Three novel structural variations at the major histocompatibility complex and IL12B predispose to psoriasis.

BACKGROUND: Structural variations (SVs; defined as DNA variants ≥ 50 base pairs) have been associated with various complex human diseases. However, research to screen the whole genome for SVs predisposing to psoriasis is lacking. OBJECTIVES: To investigate the association of SVs and psoriasis. METHODS: Using imputation, we performed a genome-wide screen of SVs on five independent cohorts with 45 386 participants from the Han Chinese population. Fine-mapping analysis, genetic interaction analysis and RNA expression analysis were conducted to explore the mechanism of SVs. RESULTS: In total, we obtained 4535 SVs and identified two novel deletions [esv3608550, odds ratio (OR) 2·73 (P < 2·00 × 10-308 ); esv3608542, OR 0·47 (P = 7·40 × 10-28 )] at 6q21·33 (major histocompatibility complex), one novel Alu element insertion [esv3607339; OR 1·22 (P = 1·18 × 10-35 )] at 5q33·3 (IL12B) and confirmed one previously reported deletion [esv3587563; OR 1·30 (P = 9·52 × 10-60 )] at 1q21·2 (late cornified envelope) for psoriasis. Fine-mapping analysis including single-nucleotide polymorphisms (SNPs) and small insertions/deletions revealed that esv3608550 and esv3608542 were independently associated with psoriasis, and a novel independent SNP [rs9378188; OR, 1·65 (P = 3·46 × 10-38 )] was identified at 6q21·33. By genetic interaction analysis and RNA expression analysis, we speculate that the association of two deletions at 6q21·33 with psoriasis might relate to their influence on the expression of HLA-C. CONCLUSIONS: We have constructed the most comprehensive SV map for psoriasis thus far and enriched the genetic architecture and pathogenesis of psoriasis, and highlight the non-negligible impact of SVs on complex diseases.

Modulation of rumen fermentation and microbial community through increasing dietary cation-anion difference in Chinese Holstein dairy cows under heat stress conditions.

AIMS: The effect of increasing dietary cation-anion difference (DCAD) on rumen fermentation and ruminal microbial community in dairy cows under heat stress (HS) conditions were evaluated. METHODS AND RESULTS: This study was performed as a two-period cross-over design during the summer season, with eight lactating dairy cows randomly distributed to either a control DCAD diet (CON: 33·5 mEq/100 g DM) or high DCAD diet (HDCAD: 50·8 mEq/100 g DM). Throughout the present study, the temperature and humidity index (THI; 80·2 ± 4·29) was generally elevated above the threshold (THI = 72) that is reported to cause HS in lactating dairy cows. Rumen liquid samples were collected on 15 and 21 d during each 21 d-period. The absolute concentration of ruminal total volatile fatty acid (TVFA) in HDCAD treatment was significantly (P < 0·05) higher than those in the control, whilst the ruminal pH, NH3 -N, and VFA molar percentages were unaffected through increasing DCAD. Furthermore, the copy numbers of the cellulolytic bacteria Ruminococcus albus and Ruminococcus flavefaciens in rumen fluid significantly (P < 0·05) rose along with the increment of DCAD. Although the Alpha diversity indexes and the bacterial microbiota structure were unaffected, increasing DCAD significantly (P < 0·05) enriched the phylum Fibrobacteres and genus Fibrobacter in the microflora of rumen fluid, whilst the genera Flexilinea and Dubosiella were the most differentially abundant taxa in the control. CONCLUSIONS: Increasing DCAD under HS conditions resulted in a greater concentration of total VFA without affecting rumen bacteria diversity or structure, although the enrichment of some cellulolytic/hemicellulolytic bacteria was observed. SIGNIFICANCE AND IMPACT OF THE STUDY: The present study provides information on the modulation of rumen fermentation and microbial community through the increment of DCAD in Holstein dairy cows under HS conditions.

[Study on lipid production by reusing herb residues of Songling Xuemaikang Capsules].

