Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10−22). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l−1 (P=5.82 × 10−21) in East Asians (n=7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10−18), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10−11) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10−8). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature.
Age-related macular degeneration (AMD) is a major cause of blindness worldwide. Here, the authors carry out a two-stage genome-wide association study for AMD and identify three new AMD risk loci, highlighting the shared and distinct genetic basis of the disease in East Asians and Europeans.
Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. Breast and lung cancer cells express protocadherin 7 (PCDH7) to favor the assembly of carcinoma-astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells employ these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines IFNα and TNFα. As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, which support tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle for the applicability of this therapeutic strategy to treat established brain metastasis.
The Drosophila mushroom body (MB) is a key associative memory center that has also been implicated in the control of sleep. However, the identity of MB neurons underlying homeostatic sleep regulation, as well as the types of sleep signals generated by specific classes of MB neurons, has remained poorly understood. We recently identified two MB output neuron (MBON) classes whose axons convey sleep control signals from the MB to converge in the same downstream target region: a cholinergic sleep-promoting MBON class and a glutamatergic wake-promoting MBON class. Here we deploy a combination of neurogenetic, behavioral, and physiological approaches to identify and mechanistically dissect sleep-controlling circuits of the MB. Our studies reveal the existence of two segregated excitatory synaptic microcircuits that propagate homeostatic sleep information from different populations of intrinsic MB “Kenyon cells” (KCs) to specific sleep-regulating MBONs: sleep-promoting KCs increase sleep by preferentially activating the cholinergic MBONs, while wake-promoting KCs decrease sleep by preferentially activating the glutamatergic MBONs. Importantly, activity of the sleep-promoting MB microcircuit is increased by sleep deprivation and is necessary for homeostatic rebound sleep (i.e., the increased sleep that occurs after, and in compensation for, sleep lost during deprivation). These studies reveal for the first time specific functional connections between subsets of KCs and particular MBONs and establish the identity of synaptic microcircuits underlying transmission of homeostatic sleep signals in the MB.
The CRISPR/Cas9 system and related RNA‐guided endonucleases can introduce double‐strand breaks (DSBs) at specific sites in the genome, allowing the generation of targeted mutations in one or more genes as well as more complex genomic rearrangements. Modifications of the canonical CRISPR/Cas9 system from Streptococcus pyogenes and the introduction of related systems from other bacteria have increased the diversity of genomic sites that can be targeted, providing greater control over the resolution of DSBs, the targeting efficiency (frequency of on‐target mutations), the targeting accuracy (likelihood of off‐target mutations) and the type of mutations that are induced. Although much is now known about the principles of CRISPR/Cas9 genome editing, the likelihood of different outcomes is species‐dependent and there have been few comparative studies looking at the basis of such diversity. Here we critically analyse the activity of CRISPR/Cas9 and related systems in different plant species and compare the outcomes in animals and microbes to draw broad conclusions about the design principles required for effective genome editing in different organisms. These principles will be important for the commercial development of crops, farm animals, animal disease models and novel microbial strains using CRISPR/Cas9 and other genome‐editing tools.
genome editing; mutational signature; off‐target mutations; on‐target mutations; sgRNA design; site‐directed mutagenesis; species‐dependent effects
A good postoperative alignment in total knee arthroplasty (TKA) is the key to achieving satisfactory results. We assessed the effect of femoral and tibial resection on the overall alignment after conventional TKA.
We conducted a retrospective analysis of 212 primary TKAs in 188 patients. Intramedullary (IM)-guided resection was applied on the femoral side while extramedullary (EM)-guided resection was used on the tibial side. Using full-length X-ray, the preoperative femoral valgus angle and lower extremity alignment, as well as 2-week postoperative femoral and tibial prosthetic coronal alignment and overall lower extremity alignment, were measured.
Postoperatively, good prosthetic alignment was achieved in 191 cases (90.1%) on the tibial side and in 144 cases (67.9%) on the femoral side (χ2 = 5.441, P = 0.02). Multiple linear regression analysis was used to assess the effect of different alignment sides on the overall alignment in the coronal plane. Data were divided into five subgroups based on the valgus or varus status of the prostheses. The standardized regression coefficients of the femoral and tibial prosthetic alignment on the overall alignment were 0.666 and 0.414, respectively; in varus on both sides were 0.658 and 0.377, respectively; in valgus, 0.555 and 0.030; femoral side varus and tibial side valgus, 0.702 and 0.211; femoral side valgus and tibial side varus, −0.416 and 0.287. The study showed that the overall low extremity alignment was statistically influenced by the prosthetic alignment, except for the tibial prosthetic alignment when femoral prosthesis was in valgus (P = 0.153).
