A SNP in PLAG1 is associated with body height trait in Chinese cattle.

Stature is an important quantitative trait for cattle performance, which influences herd productivity. Previous studies have reported that an SNP (AC_000171.1:g.25015640G>T, rs109815800) in Pleomorphic adenoma gene 1 (PLAG1) on chromosome 14 (CHR14) is associated with bovine stature. To validate whether rs109815800 is associated with the body height of Chinese cattle, we carried out an association analysis using 558 adult cattle samples from seven populations. Then, 1038 samples from 38 Chinese cattle breeds were used to show the geographical distribution of this variant in China. The results showed that the Q allele (G allele) increased the height of cattle. Furthermore, the frequencies of Q allele in Chinese native breeds tend to decrease from northern China to southern China, and the frequency of Q allele in two Chinese beef cattle breeds is much higher than that in another 36 Chinese local cattle breeds. Our data suggest that the prevalence of the Q allele is correlated with latitude in China.

Genetic diversity and maternal origin of Northeast African and South American donkey populations.

To investigate the mtDNA variation and origin of maternal lineages in South American donkeys and to reassess the domestication of donkeys in northeast Africa, we analyzed sequences (489 bp of the D-loop) from 323 domestic donkeys sampled from Peru, Brazil, Ethiopia and Egypt. Altogether, the 323 sequences displayed 53 different haplotypes (45 in Ethiopia, 14 in Egypt, eight in Peru and six in Brazil). Among the four populations, Egyptian donkeys possessed the highest haplotype diversity (0.910 ± 0.032), followed by Brazilian donkeys (0.879 ± 0.060). The Clade I haplotypes dominated in Peruvian donkeys (65%), whereas Clade II haplotypes dominated in Brazilian donkeys (67%). Estimates of FST values showed a high genetic differentiation between Peruvian and Brazilian donkey populations (FST  = 0.4066), which could be explained by the complex introduction history of South American donkeys. Phylogeographic analysis indicates that northeast Africa could be the most probable domestication center for Clade I donkeys. Analysis of molecular variance confirmed a weak genetic structure in domestic donkey populations among four continents (Europe, Asia, Africa and South America).

PRLH and SOD1 gene variations associated with heat tolerance in Chinese cattle.

With the proposed global climate change, heat tolerance is becoming increasingly important to the sustainability of livestock production systems. Results from previous studies showed that variants in the prolactin releasing hormone (PRLH) (AC_000160.1:g.11764610G>A) and superoxide dismutase 1 (SOD1) (AC_000158.1:g.3116044T>A) genes play an important role in heat tolerance in African indicine cattle. However, it is unknown whether or not the mutations are associated with heat tolerance in Chinese cattle. In this study, PCR and DNA sequencing were used to genotype two missense mutations in 725 individuals of 30 cattle breeds. Analysis results demonstrated that two classes of base substitution were detected at two loci: AC_000160.1:g.11764610G>A and AC_000158.1:g.3116044T>A or T>C respectively, with amino acid substitutions arginine to histidine and phenylalanine to isoleucine or leucine. The frequencies of the G and T alleles of the two loci gradually diminished from northern groups to southern groups of native Chinese cattle, whereas the frequencies of A and A or C alleles showed a contrary pattern, displaying a significant geographical difference across native Chinese cattle breeds. Additionally, analysis of these two loci in Chinese indigenous cattle revealed that two SNPs were significantly associated with mean annual temperature (T), relative humidity (RH) and temperature humidity index (THI) (P < 0.01), suggesting that cattle with A or C alleles were distributed in regions with higher T, RH and THI. Our results suggest that the two mutations of PRLH and SOD1 genes in Chinese cattle were associated with the heat tolerance.

Population structure and ancestry of Qinchuan cattle.