Songling Xuemaikang Capsules is a Chinese patent medicine mainly made of the Chineses medicine Puerariae Lobatae Radix and leaves of Pinus massoniana. During its production, a large amount of herb extraction residues would be treated as wastes, resulting in resource wasting and serious environmental pollution. In order to solve this problem, we took the hydrolysates of Puerariae Lobatae Radix, P. massoniana leaves, and whole herb residues of Songling Xuemaikang Capsules as the fermentation substrate to explore the ability of Rhodosporidium toruloides to produce microbial lipid. The results showed that the R. toruloides could produce lipid with use of the residues from Songling Xuemaikang Capsules, and the lipid contents reached 33.6%. The lipid products had similar fatty acid composition profiles to those of vegetable oils. Herb residues were converted into fermentation substrates in this study, and were recycled into the production of high value-added compounds to realize the transformation of the wastes, laying the foundation for the sustainable utilization of herb residues.

[Discovery and study on potential effect of herbal pair of Uncariae Ramulus cum Uncis-Eucommiae Cortex on pregnancy hypertension based on network pharmacology and molecular docking].

This study aimed to explore the optimal indications and mechanism of Uncariae Ramulus cum Uncis(UR)-Eucommiae Cortex(EC) in lowering blood pressure based on network pharmacology and molecular docking. Chemical constituents were collected and screened by TCMSP database. Swiss Target Prediction platform was used to predict the related targets of the drug. OMIM, TCMIP and GeneCards databases were used to collect hypertension-related genes, and the intersections were taken to obtain potential targets for anti-hypertensive treatment of UR-EC. FunRich software was used to enrich the clinical phenotype and expression site of potential target of lowering blood pressure to analyze and predict the optimal indications of UR-EC. STRING database was used for KEGG pathway enrichment analysis, and Cytoscape 3.7.2 was used to construct the network of "composition-target-pathway". The key targets and their corresponding components in the network were analyzed and obtained, and then molecular docking was applied for preliminary verification. Twenty potential active components of UR and 24 potential active components of EC were respectively collected, and 92 anti-hypertensive potential targets of UR-EC were obtained. According to FunRich enrichment results, the optimal indication of UR-EC was pregnancy hypertension, which involved calcium signaling pathway, HIF-1 signaling pathway, neuroactive ligand receptor interaction, renin vascular tightening, VEGF signaling pathway, etc. In addition, AKT1, NOS2, ADRB2, F2, NOS3, SCN5 A, HTR2 A and JAK2 were considered as the key targets in the network. The molecular docking results showed that the screened potential active components had high binding activity with the key targets. This study preliminarily revealed that UR-EC may have therapeutic effects on pregnancy hypertension in terms of sedation, anti-hypertension, anti-inflammatory, anti-oxidation, improvement of vascular endothelial function and so on.

[Research progress on effective components of Chinese materia medica in regulating autophagy].

Autophagy is a highly conservative and multi-component activated energy metabolism and self-renewal mechanism, which plays a crucial regulatory role in maintaining the normal physiological state of cells and is involved in various pathological processes. In recent years, the mechanism study has made great progress in regulating autophagy with effective components of Chinese materia medica(CMM),which are reported to prevent and treat cancers, neurodegenerative diseases, cardiovascular diseases and metabolic and immune-related diseases. This review outlines the molecular regulation mechanisms of cell autophagy with CMM components in controlling the above-mentioned diseases. There are many relevant reports on the regulatory mechanisms of autophagy in tumor and cardiovascular cells with CMM monomers. The main chemical structural types are alkaloids, saponins, polyphenols, flavonoids and terpenes. And m-TOR pathway is the main mechanism relating to the regulatory mechanisms of autophagy with CMM. Therefore, the regulatory mec-hanisms of cell autophagy become a new research targeting strategy of therapies with CMM. This review provides evidences for the effectiveness and scientificity of CMM in regulating autophagy, in the expectation of providing references for the in-depth studies of CMM in the field of autophagy and the development of natural autophagy regulators.

Heme oxygenase-1 attenuates the inhibitory effect of bortezomib against the APRIL-NF-κB-CCL3 signaling pathways in multiple myeloma cells: Corelated with bortezomib tolerance in multiple myeloma.

