: Ten populations of F. decurvata and F. dracocephala were investigated in their entire distribution (including type localities). The statements of 5 major characters were measured from 693 annual and 693 perennial culms of 231 individuals in 10 populations, and analyzed at population, individual and culm levels. UPGMA cluster analysis was carried out based on 29 characters from 10 populations of F. decurvata and F. dracocephala and 2 populations of F. qinlingensis as outgroup. The ITS sequences were also sequenced and analyzed. IMPORTANT FINDINGS: Five major characters exhibited great variation not only at population level, but at individual level within a population, even the culm level within an individual and in different parts of the same culm. Cluster analyses showed that 10 populations of F. decurvata and F. dracocephala were not divided into two species, but they were well separated with outgroup. There was no difference in floral organ between F. decurvata and F. dracocephala. MP and NJ trees based on ITS sequences showed the same results with the cluster analysis on morphological characters. All the facts indicated that the publishment of F. dracocephala was the result of discontinuous sampling of F. decurvata, and F. dracocephala should be treated as the synonym of F. decurvata.

Protein kinases play important roles in tumor development and progression. Lots of kinase inhibitors have entered into market and show promising clinical benefits. Here we report the discovery of a novel small molecule, well-tolerated, orally active kinase inhibitor, R1498, majorly targeting both angiogenic and mitotic pathways for the treatment of hepatocellular carcinoma (HCC) and gastric cancer (GC). A series of biochemical and cell-based assays indicated that the target kinase cluster of R1498 included Aurora kinases and VEGFR2 et al. R1498 showed moderate in vitro growth inhibition on a panel of tumor cells with IC50 of micromole range. The in vivo anti-tumor efficacy of R1498 was evaluated on a panel of GC and HCC xenografts in a parallel comparison with another multikinase inhibitor sorafenib. R1498 demonstrated superior efficacy and toxicity profile over sorafenib in all test models with >80% tumor growth inhibition and tumor regression in some xenogratfts. The therapeutic potential of R1498 was also highlighted by its efficacy on three human GC primary tumor derived xenograft models with 10-30% tumor regression rate. R1498 was shown to actively inhibit the Aurora A activity in vivo, and decrease the vascularization in tumors. Furthermore, R1498 presented good in vivo exposure and therapeutic window in the pharmacokinetic and dose range finding studies. Theses evidences indicate that R1498 is a potent, well-tolerated, orally active multitarget kinase inhibitor with a unique antiangiogenic and antiproliferative profile, and provide strong confidence for further development for HCC and GC therapy.

AIMS: Both Rheum palmatum and R. tanguticum are important but endangered medicinal plants endemic to China. In this study, we aimed to (i) investigate the level and pattern of genetic variability within/among populations of those species; (ii) evaluate genetic differentiation between both species and its relationships and ascertain whether both species are consistent with their current taxonomical treatment as separate species; and (iii) discuss the implications for the effective conservation of two species. METHODS: Total 574 individuals from 30 populations of R. palmatum and R. tanguticum were collected, covering the entire distribution range of two species in China. The genetic variation within and among 30 populations was evaluated using inter-simple sequence repeat (ISSR) markers. IMPORTANT FINDINGS: Twelve selected ISSR primers generated a total of 175 fragments, 173 (98.86%) of which were polymorphic. The Nei's gene diversity (H) and Shannon's index (I) of both species were high at species level (H = 0.3107, I = 0.4677 for R. palmatum; H = 0.2848, I = 0.4333 for R. tanguticum). But for both species, the genetic diversity was low at population level, and average within-population diversity of R. palmatum was H = 0.1438, I = 0.2151, and that of R. tanguticum was H = 0.1415, I = 0.2126. The hierarchical AMOVA revealed high levels of among-population genetic differentiation in both species, in line with the gene differentiation coefficient and the limited among-population gene flow (R. palmatum: Φ(st) = 0.592, G(st) = 0.537, N(m) = 0.432; R. tanguticum: Φ(st) = 0.567, G(st) = 0.497, N(m) = 0.507). By contrast, only 6.52% of the total genetic variance was partitioned between R. palmatum and R. tanguticum. Bayesian analysis, UPGMA cluster analysis, and PCoA analysis all demonstrated the similar results. A significant isolation-by-distance pattern was revealed in R. palmatum (r = 0.547, P = 0.010), but not in R. tanguticum (r = 0.241, P = 0.100). Based on these results, effective conservation strategies were proposed for these two species. The small molecular variance between R. palmatum and R. tanguticum revealed that they had a common ancestor, and we considered that these two species might not be good species.