In conventional TKA, tibial side EM-guided resection may offer satisfactory postoperative alignment, and femoral resection relying on IM guide may lead to more undesirable results. Postoperative coronal alignment is mainly affected by the femoral resection. Therefore, femoral side operation should receive adequate attention from the surgeons.
Accuracy; Conventional Resection; Extramedullary Guide; Intramedullary Guide; Prosthetic Coronal Alignment; Total Knee Arthroplasty
More than 220 million people worldwide are chronically infected with schistosomes, causing severe disease or even death. The major pathological damage occurring in schistosomiasis is attributable to the granulomatous inflammatory response and liver fibrosis induced by schistosome eggs. The inflammatory response is tightly controlled and parallels immunosuppressive regulation, constantly maintaining immune homeostasis and limiting excessive immunopathologic damage in important host organs. It is well known that the activation of programmed death 1 (PD-1) signaling causes a significant suppression of T cell function. However, the roles of PD-1 signaling in modulating CD4+ T cell responses and immunopathology during schistosome infection, have yet to be defined.
Here, we show that PD-1 is upregulated in CD4+ T cells in Schistosoma japonicum (S. japonicum)-infected patients. We also show the upregulation of PD-1 expression in CD4+ T cells in the spleens, mesenteric lymph nodes, and livers of mice with S. japonicum infection. Finally, we found that the blockade of PD-1 signaling enhanced CD4+ T helper 2 (Th2) cell responses and led to more severe liver immunopathology in mice with S. japonicum infection, without a reduction of egg production or deposition in the host liver.
Overall, our study suggests that PD-1 signaling is specifically induced to control Th2-associated inflammatory responses during schistosome infection and is beneficial to the development of PD-1-based control of liver immunopathology.
Schistosomiasis is a parasitic disease that affects approximately 220 million people and causes serious morbidity and economic problems mainly in (sub)tropical regions. After Schistosoma japonicum or Schistosoma mansoni infection, parasite eggs are trapped in host liver and induce liver inflammation and fibrosis, leading to irreversible impairment of the liver, and even death of the host. Meanwhile, schistosomes also induce strong regulatory mechanisms to suppress inflammation and prevent excessive immunopathology. Considering it is well known that PD-1 plays a critical role in suppressing T cell function, understanding the role of PD-1 in modulating immune responses during schistosome infection is necessary for the development of PD-1-based control of liver damage in schistosomiasis. Here, increased PD-1 expression in CD4+ T cells from both humans and mice with schistosome infection was shown. We further showed that PD-1 blockade preferentially augmented Th2 cell responses and ultimately resulted in more severe liver immunopathology in mice with Schistosomiasis japonica, suggesting that PD-1 signaling is beneficial to further explore therapeutic possibilities for preventing the excessive liver immunopathology.
Blast-induced traumatic brain injury (bTBI) is a signature wound of modern warfare. The current incomplete understanding of its injury mechanism impedes the development of strategies for effective protection of bTBI. Despite a considerable amount of experimental animal studies focused on the evaluation of brain neurotrauma caused by blast exposure, there is very limited knowledge on the biomechanical responses of the gyrenecephalic brain subjected to primary free-field blast waves imposed in vivo. This study aims to evaluate the external and internal mechanical responses of the brain against different levels of blast loading with Yucatan swine in free field. The incident overpressure (IOP) was generated using 3.6 kg of C4 charge placed at three standoff distances from the swine. Five swine were exposed to a total of 19 blasts. The three average peak IOP pressure levels in this study were 148.8, 278.9, and 409.2 kPa as measured by a pencil probe. The duration of the first positive wave was in the range of 2.1–3 ms. Pressure changes in the brain and head kinematics were recorded with intracranial pressure (ICP) sensors, linear accelerometers, and angular rate sensors. The corresponding average peak ICPs were in the range of 79–143, 210–281, and 311–414 kPa designated as low, medium, and high blast level, respectively. Peak head linear accelerations were in the range of 120–412 g. A positive correlation between IOP and its corresponding biomechanical responses of the brain was also observed. These experimental data can be used to validate computer models of bTBI.
