ObjectiveSystemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations.MethodsWe newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations.ResultsWe identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10−8). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (rg=−0.242) and non-albumin protein (rg=0.238).ConclusionThis study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.

A recent proposal for a background independent open string field theory is studied in detail for a class of backgrounds that correspond to general quadratic boundary interactions on the world-sheet. A short-distance cut-off is introduced to formulate the theory with a finite number of local and potentially unrenormalizable boundary couplings. It is shown that renormalization of the boundary couplings makes both the world-sheet partition function and the string field action finite and cut-off independent, although the resulting string field action has an unpalatable dependence on the leading unrenormalizable coupling.⋆ W.M.

Diagnostics is the key in screening and treatment of cancer. As an emerging tool in precision medicine, metabolic analysis detects end products of pathways, and thus is more distal than proteomic/genetic analysis. However, metabolic analysis is far from ideal in clinical diagnosis due to the sample complexity and metabolite abundance in patient specimens. A further challenge is real‐time and accurate tracking of treatment effect, e.g., radiotherapy. Here, Pd–Au synthetic alloys are reported for mass‐spectrometry‐based metabolic fingerprinting and analysis, toward medulloblastoma diagnosis and radiotherapy evaluation. A core–shell structure is designed using magnetic core particles to support Pd–Au alloys on the surface. Optimized synthetic alloys enhance the laser desorption/ionization efficacy and achieve direct detection of 100 nL of biofluids in seconds. Medulloblastoma patients are differentiated from healthy controls with average diagnostic sensitivity of 94.0%, specificity of 85.7%, and accuracy of 89.9%, by machine learning of metabolic fingerprinting. Furthermore, the radiotherapy process of patients is monitored and a preliminary panel of serum metabolite biomarkers is identified with gradual changes. This work will lead to the application‐driven development of novel materials with tailored structural design and establishment of new protocols for precision medicine in near future.

No abstract

Background: The rapidly increasing case reports revealed that neuronal intranuclear inclusion disease (NIID) had concomitant other system symptoms besides nervous system symptoms. In this study, we systematically evaluated the symptoms, signs, auxiliary examination, and pathological changes in different systems in NIID patients. Methods: NIID patients were confirmed by examining GGC repeats in the NOTCH2NLC gene. Clinical data of NIID patients including symptoms, signs, and auxiliary examinations were collected for analysis. Ubiquitin and p62 were detected in different tissues from previous surgical samples. Results: Fifty-one NIID patients from 17 families were included in this study. Except neurological symptoms, clinical manifestations from other systems were very notable and diverse. The proportions of different system symptoms were 88.2% in nervous system, 78.4% in respiratory system, 72.5% in circulatory system, 72.5% in locomotor system, 66.7% in urinary system, 64.7% in digestive system, 61.5% in reproductive system, and 50.0% in endocrine system. In addition, other common symptoms included sexual dysfunction (43.1%), pupil constriction (56.9%), blurred vision (51.0%), and hearing loss (23.5%). Ubiquitin and p62-positive cells were found in different tissues and systems in 24 NIID patients with previous surgery. Initial symptoms of NIID and median onset age in different systems also revealed system heterogeneity of NIID. Interpretation: For the first time, we systematically demonstrated that NIID is a heterogeneous and systemic neurodegenerative disease by providing clinical and pathological evidence. In addition to the nervous system, the clinical symptomatic and pathological spectrum of NIID has been extended to almost all systems.

BackgroundIL-17, a Th17 cell-derived proinflammatory molecule, has been found to play an important role in the pathogenesis of autoimmune diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). While IL-17 receptor (IL-17R) is expressed in many immune-related cells, microglia, and astrocytes, it is not known whether IL-17 exerts a direct effect on neural stem cells (NSCs) and oligodendrocytes, thus inducing inflammatory demyelination in the central nervous system.MethodsWe first detected IL-17 receptor expression in NSCs with immunostaining and real time PCR. We then cultured NSCs with IL-17 and determined NSC proliferation by neurosphere formation capability and cell number count, differentiation by immunostaining neural specific markers, and apoptosis of NSCs by flow cytometry.ResultsNSCs constitutively express IL-17R, and when the IL-17R signal pathway was activated by adding IL-17 to NSC culture medium, the number of NSCs was significantly reduced and their ability to form neurospheres was greatly diminished. IL-17 inhibited NSC proliferation, but did not induce cytotoxicity or apoptosis. IL-17 hampered the differentiation of NSCs into astrocytes and oligodendrocyte precursor cells (OPCs). The effects of IL-17 on NSCs can be partially blocked by p38 MAPK inhibitor.ConclusionsIL-17 blocks proliferation of NSCs, resulting in significantly reduced numbers of astrocytes and OPCs. Thus, in addition to its proinflammatory role in the immune system, IL-17 may also play a direct role in blocking remyelination and neural repair in the CNS.

Exenatide, a 39-amino-acid peptide with a molecular weight of 4186 Da and isoelectric point of pH 4.86, is similar to glucagon like peptide-1 (GLP-1) in terms of glucoregulatory actions and is used for type 2 diabetes therapy 1 . The marketed products include Byetta, with subcutaneous (s.c.) administration twice a day. Thus, long-acting formulations are being developed for clinical application. The sustained release microsphere product of exenatide (Bydureon ® ) was approved by the FDA in 2012 2 . In addition, an implantable osmotic pump for exenatide with 6 to 12 months delivery (ITCA650) has finished phase 3 clinical trials 3,4 ; however, patient acceptance of this implantable device is uncertain. Exenatide administration is limited to parenteral routes, resulting in low patient compliance. Presently, one of the major challenges is the development of a patient-friendly delivery of proteins/ peptides in the pharmaceutical field.Oral delivery is a preferred route for patients due to the convenience and strong compliance. However, oral delivery of proteins/peptides is still challenging mainly because of the instability of these molecules in the gastrointestinal tract, their considerably low permeation efficiency through the intestinal epithelium, and their rapid indigestive degradation 5,6 .The advance of nanotechnology has opened a new era for protein/peptide oral delivery. Nanocarriers exhibit several prominent advantages, such as protection of proteins via encapsulation in the nanocarriers and mitigation of drug modification. Numerous nanocarriers have emerged for protein oral administration, such as chitosan nanoparticles 5 , starch-based nanoparticles 7 , and liposomes 8 . PEG-PLGA nanoparticles have been studied owing to their great potential for performing a longer circulation time. Additionally, the biocompatibility of the delivery

Neurosurgeries to remove pituitary tumors using the endonasal, transsphenoidal approach often incur the risk of patient death caused by injury to the carotid arteries hidden by surrounding sphenoid bone. To avoid this risk, we propose intraoperative photoacoustic vessel visualization with an optical fiber attached to the surgical tool and an external ultrasound transducer placed on the temple. Vessel detection accuracy is limited by acoustic propagation properties, which were investigated with k-Wave simulations. In a two-layer model of temporal bone (3200 m/s sound speed, 1-4 mm thickness) and surrounding tissues, the localization error was ≤2 mm in the tranducer's axial dimension, while temporal bone curvature further degraded target localization. Phantom experiments revealed that multiple image targets (e.g. sphenoid bone and vessels) can be visualized, particularly with coherence-based beamforming, to determine tool-to-vessel proximity despite expected localization errors. In addition, the potential flexibility of the fiber position relative to the transducer and vessel was elucidated.