The aim of this study was to estimate population structure and ancestry of Qinchuan cattle by genotyping 27 individuals using the GeneSeek HD 77k BeadChip, and another 1355 cattle representing breeds distributed worldwide, which had been genotyped using the Illumina Bovine 50k BeadChip. Qinchuan cattle were characterized by a dominant Bos taurus ancestry, accompanied by a considerable proportion of Bos indicus ancestry based on principal components analysis and supervised admixture analysis. A small proportion of Bos javanicus ancestry was detected as well. A similar admixture pattern in both Qinchuan and Turkish cattle breeds reflects their similar degrees of zebu introgression. Our study presents a relatively clear view of the population structure and ancestry of Qinchuan cattle, serving to benefit our understanding of this breed and leading to better targeted conservation approaches moving forward.

Genetic diversity and paternal origin of domestic donkeys.

Numerous studies have been conducted to investigate genetic diversity, origins and domestication of donkey using autosomal microsatellites and the mitochondrial genome, whereas the male-specific region of the Y chromosome of modern donkeys is largely uncharacterized. In the current study, 14 published equine Y chromosome-specific microsatellites (Y-STR) were investigated in 395 male donkey samples from China, Egypt, Spain and Peru using fluorescent labeled microsatellite markers. The results showed that seven Y-STRs-EcaYP9, EcaYM2, EcaYE2, EcaYE3, EcaYNO1, EcaYNO2 and EcaYNO4-were male specific and polymorphic, showing two to eight alleles in the donkeys studied. A total of 21 haplotypes corresponding to three haplogroups were identified, indicating three independent patrilines in domestic donkey. These markers are useful for the study the Y-chromosome diversity and population genetics of donkeys in Africa, Europe, South America and China.

HSFY and ZNF280BY show copy number variations within 17 water buffalo populations.

Recent transcriptomic analysis of the bovine Y chromosome revealed abundant presence of multi-copy protein coding gene families on the male-specific region of the Y chromosome (MSY). Copy number variations (CNVs) of several MSY genes are closely related to semen quality and male reproduction in cattle. However, the CNVs of MSY genes in water buffalo are largely unknown. Therefore, this study aimed to investigate the CNVs of HSFY and ZNF280BY of 298 buffaloes from 17 populations distributed in China, Vietnam and Laos using quantitative PCR. Our results revealed that the median copy numbers of the HSFY and ZNF280BY genes were 47 (ranging from 20 to 145) and 269 (ranging from 73 to 974) respectively. In conclusion, this study indicated that HSFY and ZNF280BY showed abundant CNVs within swamp buffalo populations.

Frequency of gray coat color in native Chinese horse breeds.

Gray horses are born colored, and they then gradually lose their hair pigmentation. Tremendous progress has been made in identifying the genes responsible for graying with age in horses in recent years. Results show that gray coat color in horses is caused by a 4.6-kb duplication in intron 6 of the syntaxin 17 gene (STX17), which constitutes a cis-acting-regulatory mutation. However, little is known about the gray phenotype in native Chinese horses. This study was conducted to explore the frequency distribution of the gray mutation in native Chinese horse breeds. A total of 489 samples from 14 native Chinese horse breeds were genotyped for the STX17 duplication using a simplified conventional PCR-based method. The results show that the gray mutation was present in 12 native Chinese horse breeds, except the Balikun and Guanzhong breeds. The Chakouyi and Hequ breeds had the highest frequency of the gray mutation (P(G) = 0.367 and P(G) = 0.274, respectively). There was no significant geographical difference in the distribution of gray coat color across native Chinese horse breeds. Our results suggest that gray is a common coat color in Chinese horses.

Chronic stress causes neuroendocrine-immune disturbances without affecting renal vitamin D metabolism in rats.