free-field blast; head kinematics; traumatic brain injury; swine; intracranial pressure
Bacillus thuringiensis (Bt), one of the most successful biopesticides, may expand its potential by producing bacteriocins (thuricins). The aim of this study was to investigate the antimicrobial potential of a novel Bt bacteriocin, thuricin BtCspB, produced by Bt BRC-ZYR2. The results showed that this bacteriocin has a high similarity with cold-shock protein B (CspB). BtCspB lost its activity after proteinase K treatment; however it was active at 60 °C for 30 min and was stable in the pH range 5–7. The partial loss of activity after the treatments of lipase II and catalase were likely due to the change in BtCspB structure and the partial degradation of BtCspB, respectively. The loss of activity at high temperatures and the activity variation at different pHs were not due to degradation or large conformational change. BtCspB did not inhibit four probiotics. It was only active against B. cereus strains 0938 and ATCC 10987 with MIC values of 3.125 μg/mL and 0.781 μg/mL, and MBC values of 12.5 μg/mL and 6.25 μg/mL, respectively. Taken together, these results provide new insights into a novel cold shock protein-like bacteriocin, BtCspB, which displayed promise for its use in food preservation and treatment of B. cereus-associated diseases.
The present study aimed to examine the anti-inflammatory actions of oleoylethanolamide (OEA) in lipopolysaccharide (LPS)-induced THP-1 cells. The cells were stimulated with LPS (1 μg/ml) in the presence or absence of OEA (10, 20 and 40 μM). The pro-inflammatory cytokines were evaluated by qRT-PCR and ELISA. The THP-1 cells were transiently transfected with PPARα small-interfering RNA, and TLR4 activity was determined with a blocking test using anti-TLR4 antibody. Additionally, a special inhibitor was used to analyse the intracellular signaling pathway. OEA exerted a potent anti-inflammatory effect by reducing the production of pro-inflammatory cytokines and TLR4 expression, and by enhancing PPARα expression. The modulatory effects of OEA on LPS-induced inflammation depended on PPARα and TLR4. Importantly, OEA inhibited LPS-induced NF-κB activation, IκBα degradation, expression of AP-1, and the phosphorylation of ERK1/2 and STAT3. In summary, our results demonstrated that OEA exerts anti-inflammatory effects by enhancing PPARα signaling, inhibiting the TLR4-mediated NF-κB signaling pathway, and interfering with the ERK1/2-dependent signaling cascade (TLR4/ERK1/2/AP-1/STAT3), which suggests that OEA may be a therapeutic agent for inflammatory diseases.
The aim of this study was to evaluate clinicopathological risk factors associated with the fatal outcome of oral squamous cell carcinoma (OSCC) in a large cohort of Chinese patients, and to construct tissue microarrays (TMAs) using this cohort. Univariate and multiple logistic regression analyses were performed to evaluate the predictors of poor prognosis in a cohort of 232 patients with OSCC, after which the patient tumor tissues were used to construct TMAs. Univariate logistic regression analysis indicated that a poor outcome of OSCC was associated with the male gender, a history of smoking, the tumor-node-metastasis stage and lymph node metastasis. Multiple logistic regression analysis demonstrated that an increased risk of mortality in patients with OSCC was significantly and independently associated with lymph node metastasis (odds ratio, 3.421; 95% confidence interval, 1.609–7.273). Therefore, the results of the present study suggested that lymph node metastasis is an independent risk factor associated with a poor prognosis of OSCC patients. TMAs of OSCC were successfully constructed, and are the first TMAs to be reported in mainland Chinese patients.
oral squamous cell carcinoma; cohort study; tissue microarrays; lymph node metastasis
Examine whether osteoarthritis (OA) progression can be delayed by halofuginone in anterior cruciate ligament transection (ACLT) rodent models.
3-month-old male C57BL/6J (wild type; WT) mice and Lewis rats were randomised to sham-operated, ACLT-operated, treated with vehicle, or ACLT-operated, treated with halofuginone. Articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. Immunostaining, flow cytometry, RT-PCR and western blot analyses were conducted to detect relative protein and RNA expression. Bone micro CT (μCT) and CT-based microangiography were quantitated to detect alterations of microarchitecture and vasculature in tibial subchondral bone.