Osteoclasts (OCs) play an essential role in bone destruction in patients with multiple myeloma (MM). Bortezomib can ameliorate bone destruction in patients with MM, but advanced MM often resists bortezomib. We studied the molecular mechanisms of bortezomib tolerance in MM. The expression of the MM-related genes in newly diagnosed patients with MM and normal donors were studied. C-C motif chemokine ligand 3 (CCL3) is a cytokine involved in the differentiation of OCs, and its expression is closely related to APRIL (a proliferation-inducing ligand). We found that bortezomib treatment inhibited APRIL and CCL3. But the heme oxygenase-1 (HO-1) activator hemin attenuated the inhibitory effects of bortezomib on APRIL and CCL3. We induced mononuclear cells to differentiate into OCs, and the enzyme-linked immunosorbent assay showed that the more OCs differentiated, the higher the levels CCL3 secretions detected. Animal experiments showed that hemin promoted MM cell infiltration in mice. The weight and survival rate of tumor mice were associated with HO-1 expression. Immunohistochemical staining showed that HO-1, APRIL, and CCL3 staining were positively stained in the tumor infiltrating sites. Then, MM cells were transfected with L-HO-1/si-HO-1 expression vectors and cultured with an nuclear factor (NF)-kappa B (κB) pathway inhibitor, QNZ. The results showed that HO-1 was the upstream gene of APRIL, NF-κB, and CCL3. We showed that HO-1 could attenuate the inhibitory effect of bortezomib against the APRIL-NF-κB-CCL3 signaling pathways in MM cells, and the tolerance of MM cells to bortezomib and the promotion of bone destruction are related to HO-1.

[Liquid milk exposure and risk assessment of thiocyanate in Chinese populations].

Objective: To analyze liquid milk exposure of thiocyanate among Chinese population and preliminarily assess its health risk. Methods: A total of 2 059 raw milk samples were collected during 2013 and 2014 from 12 Chinese provinces, New Zealand and Netherlands. Farms were chosed according to the main sources of dairy companies, the distribution of farms and the yield of milk. Content of thiocyanate were detected by ion chromatography. Liquid milk consumption data were taken from Chinese beverage and alcoholic beverage consumption survey in 18 cities or counties in 9 provinces, including 16 775 subjects older than 3. A simple distribution model was used to estimate the exposure of thiocyanate from liquid milk. The tolerable daily intake (TDI) of thiocyanate was made 0.08 mg·kg(-1)·d(-1). Then the exposures of different age groups were compared with TDI. Results: Finally, 1 331 samples out of 2 059 were detected to contain thiocyanate. The detection rate was 65%. The average concentration of thiocyanate was 2.11 mg/kg, with a range of 0.10-16.20 mg/kg. The general population's consumption of thiocyanate by drinking liquid milk was 0.001 mg · kg(-1) · d(-1), which was lower than TDI. The P(95) of general population and consumers were 0.009 mg · kg(-1) · d(-1) and 0.020 mg·kg( -1)·d(-1) respectively, which were also lower than TDI. Mean exposures of population aged 3-6, 7-12, 13-17, 18-59 as well as elderly aged 60 and above were 0.007, 0.003, 0.002, 0.001 and 0.001 mg · kg(-1)·d(-1) respectively, which were all lower than TDI. Conclusion: The results suggested that the health risk of thiocyanate exposure by drinking liquid milk among Chinese population was at a low level. However, milk products for children deserve more concern.

Atypical focal cortical dysplasia in a patient with Cowden syndrome.

A macrocephalic girl presented with generalised epilepsy due to focal cortical dysplasia. She later developed multiple hamartomatous lesions and was diagnosed to have Cowden syndrome. The diagnosis was confirmed by identification of a novel frameshift mutation in the PTEN gene of the patient.

Solid-state polymer-particle hybrid electrolytes: Structure and electrochemical properties.