INTRODUCTION: Vitamin D (VD) insufficiency has been repeatedly observed in the medical conditions associated with inflammation, such as cardiovascular disease, diabetes and depression. However, contrasting to the observational evidence, randomized trials of VD supplementation failed to demonstrate such link. Given the recent evidence that the inflammatory process can in turn alter VD metabolism, it has been hypothesized that the insufficient VD status could be the result rather than the cause of chronic inflammation involved in the onset of depression and other disease conditions. MATERIALS AND METHODS: Chronic mild stress (CMS) is a valid animal model of depression that accompanied with neuroendocrine-immune disturbances. In the present research, we assessed serum VD concentrations and renal expression of the cytochromes P450 enzymes involved in VD activation (CYP27B1) and catabolism (CYP24A1) of rats following 8-week exposure to CMS. RESULTS: While CMS induced the rats to a depression-like state and increased serum levels of the proinflammatory cytokines and corticosterone, and the antidepressant, sertraline, mitigated depression-like behaviors and neuroendocrine-immune disturbances, neither the stress regimen nor sertraline significantly affected endocrine metabolism of VD. CONCLUSION: Our data suggest that the stress-induced neuroendocrine-immune disturbances may account for the development of depression, but are not responsible for the insufficient VD status that frequently observed in depressed patients.

Novel Y-chromosome polymorphisms in Chinese domestic yak.

Y-chromosome-specific haplotypes (Y-haplotypes) constructed using single nucleotide polymorphisms (Y-SNPs) in the MSY (male-specific region of the Y-chromosome) are valuable in population genetic studies. But sequence variants in the yak MSY region have been poorly characterized so far. In this study, we screened a total of 16 Y-chromosome-specific gene segments from the ZFY, SRY, UTY, USP9Y, AMELY and OFD1Y genes to identify Y-SNPs in domestic yaks. Six novel Y-SNPs distributed in the USP9Y (g.223C>T), UTY19 (g.158A>C and g.169C>T), AMELY2 (g.261C>T), OFD1Y9 (g.165A>G) and SRY4 (g.104G>A) loci, which can define three Y-haplotypes (YH1, YH2 and YH3) in yaks, were discovered. YH1 was the dominant and presumably most ancient haplotype based on the comparison of UTY19 locus with other bovid species. Interestingly, we found informative UTY19 markers (g.158A>C and g.169C>T) that can effectively distinguish the three yak Y-haplotypes. The nucleotide diversity was 1.7 × 10(-4) ± 0.3 × 10(-4) , indicating rich Y-chromosome diversity in yaks. We identified two highly divergent lineages (YH1 and YH2 vs. YH3) that share similar frequencies (YH1 + YH2: 0.82-0.89, YH3: 0.11-0.18) among all three populations. In agreement with previous mtDNA studies, we supported the hypothesis that the two highly divergent lineages (YH1 and YH2 vs. YH3) derived from a single gene pool, which can be explained by the reunion of at least two paternal populations with the divergent lineages already accumulated before domestication. We estimated a divergence time of 408 110 years between the two divergent lineages, which is consistent with the data from mitochondrial DNA in yaks.

Non-malignant haematology research in the UK: looking forward to new opportunities.

Over the last few years there has been rapid and radical change in the way clinical research in the UK is funded and supported within the NHS. This has resulted from restructuring and major new investment in research infrastructure, co-ordinated through Clinical Local Research Networks (CLRNs) and equivalent organisations in the devolved nations. CLRNs have resources to support local researchers undertake studies that have been adopted on to the national research portfolio. For example, CLRNs can help with gaining local approvals or provide research nurses to recruit patients, undertake study procedures and perform data entry. CLRNs can establish Local Speciality Groups in a number of areas of medicine, including nonmalignant haematology. These new networks offer non-malignant haematology access to significant new resources and a major opportunity to support clinical research for the benefit of our patients.

[Design and application of static progressive ankle foot orthosis].