As part of our ongoing efforts to sequence and map the watermelon (Citrullus spp.) genome, we have constructed a high density genetic linkage map. The map positioned 234 watermelon genome sequence scaffolds (an average size of 1.41 Mb) that cover about 330 Mb and account for 93.5% of the 353 Mb of the assembled genomic sequences of the elite Chinese watermelon line 97103 (Citrullus lanatus var. lanatus). The genetic map was constructed using an F(8) population of 103 recombinant inbred lines (RILs). The RILs are derived from a cross between the line 97103 and the United States Plant Introduction (PI) 296341-FR (C. lanatus var. citroides) that contains resistance to fusarium wilt (races 0, 1, and 2). The genetic map consists of eleven linkage groups that include 698 simple sequence repeat (SSR), 219 insertion-deletion (InDel) and 36 structure variation (SV) markers and spans ∼800 cM with a mean marker interval of 0.8 cM. Using fluorescent in situ hybridization (FISH) with 11 BACs that produced chromosome-specifc signals, we have depicted watermelon chromosomes that correspond to the eleven linkage groups constructed in this study. The high resolution genetic map developed here should be a useful platform for the assembly of the watermelon genome, for the development of sequence-based markers used in breeding programs, and for the identification of genes associated with important agricultural traits.

A major problem hindering the development of autograft alternatives for repairing peripheral nerve injuries is immunogenicity. We have previously shown successful regeneration in transected rat sciatic nerves using conduits filled with allogeneic dorsal root ganglion (DRG) cells without any immunosuppression. In this study, we re-examined the immunogenicity of our DRG neuron implanted conduits as a potential strategy to overcome transplant rejection. A biodegradable NeuraGen® tube was infused with pure DRG neurons or Schwann cells cultured from a rat strain differing from the host rats and used to repair 8 mm gaps in the sciatic nerve. We observed enhanced regeneration with allogeneic cells compared to empty conduits 16 weeks post-surgery, but morphological analyses suggest recovery comparable to the healthy nerves was not achieved. The degree of regeneration was indistinguishable between DRG and Schwann cell allografts although immunogenicity assessments revealed substantially increased presence of Interferon gamma (IFN-γ) in Schwann cell allografts compared to the DRG allografts by two weeks post-surgery. Macrophage infiltration of the regenerated nerve graft in the DRG group 16 weeks post-surgery was below the level of the empty conduit (0.56 fold change from NG; p

Curcumin, the active component of turmeric, has been shown to protect against carcinogenesis and prevent tumor development. However, little is known about its anti-tumor mechanism in small cell lung cancer (SCLC). In this study, we found that curcumin can inhibit SCLC cell proliferation, cell cycle, migration, invasion and angiogenesis through suppression of the STAT3. SCLC cells were treated with curcumin (15 µmol/L) and the results showed that curcumin was effective in inhibiting STAT3 phosphorylation to downregulate of an array of STAT3 downstream targets ,which contributed to suppression of cell proliferation, loss of colony formation, depression of cell migration and invasion. Curcumin also suppressed the expression of proliferative proteins (Survivin, Bcl-X(L) and Cyclin B1), and invasive proteins (VEGF, MMP-2, MMP-7 and ICAM-1). Knockdown of STAT3 expression by siRNA was able to induce anti-invasive effects in vitro. In contrast, activation of STAT3 upstream of interleukin 6 (IL-6) leads to the increased cell proliferation ,cell survival, angiogenesis, invasion, migration and tumor growth. Our findings illustrate the biologic significance of IL-6/JAK/STAT3 signaling in SCLC progression and provide novel evidence that the pathway may be a new potential target for therapy of SCLC. It was concluded that curcumin is a potent agent in the inhibition of STAT3 with favorable pharmacological activity,and curcumin may have translational potential as an effective cancer therapeutic or preventive agent for SCLC.