Solid-state electrolytes (SSEs) are challenged by complex interfacial chemistry and poor ion transport through the interfaces they form with battery electrodes. Here, we investigate a class of SSE composed of micrometer-sized lithium oxide (Li2O) particles dispersed in a polymerizable 1,3-dioxolane (DOL) liquid. Ring-opening polymerization (ROP) of the DOL by Lewis acid salts inside a battery cell produces polymer-inorganic hybrid electrolytes with gradient properties on both the particle and battery cell length scales. These electrolytes sustain stable charge-discharge behavior in Li||NCM811 and anode-free Cu||NCM811 electrochemical cells. On the particle length scale, Li2O retards ROP, facilitating efficient ion transport in a fluid-like region near the particle surface. On battery cell length scales, gravity-assisted settling creates physical and electrochemical gradients in the hybrid electrolytes. By means of electrochemical and spectroscopic analyses, we find that Li2O particles participate in a reversible redox reaction that increases the effective CE in anode-free cells to values approaching 100%, enhancing battery cycle life.

Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates.

The structure-activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond. This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio.

Design and synthesis of thiophene dihydroisoquinolines as novel BACE1 inhibitors.

Utilizing a structure based design approach, combined with extensive medicinal chemistry execution, highly selective, potent and novel BACE1 inhibitor 8 (BACE1 Alpha assay IC50=8nM) was made from a weak µM potency hit in an extremely efficient way. The detailed SAR and general design approaches will be discussed.

Design and synthesis of highly selective, orally active Polo-like kinase-2 (Plk-2) inhibitors.

Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-α-synuclein levels in the cerebral cortex.

Association between estimated glomerular filtration rate, ankle-brachial index, and recurrent ischemic stroke in a Chinese population of ischemic stroke patients.

BACKGROUND: Very few studies have examined combined association of estimated glomerular filtration rate (eGFR) and ankle-brachial index (ABI) on recurrent ischemic stroke in patients with ischemic stroke in Chinese populations. PATIENTS AND METHODS: A Chinese population of 1219 ischemic stroke patients was followed up in this six-year prospective study. RESULTS: 1080 ischemic stroke patients with complete follow-up data were included in the statistical analysis. A total of 245 ischemic stroke patients (22.7 %) had recurrent ischemic stroke during follow-up. The Incidence of recurrent ischemic stroke was significantly increased with decreasing eGFR levels and that of patients with eGFR < 30 ml/min/1.73m2 was the highest. Hazard ratio (HR) of eGFR < 30 ml/min/1.73m2 to recurrent ischemic stroke was 2.633 (95 % CI: 1.653 - 4.194) compared with that of eGFR ≥ 60 ml/min/1.73m2 after adjusting for other potential confounders using Cox regression analysis. Incidence of recurrent ischemic stroke was significantly increased with simultaneously decreasing eGFR and ABI. The highest percentage (71.4 %) of patients with eGFR < 30 ml/min/1.73m2 and ABI ≤ 0.4 simultaneously had recurrent ischemic stroke during follow-up. HR of eGFR < 30 ml/min/1.73m2 and ABI ≤ 0.4 simultaneously with recurrent ischemic stroke was 9.415 (95 % CI: 3.479 - 25.483) compared with that of eGFR ≥ 60 ml/min/1.73m2 and ABI > 1.0 to ≤ 1.4 respectively CONCLUSIONS: Low ABI and low eGFR together had synergistic effects on increasing recurrent ischemic stroke of ischemic stroke patients during a long-term follow-up.

Modelling, Characterization of Data-Dependent and Process-Dependent Errors in DNA Data Storage.

Using DNA as the medium to store information has recently been recognized as a promising solution for long-term data storage. While several system prototypes have been demonstrated, the error characteristics in DNA data storage are discussed with limited content. Due to the data and process variations from experiment to experiment, the error variation and its effect on data recovery remain to be uncovered. To close the gap, we systematically investigate the storage channel, i.e., error characteristics in the storage process. In this work, we first propose a new concept named sequence corruption to unify the error characteristics into the sequence level, easing the channel analysis. Then we derived the formulations of the data imperfection at the decoder including both sequence loss and sequence corruption, revealing the decoding demand and monitoring the data recovery. Furthermore, we extensively explored several data-dependent unevenness observed in the base error patterns and studied a few potential factors and their impacts on the data imperfection at the decoder both theoretically and experimentally. The results presented here introduce a more comprehensive channel model and offer a new angle towards the data recovery issue in DNA data storage by further elucidating the error characteristics of the storage process.