The scar contracture of Achilles tendon in burn patients after operation is easy to cause " foot drop" , which leads to ankle dorsiflexion dysfunction. To solve this problem, the authors designed and made a static progressive ankle foot orthosis. The foot support part and the crus support part of the orthotic device are connected by rivets, and the distal end of the foot support part and the proximal end of the crus support part are pulled by the traction belt on both sides, gradually improving the ankle dorsiflexion function. This static progressive ankle foot orthosis is simple, practical, cost-effective, and worthy of clinical promotion.

[Effect of high-titer plasma in pediatric patients with severe adenovirus pneumonia].

Objective: To explore the efficacy and safety of high-titer plasma in the treatment of pediatric patients with severe adenovirus pneumonia. Methods: The clinical data of 92 pediatric patients with severe adenovirus pneumonia admitted to pediatric intensive care unit (PICU) in Guangzhou Women and Children's Medical Center from January 2016 to October 2019 were retrospectively collected. According to the treatment with or without high-titer plasma, the patients were divided into plasma treatment group (n=41) and non-plasma treatment group (n=51). The 51 patients with chest radiograph showing more than half the lungs involved were divided into plasma treatment group (n=29) and non-plasma treatment group (n=22). According to fever duration before plasma treatment, patients were divided into early group (≤5 days, n=5), middle group (>5-10 days, n=14), and late group (>10 days, n=22). Baseline data, therapeutic effects, and prognosis of patients in each group were analyzed with t test, non-parametric rank sum test, one-way ANOVA and chi-square test. Results: Ninety-two patients were included. There were no significant differences in age, gender, body weight, fever duration, sequential organ failure assessment, and Murray lung injury score between plasma treatment group and non-plasma treatment group before admission (all P>0.05). The proportion of patients whose temperature drop to normal within 5 days was higher in plasma treatment group than that in non-plasma treatment group (88% (36/41) vs. 69% (35/51), χ(2)=4.745, P=0.029). However, there were no significant differences between the two groups in the proportions of invasive ventilator weaning within 14 days (63% (26/41) vs. 76% (39/51), χ(2)=1.868, P=0.172), transfer out from PICU within 14 days (49% (20/41) vs. 69% (35/51), χ(2)=3.724, P=0.054), discharge within 28 days (51% (21/41) vs. 61%(31/51), χ(2)=0.846, P=0.358) and survived patients (85% (35/41) vs. 76%(39/51), χ(2)=1.143, P=0.285). Among patients with severe chest radiograph, the proportions of patients whose temperature drop to normal within 5 days and survived patients were higher in plasma treatment group than those in non-plasma treatment group (86% (25/29) vs. 59% (13/22), χ(2)=4.843, P=0.028; 83% (24/29) vs. 55%(12/22), χ(2)=4.796, P=0.029, respectively). However, there were no significant differences between the two groups in the proportions of invasive ventilator weaning within 14 days (52% (15/29) vs. 59% (13/22), χ(2)=0.274, P=0.601), transfer out from PICU within 14 days (34% (10/29) vs. 45% (10/22), χ(2)=0.632, P=0.427), and discharge within 28 days (45% (13/29) vs. 45% (10/22), χ(2)=0.002, P=0.964). Among early, middle and late group, the proportions of invasive ventilator weaning within 14 days were 2/5, 13/14 and 50% (11/22), respectively, with statistically significant difference (χ(2)=8.119, P=0.017). There were no significant differences in the proportions of patients whose temperature drop to normal within 5 days (4/5, 14/14, 82% (18/22), χ(2)=2.965, P=0.227), transfer out from PICU within 14 days (2/5, 10/14, 36%(8/22), χ(2)=4.386, P=0.112), discharge within 28 days (2/5, 8/14, 50% (11/22), χ(2)=0.462, P=0.794) and survived patients (4/5, 13/14, 82% (18/22), χ(2)=0.966, P=0.617) in the three groups. Only one case with high-titer plasma therapy had rash in the course of infusing plasma and no other adverse reactions were observed. Conclusions: High-titer plasma can shorten the fever time and improve the proportion of survival patients in pediatric severe adenovirus pneumonia. The clinical effect of high-titer plasma is better in 5-10 days of fever course. High-titer plasma is an effective and safe treatment.