Halofuginone attenuated articular cartilage degeneration and subchondral bone deterioration, resulting in substantially lower OARSI scores. Specifically, we found that proteoglycan loss and calcification of articular cartilage were significantly decreased in halofuginone-treated ACLT rodents compared with vehicle-treated ACLT controls. Halofuginone reduced collagen X (Col X), matrix metalloproteinase-13 and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS 5) and increased lubricin, collagen II and aggrecan. In parallel, halofuginone-attenuated uncoupled subchondral bone remodelling as defined by reduced subchondral bone tissue volume, lower trabecular pattern factor (Tb.pf) and increased thickness of subchondral bone plate compared with vehicle-treated ACLT controls. We found that halofuginone exerted protective effects in part by suppressing Th17-induced osteoclastic bone resorption, inhibiting Smad2/3-dependent TGF-β signalling to restore coupled bone remodelling and attenuating excessive angiogenesis in subchondral bone.
Halofuginone attenuates OA progression by inhibition of subchondral bone TGF-β activity and aberrant angiogenesis as a potential preventive therapy for OA.
Osteoarthritis; Arthritis; Treatment
Recent upsurge of new HIV infections among men who have sex with men (MSM) is a major concern in China. Paucity of national-level information regarding the burden and predictors of this progressive epidemic of new infections called for a multi-centric, timely and comprehensive investigation.
Mixed methods were used to recruit MSM from seven cities in China between 2012 and 2013. Recent and established HIV infections were estimated by Western Blot and BED HIV-1 capture enzyme immunoassay. Syphilis and herpes simplex virus-2 (HSV-2) were also tested.
A total of 4496 eligible MSM were recruited. The majority was aged ≤35 years (77.5 %), migrants (60.3 %), never married (69.8 %), and played receptive role in anal sex (70.5 %). The HIV prevalence was 9.9 %, and 41.9 % were recently infected, with sensitivity/specificity adjusted HIV incidence of 8.9 (95 % CI: 7.6-10.2)/100 Person-Years. The prevalence of history HSV-2 and syphilis were 12.5 % and 8.5 %, respectively. Recent HIV infection was associated with having multiple male partners (aOR = 1.4, 95 % CI 1.1-1.9), recreational drug use (aOR = 2.2, 95 % CI 1.6-3.0), anal bleeding (aOR = 2.1, 95 % CI 1.4-3.0), syphilis infection (aOR = 2.8, 95 % CI 1.9-4.3) and history HSV-2 infection (aOR = 2.3, 95 % CI 1.5-3.3).
High rate of recent HIV infection is potentially resulting in progressive deterioration of the overall HIV epidemic among MSM in China. Targeted interventions to address high-risk MSM including those having multiple partners, history of recreational drug use and syphilis or HSV-2 infection seemed to be the need of the hour.
Electronic supplementary material
The online version of this article (doi:10.1186/s40249-016-0178-x) contains supplementary material, which is available to authorized users.
Men who have sex with men (MSM); HIV; Incidence; BED HIV-1 capture enzyme immunoassay (BED-CEIA)
Hypoxia-inducible factor (HIF)-1α plays a critical role in coupling angiogenesis with osteogenesis during bone development and regeneration. Salidroside (SAL) has shown anti-hypoxic effects in vitro and in vivo. However, the possible roles of SAL in the prevention of hypoxia-induced osteoporosis have remained unknown. Two osteoblast cell lines, MG-63 and ROB, were employed to evaluate the effects of SAL on cell viability, apoptosis, differentiation and mineralization in vitro. Rats subjected to ovariectomy-induced bone loss were treated with SAL in vivo. Our results showed that pre-treatment with SAL markedly attenuated the hypoxia-induced reductions in cell viability, apoptosis, differentiation and mineralization. SAL down-regulated HIF-1α expression and inhibited its translocation; however, SAL increased its transcriptional activity and, consequently, up-regulated vascular endothelial growth factor (VEGF). In vivo studies further demonstrated that SAL caused decreases in the mineral, alkaline phosphatase (ALP), and BGP concentrations in the blood of ovariectomized (OVX) rats. Moreover, SAL improved the trabecular bone microarchitecture and increased bone mineral density in the distal femur. Additionally, SAL administration partially ameliorated this hypoxia via the HIF-1α-VEGF signalling pathway. Our results indicate that SAL prevents bone loss by enhancing angiogenesis and osteogenesis and that these effects are associated with the activation of HIF-1α signalling.