Electrostatic polarization is critical for the strong binding in streptavidin-biotin system.

The origin of strong affinity of biotin and its analogs binding to (strept)avidin is still the subject of an ongoing controversy. In this work, thermodynamic integration is carried out to study of the difference of binding free energies between biotin and iminobiotin to streptavidin. Three atomic charge schemes are implemented and compared. One is the traditional AMBER charge, and the other two, termed the polarized protein-specific charge, are based on a linear scaling quantum mechanical method and a continuous solvation model and have polarization effect partially or fully included. The result indicates that when nonpolarized AMBER force field is applied, the result is much underestimated. When electronic polarization is gradually included, the difference of binding affinity increases along with it. Using the linear-response approximation to eliminate the error in self-charging process, the corrected binding affinity agrees well with the experimental observation. This study is direct evidence indicating that polarization effect is critical for the strong binding in streptavidin-biotin system.

Electrostatic polarization makes a substantial contribution to the free energy of avidin-biotin binding.

Avidin-biotin is one of the strongest protein-ligand binding systems, with broad applications in biomedical science. Here we report a quantum-based computational study to help elucidate the mechanism of binding avidin to biotin (BTN1) and its close analogue, 2'-iminobiotin (BTN2). Our study reveals that electronic polarization of protein plays a critical role in stabilizing the beta sheet (Thr113-Arg122) at the binding site and makes a substantial contribution to the free energy of avidin-biotin binding. The current finding is in contradiction to the previous notion that electrostatic interaction has no effect on or makes an unfavorable contribution to the free energy of avidin-biotin binding. Our calculations also show that the difference in binding free energy of avidin to BTN1 and BTN2 is almost entirely due to the contribution of electrostatic interaction resulting from polarization-induced stabilization of a hydrogen bond between avidin and BTN1. The current result provides strong evidence that protein polarization accounts for the electrostatic contribution to binding free energy that was missing in previous studies of avidin-biotin binding.

Oligo Design with Single Primer Binding Site for High Capacity DNA-Based Data Storage.

DNA has become an attractive medium for long-term data archiving due to its extremely high storage density and longevity. Short single-stranded DNAs, called oligonucleotides (oligos), have been designed and synthesized to store digital data. Previous works designed the oligos with a pair of primer binding sites (PBSs) (each with a length of around 200) attached at the two ends of each basic readable data block. The addition of PBSs decreases the data density significantly because in the current DNA synthesis, the maximum length of a synthesized oligo in good quality is around 200. Furthermore, the maximum homopolymer run allowed by the existing experiments has been reported to be three nucleotides. In this work, to increase the data density, we have devised and tested an oligo design for DNA-based storage with the basic readable data block appended by a single PBS at one end only, while allowing the maximum homopolymer run to be increased to 4. We also present an oligo assembly algorithm that can reconstruct oligos with a single PBS from the error-prone raw readouts obtained from the sequencing process. We have conducted a wet lab experiment to validate the proposed design, where we tested with 398KB of data stored into 10,750 oligos. The experimental results show that it is possible to recover over 99 percent of the oligo sequences without error, which proves that one PBS is sufficient for implementing a DNA-based data storage system with maximum homopolymer run relaxed to 4. The use of single PBS leads to a significant data density gain from 14.3 to 140.2 percent over the existing short-strand DNA data storage schemes by reserving more nucleotides for storing information bits.

Genome-wide Analyses Identify a Novel Risk Locus for Nonsyndromic Cleft Palate.