[Application of low temperature thermoplastic plate combined with special abdominal band in fixing abdominal pedicled flap for repairing 17 patients with deep electric burn wounds in hands].

If the abdominal pedicled flaps are not well fixed after repair of deep electric burn wounds in hands, many problems such as poor blood supply may occur. In order to solve the above problems, we designed and manufactured the individualized low temperature thermoplastic plate combined with special abdominal band to fix abdominal pedicled flaps for repairing of 17 patients (12 males and 5 females, aged 2-35 years) with deep electric burn wounds in hands from February 2016 to August 2018, and achieved the desired results. The shoulder joint, elbow joint, and wrist joint were fixed by low temperature thermoplastic plate according to the 1/2 circumference of the patient's side chest and upper arm, and the braking of wrist joint and elbow joint was strengthened by special abdominal band. Application of the combined method of fixing abdominal pedicled flaps in repairing deep electric burn wounds in hands has high success rate of flap transplantation. It is simple to make and practical, and worthy of clinical promotion.

[Clinical efficacy observation on combination of narrow-spectrum medium-wave ultraviolet, red light, and low power He-Ne laser in treating post-burn eczema].

Objective: To investigate the clinical effects of combined utilization of narrow-spectrum medium-wave ultraviolet, red light, and low power He-Ne laser on treatment of post-burn eczema. Methods: From July 2014 to July 2017, 80 patients with post-burn eczema who met the study inclusion criteria were treated in our burn rehabilitation center, and their clinical data were analyzed retrospectively. Patients were divided into ultraviolet treatment group, red light treatment group, laser treatment group, and combination treatment group according to the utilized treatment methods, with 20 cases in each group. Patients in ultraviolet treatment group were treated with narrow-spectrum medium-wave ultraviolet once every other day for 10 minutes each time. Patients in red light treatment group and laser treatment group were treated with red-light and low power He-Ne laser respectively once a day for 10 minutes each time. Patients in combination treatment group were treated with combination of the above three methods without sequence or interval time, and the treatment time and interval time were the same as the previously described. All patients were treated for four weeks since the time of admission. The itching degree, surface area of the affected body, degree of keratosis, and degree of cracking of target tissue were evaluated using Eczema Area and Severity Index (EASI) scoring method after each treatment. Eczema improvement rate was calculated according to the total score of EASI to determine the curative effect. The therapeutic effective time was recorded. The therapeutic effective rate was calculated according to the total scores of EASI before treatment for the first time and 4 weeks after treatment. Besides, the adverse reactions of patients were also observed and recorded. Data were analyzed by Chi-square test, Kruskal-Wallis rank sum test, Wilcoxon signed rank sum test, one-way analysis of variance, Least Significant Difference-t test, and Bonferroni correction. Results: Therapeutic effective times of eczema of patients in ultraviolet treatment group, red light treatment group, and laser treatment group were similar, respectively (13.7±1.3), (16.4±1.6), and (15.1±1.7) d (t=0.32, 0.58, 0.74, P>0.05). The therapeutic effective time of combination treatment group was (6.3±0.9) d, significantly shorter than that of ultraviolet treatment group, red light treatment group, or laser treatment group (t=5.62, 4.72, 4.61, P<0.05 or P<0.01). Compared with those before treatment for the first time, eczema itching degree, surface area of affected body, degree of keratosis, degree of cracking, and total score of EASI of patients in ultraviolet treatment group, red light treatment group, laser treatment group, and combination treatment group showed obvious improvement in 4 weeks after treatment (Z=5.372, 4.392, 4.284, 3.998, 4.092, 3.904, 4.042, 4.216, 3.684, 3.890, 5.081, 4.794, 4.094, 3.493, 3.995, 5.084, 4.903, 4.384, 3.995, 4.063, P<0.05 or P<0.01). Each item score and total score of EASI of eczema of patients in the first three groups were close (P>0.05), while each item score and total score of EASI of eczema of patients in combination treatment group was significantly better than those of ultraviolet treatment group, red light treatment group, and laser treatment group (H=2.482, 2.491, 3.583, 3.462, 6.025, 2.492, 3.693, 3.085, 3.482, 6.042, 5.831, 5.831, 4.893, 4.092, 6.931, P<0.05). Therapeutic effective rates of eczema of patients in ultraviolet treatment group, red light treatment group, and laser treatment group were close, respectively 60%, 60%, and 55% (χ(2)=1.46, 1.63, 0.97, P>0.05). The therapeutic effective rate of eczema of patients in combination treatment group was 90%, significantly higher than that of ultraviolet treatment group, red light treatment group, or laser treatment group (χ(2)=3.43, 4.15, 2.97, P<0.05 or P<0.01). There were no serious adverse reactions appeared in patients of all the four groups after treatment. Three patients in ultraviolet treatment group had local skin erythema, which was alleviated after symptomatic treatment. Conclusions: Combination of narrow-spectrum medium-wave ultraviolet, red light, and low power He-Ne laser in treating post-burn eczema is superior to single therapy in terms of clinical effective time and efficacy, which has no obvious adverse reaction and is worthy of promotion.