Several lines of evidence suggest that neuregulin 1 (NRG1) signaling may influence cognitive function and neuropathology in Alzheimer’s disease (AD). To test this possibility, full-length type I or type III NRG1 was overexpressed via lentiviral vectors in the hippocampus of line 41 AD mouse. Both type I and type III NRG1 improves deficits in the Morris water-maze behavioral task. Neuropathology was also significantly ameliorated. Decreased expression of the neuronal marker MAP2 and synaptic markers PSD95 and synaptophysin in AD mice was significantly reversed. Levels of Aβ peptides and plaques were markedly reduced. Furthermore, we showed that soluble ectodomains of both type I and type III NRG1 significantly increased expression of Aβ-degrading enzyme neprilysin (NEP) in primary neuronal cultures. Consistent with this finding, immunoreactivity of NEP was increased in the hippocampus of AD mice. These results suggest that NRG1 provides beneficial effects in candidate neuropathologic substrates of AD and, therefore, is a potential target for the treatment of AD.
De novo mutations (DNMs) are important in Autism Spectrum Disorder (ASD), but so far analyses have mainly been on the ~1.5% of the genome encoding genes. Here, we performed whole genome sequencing (WGS) of 200 ASD parent-child trios and characterized germline and somatic DNMs. We confirmed that the majority of germline DNMs (75.6%) originated from the father, and these increased significantly with paternal age only (p=4.2×10−10). However, when clustered DNMs (those within 20kb) were found in ASD, not only did they mostly originate from the mother (p=7.7×10−13), but they could also be found adjacent to de novo copy number variations (CNVs) where the mutation rate was significantly elevated (p=2.4×10−24). By comparing DNMs detected in controls, we found a significant enrichment of predicted damaging DNMs in ASD cases (p=8.0×10−9; OR=1.84), of which 15.6% (p=4.3×10−3) and 22.5% (p=7.0×10−5) were in the non-coding or genic non-coding, respectively. The non-coding elements most enriched for DNM were untranslated regions of genes, boundaries involved in exon-skipping and DNase I hypersensitive regions. Using microarrays and a novel outlier detection test, we also found aberrant methylation profiles in 2/185 (1.1%) of ASD cases. These same individuals carried independently identified DNMs in the ASD risk- and epigenetic- genes DNMT3A and ADNP. Our data begins to characterize different genome-wide DNMs, and highlight the contribution of non-coding variants, to the etiology of ASD.
PMID: 27525107 CAMSID: cams5778
Primitive neuroectodermal tumors (PNETs) are small, round cell tumors that may be classified as peripheral or central, based on their site of origin. PNETs often arise in the soft tissue or bone of young adults. Although not common, PNETs have been described in other organs, including the gonads, kidneys, myocardium and pancreas, but rarely in the lungs without chest wall or pleural involvement. The present study reports a rare case of peripheral PNET (pPNET), which originated in the lung. A 37-year-old female patient presented at Xuzhou Central Hospital (Xuzhou, China) with a history of a dry cough, mild dyspnea and slight pain in the left chest. Histopathological and immunohistochemical analyses permitted the diagnosis of a pPNET. The patient was treated with surgical resection, followed by chemotherapy (including cyclophosphamide, cisplatin and vincristine), radiotherapy and traditional Chinese medicine (including Kanglaite and Shenqi Fuzheng injections). At the time of writing, the patient was alive with no sign of recurrence and under regular follow-ups at the Outpatient Clinic of Xuzhou Central Hospital.
primitive neuroectodermal tumor; lung; diagnosis; treatment
Many behaviors necessary for organism survival are learned anew and become organized as complex sequences of actions. Recent studies suggest that cortico-basal ganglia circuits are important for chunking isolated movements into precise and robust action sequences that permit the achievement of particular goals. During sequence learning many neurons in the basal ganglia develop sequence-related activity - related to the initiation, execution, and termination of sequences - suggesting that action sequences are processed as action units. Corticostriatal plasticity is critical for the crystallization of action sequences, and for the development of sequence-related neural activity. Furthermore, this sequence-related activity is differentially expressed in direct and indirect basal ganglia pathways. These findings have implications for understanding the symptoms associated with movement and psychiatric disorders.