The 3 major subphenotypes observed in patients with nonsyndromic orofacial clefts (NSOFCs) are nonsyndromic cleft lip only (NSCLO), nonsyndromic cleft lip with palate (NSCLP), and nonsyndromic cleft palate only (NSCPO). However, the genetic architecture underlying NSCPO is largely unknown. Here we performed a 2-stage genome-wide association study (GWAS) on NSCPO and replication analyses of selected variants in other NSOFCs from the Chinese Han population. We identified a novel locus (15q24.3) and a known locus (1q32.2) where variants in or near the gene reached genome-wide significance (2.80 × 10-13 < P < 1.72 × 10-08) in a test for association with NSCPO in a case-control design. Although a variant from 15q24.3 was found to be significantly associated with both NSCPO and NSCLP, the direction of estimated effects on risk were opposite. Our functional annotation of the risk alleles within 15q24.3 coupled with previously established roles of the candidate genes within identified risk loci in periderm development, embryonic patterning, and/or regulation of cellular processes supports their involvement in palate development and the pathogenesis of cleft palate. Our study advances the understanding of the genetic basis of NSOFCs and provides novel insights into the pathogenesis of NSCPO.

Increased frequency of chromosome translocations in airline pilots with long-term flying experience.

BACKGROUND: Chromosome translocations are an established biomarker of cumulative exposure to external ionising radiation. Airline pilots are exposed to cosmic ionising radiation, but few flight crew studies have examined translocations in relation to flight experience. METHODS: We determined the frequency of translocations in the peripheral blood lymphocytes of 83 airline pilots and 50 comparison subjects (mean age 47 and 46 years, respectively). Translocations were scored in an average of 1039 cell equivalents (CE) per subject using fluorescence in situ hybridisation (FISH) whole chromosome painting and expressed per 100 CE. Negative binomial regression models were used to assess the relationship between translocation frequency and exposure status and flight years, adjusting for age, diagnostic x ray procedures, and military flying. RESULTS: There was no significant difference in the adjusted mean translocation frequency of pilots and comparison subjects (0.37 (SE 0.04) vs 0.38 (SE 0.06) translocations/100 CE, respectively). However, among pilots, the adjusted translocation frequency was significantly associated with flight years (p = 0.01) with rate ratios of 1.06 (95% CI 1.01 to 1.11) and 1.81 (95% CI 1.16 to 2.82) for a 1- and 10-year incremental increase in flight years, respectively. The adjusted rate ratio for pilots in the highest compared to the lowest quartile of flight years was 2.59 (95% CI 1.26 to 5.33). CONCLUSIONS: Our data suggests that pilots with long-term flying experience may be exposed to biologically significant doses of ionising radiation. Epidemiological studies with longer follow-up of larger cohorts of pilots with a wide range of radiation exposure levels are needed to clarify the relationship between cosmic radiation exposure and cancer risk.

Autologous breast reconstruction using the immediately lipofilled extended latissimus dorsi flap.

BACKGROUND: The latissimus dorsi flap is a popular choice for autologous breast reconstruction. To dramatically improve volume, we report our experience of using the immediately lipofilled extended latissimus dorsi (ELD) flap and show it as a valid option for autologous breast reconstruction. METHODS: Patients undergoing the procedure between December 2013 and June 2016 were included. Demographic, clinical and operative factors were analysed, together with in-hospital morbidity and duration of postoperative hospital stay. RESULTS: A total of 71 ELD flaps with immediate lipofilling were performed. Forty-five reconstructions were immediate and the remaining 26 delayed. Median (range) volume of autologous fat injected immediately was 171 ml (40-630 ml). Contralateral reductions were performed in 25 patients with the median reduction volume 185 g (89-683 g). Median duration of admission was 6.5 (3-18) days and patients were followed up for 12 months (1-37). Three total flap failures occurred and had to be excised (4%). One haematoma occurred requiring drainage (1%). Signs of infection requiring intravenous antibiotics occurred in five patients (7%). In 5 patients wound dehiscence occurred, and only two of these required resuturing (3%). In total, 7 patients developed a seroma requiring repeated drainage (10%). Three reconstructions experienced mild mastectomy flap necrosis with no needing reoperation (4%). CONCLUSIONS: Our experience represents the largest series to date and shows that in carefully selected patients the technique is safe, can avoid the requirement for implants, and has the potential to streamline the reconstructive journey.