Accuracy of three-dimensional soft tissue prediction for Le Fort I osteotomy using Dolphin 3D software: a pilot study.

Three-dimensional (3D) soft tissue prediction is replacing two-dimensional analysis in planning for orthognathic surgery. The accuracy of different computational models to predict soft tissue changes in 3D, however, is unclear. A retrospective pilot study was implemented to assess the accuracy of Dolphin 3D software in making these predictions. Seven patients who had a single-segment Le Fort I osteotomy and had preoperative (T0) and >6-month postoperative (T1) cone beam computed tomography (CBCT) scans and 3D photographs were included. The actual skeletal change was determined by subtracting the T0 from the T1 CBCT. 3D photographs were overlaid onto the T0 CBCT and virtual skeletal movements equivalent to the achieved repositioning were applied using Dolphin 3D planner. A 3D soft tissue prediction (TP) was generated and differences between the TP and T1 images (error) were measured at 14 points and at the nasolabial angle. A mean linear prediction error of 2.91±2.16mm was found. The mean error at the nasolabial angle was 8.1±5.6°. In conclusion, the ability to accurately predict 3D soft tissue changes after Le Fort I osteotomy using Dolphin 3D software is limited.

[Effects of functional training combined with self-made hand flexing training band in treatment of scar contracture after burn injury of dorsal hand].