Cardiovascular diseases are the major challenge to modern medicine. Intervention to cardiovascular cells is crucial for treatment of the diseases. Here we report a novel intervention to vascular smooth muscle (VSM) cells by optogenetics. Channelrhodopsin in a tandem with YFP was selectively expressed in smooth muscle of transgenic mice in which YFP fluorescence was found in arterial walls of various tissues. In dissociated VSM cells from the mice blue light evoked inward currents, leading to depolarization and contraction. In isolated mesenteric arterial rings, optostimulation produced vasoconstriction that was reproducible, sustained, light intensity-dependent and comparable to popular vasoconstrictors. Blue light raised robustly coronary resistance without significant effects on heart rate and pulse pressure. Optostimulation produced renal vasoconstriction as well. The optical vasoconstriction had temporal resolutions less than 40s in these organs. These results indicate that optical vasoconstriction can be effectively produced in various organs with channelrhodopsin expression in VSM cells.
vascular smooth muscle cells; cardiovascular rhodopsin; transgenic mice; optogenetics; Channelrhodopsin
Aneuploidy and copy-number alterations (CNAs) are a hallmark of human cancer. Although genetically engineered mouse models (GEMMs) are commonly used to model human cancer, their chromosomal landscapes remain underexplored. Here we use gene expression profiles to infer CNAs in 3,108 samples from 45 mouse models, providing the first comprehensive catalogue of chromosomal aberrations in cancer GEMMs. Mining this resource, we find that most chromosomal aberrations accumulate late during breast tumorigenesis, and observe marked differences in CNA prevalence between mouse mammary tumours initiated with distinct drivers. Some aberrations are recurrent and unique to specific GEMMs, suggesting distinct driver-dependent routes to tumorigenesis. Synteny-based comparison of mouse and human tumours narrows critical regions in CNAs, thereby identifying candidate driver genes. We experimentally validate that loss of Stratifin (SFN) promotes HER2-induced tumorigenesis in human cells. These results demonstrate the power of GEMM CNA analysis to inform the pathogenesis of human cancer.
Genetically engineered mouse models of cancer are useful in identifying oncogenes and tumour suppressors. Here, the authors use gene expression profiles to generate a catalogue of copy number aberrations in 45 mouse models, and compare mouse and human tumours to identify additional drivers of tumorigenesis.
Phosphorus (P) is an essential nutrient for aquatic organisms; however, excessive P inflow to limnetic ecosystems can induce eutrophication. P concentrations in the rivers, wetlands and lakes of Eastern China have been amplified by fertilizer and sewage inputs associated with the development of industry and agriculture. Yet, knowledge of the distribution and speciation of P is lacking at the regional scale. We determined the distribution and speciation of P in limnetic ecosystems in Eastern China using Standards, Measurements and Testing (SMT) and phosphorus nuclear magnetic resonance (31P-NMR). The results indicate that P pollution in surface sediments was serious. Inorganic P (Pi) was the primary drive of variation in total P (TP) among different river systems, and Pi accounted for 71% to 90% of TP in surface sediment in Eastern China. Also, the concentrations of TP and Pi varied among watersheds and Pi primarily drove the variation in TP in different watersheds. Sediments less than 10-cm deep served as the main P reservoir. Environmental factors affect the speciation and origin of P. NaOH-Pi, HCl-Pi and organic P (Po) were related to pH accordingly at the regional scale. The physicochemical properties of sediments from different limnetic ecosystems affect the P speciation. HCl-Pi was higher in wetland sediments than in riverine and lake sediments in Eastern China. Conversely, NaOH-Pi was lowest in wetland sediments. Total Po concentration was lower in riverine sediments than in other sediments, but Mono-P was higher, with an average concentration of 48 mg kg−1. Diesters-P was highest in lake sediments. By revealing the regional distribution of TP, Pi and Po, this study will support eutrophication management in Eastern China.