Transplanted neural stem and progenitor cells (NSCs) produce mostly astrocytes in injured spinal cords. Lithium stimulates neurogenesis by inhibiting GSK3b (glycogen synthetase kinase 3-beta) and increasing WNT/beta catenin. Lithium suppresses astrogliogenesis but the mechanisms were unclear. We cultured NSCs from subventricular zone of neonatal rats and showed that lithium reduced NSC production of astrocytes as well as proliferation of glia restricted progenitor (GRP) cells. Lithium strongly inhibited STAT3 (signal transducer and activator of transcription 3) activation, a messenger system known to promote astrogliogenesis and cancer. Lithium abolished STAT3 activation and astrogliogenesis induced by a STAT3 agonist AICAR (5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside), suggesting that lithium suppresses astrogliogenesis by inhibiting STAT3. GSK3β inhibition either by a specific GSK3β inhibitor SB216763 or overexpression of GID5-6 (GSK3β Interaction Domain aa380 to 404) did not suppress astrogliogenesis and GRP proliferation. GSK3β inhibition also did not suppress STAT3 activation. Together, these results indicate that lithium inhibits astrogliogenesis through non-GSK3β-mediated inhibition of STAT. Lithium may increase efficacy of NSC transplants by increasing neurogenesis and reducing astrogliogenesis. Our results also may explain the strong safety record of lithium treatment of manic depression. Millions of people take high-dose (>1 gram/day) lithium carbonate for a lifetime. GSK3b inhibition increases WNT/beta catenin, associated with colon and other cancers. STAT3 inhibition may reduce risk for cancer.

Inflammatory response following central nervous system (CNS) injury contributes to progressive neuropathology and reduction in functional recovery. Axons are sensitive to mechanical injury and toxic inflammatory mediators, which may lead to demyelination. Although it is well documented that degenerated myelin triggers undesirable inflammatory responses in autoimmune diseases such as multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), there has been very little study of the direct inflammatory consequences of damaged myelin in spinal cord injury (SCI), i.e., there is no direct evidence to show that myelin debris from injured spinal cord can trigger undesirable inflammation in vitro and in vivo. Our data showed that myelin can initiate inflammatory responses in vivo, which is complement receptor 3 (CR3)-dependent via stimulating macrophages to express pro-inflammatory molecules and down-regulates expression of anti-inflammatory cytokines. Mechanism study revealed that myelin-increased cytokine expression is through activation of FAK/PI3K/Akt/NF-kappaB signaling pathways and CR3 contributes to myelin-induced PI3K/Akt/NF-kappaB activation and cytokine production. The myelin induced inflammatory response is myelin specific as sphingomyelin (the major lipid of myelin) and myelin basic protein (MBP, one of the major proteins of myelin) are not able to activate NF-kappaB signaling pathway. In conclusion, our results demonstrate a crucial role of myelin as an endogenous inflammatory stimulus that induces pro-inflammatory responses and suggest that blocking myelin-CR3 interaction and enhancing myelin debris clearance may be effective interventions for treating SCI.

The Cucurbitaceae includes important crops such as cucumber, melon, watermelon, squash and pumpkin. However, few genetic and genomic resources are available for plant improvement. Some cucurbit species such as cucumber have a narrow genetic base, which impedes construction of saturated molecular linkage maps. We report herein the development of highly polymorphic simple sequence repeat (SSR) markers originated from whole genome shotgun sequencing and the subsequent construction of a high-density genetic linkage map. This map includes 995 SSRs in seven linkage groups which spans in total 573 cM, and defines approximately 680 recombination breakpoints with an average of 0.58 cM between two markers. These linkage groups were then assigned to seven corresponding chromosomes using fluorescent in situ hybridization (FISH). FISH assays also revealed a chromosomal inversion between Cucumis subspecies [C. sativus var. sativus L. and var. hardwickii (R.) Alef], which resulted in marker clustering on the genetic map. A quarter of the mapped markers showed relatively high polymorphism levels among 11 inbred lines of cucumber. Among the 995 markers, 49%, 26% and 22% were conserved in melon, watermelon and pumpkin, respectively. This map will facilitate whole genome sequencing, positional cloning, and molecular breeding in cucumber, and enable the integration of knowledge of gene and trait in cucurbits.