Objective: To observe the effects of functional training combined with self-made hand flexing training band in treatment of scar contracture after burn injury of dorsal hand. Methods: Forty-six patients with scar contracture after deep partial-thickness or full-thickness burn injury of dorsal hand hospitalized in our department from March 2013 to February 2015 were divided into routine training group (RT, n=18) and comprehensive training group (CT, n=28) according to their willingness. Two weeks after the wounds were healed, patients in group RT were treated with functional training of hands and self-made pressure gloves, while patients in group CT were treated with self-made hand flexing training band (consisting of nylon strap, flexing band, and velcro) on the basis of those in group RT. All patients were treated for 3 months. Before and after treatment, scar condition of affected hands was assessed with Vancouver Scar Scale (VSS). The range of motion of joints of affected hands was measured by Total Active Movement (TAM) Scale. The function of affected hands was evaluated by Carroll Upper Extremity Function Test. Data were processed with t test, chi-square test, and Mann-Whitney U test. Results: (1) The score of VSS in patients of group RT was (10.0±1.9) points before treatment and (4.4±1.4) points after treatment, with the improved score of (5.6±1.0) points. The score of VSS in patients of group CT was (10.5±1.8) points before treatment and (4.6±1.4) points after treatment, with the improved score of (5.9±1.2) points. There was no statistically significant difference in the improved score of patients between the two groups (t=0.834, P>0.05). The score of VSS in patients of groups RT and CT after treatment was significantly lower than that before treatment (with t values respectively 14.014 and 10.003, P values below 0.01). (2) Before treatment, the ratios of excellent and good results according to TAM were 2/9 in patients of group RT and 3/14 in group CT, with no statistical differences between them (χ(2)=2.140, P>0.05). After treatment, the ratio of excellent and good results according to TAM in patients of group CT (6/7) was higher than that in group RT (5/9, χ(2)=0.023, P=0.038). The ratios of excellent and good results according to TAM in patients of groups RT and CT after treatment were significantly higher than those before treatment (with Z values respectively -2.023 and -4.780, P values below 0.05). (3) The improved score of hand function in patients of group CT was (26±12) points, which was higher than (15±7) points in group RT (t=3.278, P=0.002). The score of hand function in patients of groups RT and CT after treatment was significantly higher than that before treatment (with t values respectively 2.628 and 6.125, P values below 0.05). There were no significant differences in grades of hand function of patients between the two groups before treatment (Z=-0.286, P>0.05). After treatment, the grade of hand function in patients of group CT was higher than that in group RT(Z=-1.993, P=0.046). The grades of hand function in patients of groups RT and CT after treatment were significantly higher than those before treatment (with Z values respectively -2.717 and -4.998, P values below 0.01). Conclusions: For patients with scar contracture after burn injury of dorsal hand, early functional training combined with hand flexing training band can improve the range of motion of hand joints and functional recovery of hand, and the result was better than functional training alone.

Therapeutic efficacy of atypical antipsychotic drugs by targeting multiple stress-related metabolic pathways.

Schizophrenia (SZ) is considered to be a multifactorial brain disorder with defects involving many biochemical pathways. Patients with SZ show variable responses to current pharmacological treatments of SZ because of the heterogeneity of this disorder. Stress has a significant role in the pathophysiological pathways and therapeutic responses of SZ. Atypical antipsychotic drugs (AAPDs) can modulate the stress response of the hypothalamic-pituitary-adrenal (HPA) axis and exert therapeutic effects on stress by targeting the prefrontal cortex (PFC) and hippocampus. To evaluate the effects of AAPDs (such as clozapine, risperidone and aripiprazole) on stress, we compared neurochemical profile variations in the PFC and hippocampus between rat models of chronic unpredictable mild stress (CUMS) for HPA axis activation and of long-term dexamethasone exposure (LTDE) for HPA axis inhibition, using an ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS)-based metabolomic approach and a multicriteria assessment. We identified a number of stress-induced biomarkers comprising creatine, choline, inosine, hypoxanthine, uric acid, allantoic acid, lysophosphatidylcholines (LysoPCs), phosphatidylethanolamines (PEs), corticosterone and progesterone. Specifically, pathway enrichment and correlation analyses suggested that stress induces oxidative damage by disturbing the creatine-phosphocreatine circuit and purine pathway, leading to excessive membrane breakdown. Moreover, our data suggested that the AAPDs tested partially restore stress-induced deficits by increasing the levels of creatine, progesterone and PEs. Thus, the present findings provide a theoretical basis for the hypothesis that a combined therapy using adenosine triphosphate fuel, antioxidants and omega-3 fatty acids as supplements may have synergistic effects on the therapeutic outcome following AAPD treatment.

Whole Mitogenomes Reveal the History of Swamp Buffalo: Initially Shaped by Glacial Periods and Eventually Modelled by Domestication.