Hepatitis B virus (HBV) infection is a common infectious disease. Here we perform a genome-wide association study (GWAS) among Chinese populations to identify novel genetic loci involved in persistent HBV infection. GWAS scan is performed in 1,251 persistently HBV infected subjects (PIs, cases) and 1,057 spontaneously recovered subjects (SRs, controls), followed by replications in four independent populations totally consisting of 3,905 PIs and 3,356 SRs. We identify a novel locus at 8p21.3 (index rs7000921, odds ratio=0.78, P=3.2 × 10−12). Furthermore, we identify significant expression quantitative trait locus associations for INTS10 gene at 8p21.3. We demonstrate that INST10 suppresses HBV replication via IRF3 in liver cells. In clinical plasma samples, we confirm that INST10 levels are significantly decreased in PIs compared with SRs, and negatively correlated with the HBV load. These findings highlight a novel antiviral gene INTS10 at 8p21.3 in the clearance of HBV infection.
This genome-wide association study on persistent hepatitis B virus (HBV) infection among Chinese confirms previously associated genetic loci while discovering a novel protective locus at 8p21.3. The study also demonstrates the nearby gene INST10 suppresses HBV replication in vitro.
The effects of induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) in high-risk (stage III-IVb with EBV DNA≥4000 copies/ml) nasopharyngeal carcinoma (NPC) patients are unclear.
A total of 325 high-risk NPC patients treated with IC+CCRT or CCRT alone who were treated with intensity-modulated radiation therapy (IMRT) between March 2007 and March 2013 were included. For each patient in the IC+CCRT group, a matched pair in the CCRT group was matching for: gender, age, T stage, N stage, clinical stage and WHO (World Health Organization) type. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRFS).
There were no significant differences in OS, PFS, DMFS, and LRFS between the IC+CCRT (148 patients) and CCRT (177 patients) groups. After matching, 103 paired patients were analyzed, and there were no differences between the IC+CCRT and CCRT groups regarding clinical outcomes. Based on the subgroup analysis of 156 very-high-risk patients (stage N2-3 with EBV DNA ≥4000 copies/ml), the 5-year OS of the IC+CCRT and CCRT groups was 84.3% and 67.5% (P =0.033), respectively. Based on our multivariate analysis, the treatment group was significantly associated with OS (P=0.034; HR0.451, 95%CI 0.216-0.941).
IC+CCRT did not improve the clinical outcomes of high-risk NPC patients compared to CCRT alone. However, in very-high-risk patients, IC+CCRT treatment led to increased OS compared to patients received CCRT treatment alone.
nasopharyngeal carcinoma; induction chemotherapy; concurrent chemotherapy; IMRT; EBV DNA
Both bisphenol A (BPA, an endocrine disrupting chemicals) and genistein (a phytoestrogen mainly derived from leguminosae) are able to bind to estrogen receptors, but they are considered to have different effects on metabolic syndrome, surprisingly. We here investigate the effects of an environmentally relevant dose of BPA alone and the combined effects with genistein on lipid metabolism in rats. Eight groups of adult male Wistar rats, fed with either standard chow diet or high-fat diet, were treated with BPA (50μg/kg/day), genistein (10mg/kg/day), and BPA plus genistein for 35 weeks, respectively. Metabolic parameters in serum and liver were determined; the hematoxylin/eosin and oil Red O staining were used to observe liver histologically; gene expressions related to hepatic lipid metabolism were analyzed by Real-time PCR; protein expressions of PPARγ, PPARα and LC3 in liver were analyzed by western blotting. No difference of body weight gain, total energy intake, liver weight/body weight or body fat percentage in both STD- and HFD-fed sub-groups was observed after treatment with BPA, genistein, or BPA plus genistein (P>0.05). Genistein alleviated lipid metabolism disorder and decreased the mRNA and protein expression of PPARγ (P<0.05), and increased the protein expression of LC3II (P<0.05) in liver of HFD-fed rats. However, BPA treatment had no effect on lipid metabolism in rats alone (P>0.05) or combined with genistein. Our findings suggest that long-term environmentally relevant dose of BPA did not affect lipid metabolism, and had no synergetic or antagonistic roles on genistein’s beneficial function on hepatic lipid metabolism.
PRIME time: We report the synthesis of a pH-insensitive blue fluorophore, 7-aminocoumarin, by using palladium-catalyzed Buchwald–Hartwig cross coupling. 7-Aminocoumarin can be used to tag recombinant proteins on the cell surface and inside living cells through PRIME (probe incorporation mediated by enzymes), and unlike 7-hydroxycoumarin, can be visualized in acidic organelles such as endosomes.
cell imaging; cross-coupling; enzyme engineering; fluorescent probes; palladium