Cholera, caused by Vibrio cholerae, erupted globally from South Asia in 7 pandemics, but there were also local outbreaks between the 6(th) (1899-1923) and 7(th) (1961-present) pandemics. All the above are serotype O1, whereas environmental or invertebrate isolates are antigenically diverse. The pre 7th pandemic isolates mentioned above, and other minor pathogenic clones, are related to the 7(th) pandemic clone, while the 6(th) pandemic clone is in the same lineage but more distantly related, and non-pathogenic isolates show no clonal structure. To understand the origins and relationships of the pandemic clones, we sequenced the genomes of a 1937 prepandemic strain and a 6(th) pandemic isolate, and compared them with the published 7(th) pandemic genome. We distinguished mutational and recombinational events, and allocated these and other events, to specific branches in the evolutionary tree. There were more mutational than recombinational events, but more genes, and 44 times more base pairs, changed by recombination. We used the mutational single-nucleotide polymorphisms and known isolation dates of the prepandemic and 7(th) pandemic isolates to estimate the mutation rate, and found it to be 100 fold higher than usually assumed. We then used this to estimate the divergence date of the 6(th) and 7(th) pandemic clones to be about 1880. While there is a large margin of error, this is far more realistic than the 10,000-50,000 years ago estimated using the usual assumptions. We conclude that the 2 pandemic clones gained pandemic potential independently, and overall there were 29 insertions or deletions of one or more genes. There were also substantial changes in the major integron, attributed to gain of individual cassettes including copying from within, or loss of blocks of cassettes. The approaches used open up new avenues for analysing the origin and history of other important pathogens.

Tuberous sclerosis complex is a dominant genetic disorder produced by mutations in either of two tumor suppressor genes, TSC1 and TSC2; it is characterized by hamartomatous tumors, and is associated with severe neurological and behavioral disturbances. Mutations in TSC1 or TSC2 deregulate a conserved growth control pathway that includes Ras homolog enriched in brain (Rheb) and Target of Rapamycin (TOR). To understand the function of this pathway in neural development, we have examined the contributions of multiple components of this pathway in both neuromuscular junction assembly and photoreceptor axon guidance in Drosophila. Expression of Rheb in the motoneuron, but not the muscle of the larval neuromuscular junction produced synaptic overgrowth and enhanced synaptic function, while reductions in Rheb function compromised synapse development. Synapse growth produced by Rheb is insensitive to rapamycin, an inhibitor of Tor complex 1, and requires wishful thinking, a bone morphogenetic protein receptor critical for functional synapse expansion. In the visual system, loss of Tsc1 in the developing retina disrupted axon guidance independently of cellular growth. Inhibiting Tor complex 1 with rapamycin or eliminating the Tor complex 1 effector, S6 kinase (S6k), did not rescue axon guidance abnormalities of Tsc1 mosaics, while reductions in Tor function suppressed those phenotypes. These findings show that Tsc-mediated control of axon guidance and synapse assembly occurs via growth-independent signaling mechanisms, and suggest that Tor complex 2, a regulator of actin organization, is critical in these aspects of neuronal development.

End-stage kidney disease (ESKD) presents a significant public health challenge, with hemodialysis (HD) remaining one of the most prevalent kidney replacement therapies. Ensuring the longevity and functionality of arteriovenous accesses is challenging for HD patients. Blood flow sound, which contains valuable information, has often been neglected in the past. However, machine learning offers a new approach, leveraging data non-invasively and learning autonomously to match the experience of healthcare professionas. This study aimed to devise a model for detecting arteriovenous grafts (AVGs) stenosis. A smartphone stethoscope was used to record the sound of AVG blood flow at the arterial and venous sides, with each recording lasting one minute. The sound recordings were transformed into mel spectrograms, and a 14-layer convolutional neural network (CNN) was employed to detect stenosis. The CNN comprised six convolution blocks with 3x3 kernel mapping, batch normalization, and rectified linear unit activation function. We applied contrastive learning to train the pre-training audio neural networks model with unlabeled data through self-supervised learning, followed by fine-tuning. In total, 27,406 dialysis session blood flow sounds were documented, including 180 stenosis blood flow sounds. Our proposed framework demonstrated a significant improvement (p<0.05) over training from scratch and a popular pre-trained audio neural networks (PANNs) model, achieving an accuracy of 0.9279, precision of 0.8462, and recall of 0.8077, compared to previous values of 0.8649, 0.7391, and 0.6538. This study illustrates how contrastive learning with unlabeled blood flow sound data can enhance convolutional neural networks for detecting AVG stenosis in HD patients. [ABSTRACT FROM AUTHOR]