The newly sequenced mitochondrial genomes of 107 Asian swamp buffalo (Bubalus bubalis carabensis) allowed the reconstruction of the matrilineal divergence since ~900 Kya. Phylogenetic trees and Bayesian skyline plots suggest a role of the glacial periods in the demographic history of swamp buffalo. The ancestral swamp-buffalo mitogenome is dated ~232 ± 35 Kya. Two major macro-lineages diverged during the 2nd Pleistocene Glacial Period (~200-130 Kya), but most (~99%) of the current matrilines derive from only two ancestors (SA1'2 and SB) that lived around the Last Glacial Maximum (~26-19 Kya). During the late Holocene optimum (11-6 Kya) lineages differentiated further, and at least eight matrilines (SA1, SA2, SB1a, SB1b, SB2a, SB2b, SB3 and SB4) were domesticated around 7-3 Kya. Haplotype distributions support an initial domestication process in Southeast Asia, while subsequent captures of wild females probably introduced some additional rare lineages (SA3, SC, SD and SE). Dispersal of domestic buffaloes created local population bottlenecks and founder events that further differentiated haplogroup distributions. A lack of maternal gene flow between neighboring populations apparently maintained the strong phylogeography of the swamp buffalo matrilines, which is the more remarkable because of an almost complete absence of phenotypic differentiation.

PhIN: A Protein Pharmacology Interaction Network Database.

Network pharmacology is a new and hot concept in drug discovery for its ability to investigate the complexity of polypharmacology, and becomes more and more important in drug development. Here we report a protein pharmacology interaction network database (PhIN), aiming to assist multitarget drug discovery by providing comprehensive and flexible network pharmacology analysis. Overall, PhIN contains 1,126,060 target-target interaction pairs in terms of shared compounds and 3,428,020 pairs in terms of shared scaffolds, which involve 12,419,700 activity data, 9,414 targets, 314 viral targets, 652 pathways, 1,359,400 compounds, and 309,556 scaffolds. Using PhIN, users can obtain interacting target networks within or across human pathways, between human and virus, by defining the number of shared compounds or scaffolds under an activity cutoff. We expect PhIN to be a useful tool for multitarget drug development. PhIN is freely available at http://cadd.pharmacy.nankai.edu.cn/phin/.

A potential mechanism underlying atypical antipsychotics-induced lipid disturbances.

Previous findings suggested that a four-protein complex, including sterol-regulatory element-binding protein (SREBP), SREBP-cleavage-activating protein (SCAP), insulin-induced gene (INSIG) and progesterone receptor membrane component 1 (PGRMC1), within the endoplasmic reticulum appears to be an important regulator responsible for atypical antipsychotic drug (AAPD)-induced lipid disturbances. In the present study, effects of typical antipsychotic drug and AAPDs as well as treatment outcome of steroid antagonist mifepristone (MIF) on the PGRMC1/INSIG/SCAP/SREBP pathway were investigated in rat liver using real-time quantitative polymerase chain reaction (qPCR) and western blot analysis. In addition, serum triacylglycerol, total cholesterol, free fatty acids and various hormones including progesterone, corticosterone and insulin were measured simultaneously. Following treatment with clozapine or risperidone, both lipogenesis and cholesterogenesis were enhanced via inhibition of PGRMC1/INSIG-2 and activation of SCAP/SREBP expressions. Such metabolic disturbances, however, were not demonstrated in rats treated with aripiprazole (ARI) or haloperidol (HAL). Moreover, the add-on treatment of MIF was effective in reversing the AAPD-induced lipid disturbances by upregulating the expression of PGRMC1/INSIG-2 and subsequent downregulation of SCAP/SREBP. Taken together, our findings suggest that disturbances in lipid metabolism can occur at an early stage of AAPD treatment before the presence of weight gain. Such metabolic defects can be modified by an add-on treatment of steroid antagonist MIF enhancing the PGRMC1 pathway. Thus, it is likely that PGRMC1/INSIG-2 signaling may be a therapeutic target for AAPD-induced weight gain.