Thermal Relic Targets with Exponentially Small Couplings.

If dark matter was produced in the early Universe by the decoupling of its annihilations into known particles, there is a sharp experimental target for the size of its coupling. We show that if dark matter was produced by inelastic scattering against a lighter particle from the thermal bath, then its coupling can be exponentially smaller than the coupling required for its production from annihilations. As an application, we demonstrate that dark matter produced by inelastic scattering against electrons provides new thermal relic targets for direct detection and fixed target experiments.

Vasopressin-induced serine 269 phosphorylation reduces Sipa1l1 (signal-induced proliferation-associated 1 like 1)-mediated aquaporin-2 endocytosis.

The abundance of integral membrane proteins in the plasma membrane is determined by a dynamic balance between exocytosis and endocytosis, which can often be regulated by physiological stimuli. Here, we describe a mechanism that accounts for the ability of the peptide hormone vasopressin to regulate water excretion via a phosphorylation-dependent modulation of the PDZ domain-ligand interaction involving the water channel protein aquaporin-2. We discovered that the PDZ domain-containing protein Sipa1l1 (signal-induced proliferation-associated 1 like 1) binds to the cytoplasmic PDZ-ligand motif of aquaporin-2 and accelerates its endocytosis in the absence of vasopressin. Vasopressin-induced aquaporin-2 phosphorylation within the type I PDZ-ligand motif disrupted the interaction, in association with reduced aquaporin-2 endocytosis and prolonged plasma membrane aquaporin-2 retention. This phosphorylation-dependent alteration in the PDZ domain-ligand interaction was explained by 3D structural models, which showed a hormone-regulated mechanism that controls osmotic water transport and systemic water balance in mammals.

Genome-wide association study identifies novel susceptibility loci for migraine in Han Chinese resided in Taiwan.

Background Susceptibility genes for migraine, despite it being a highly prevalent and disabling neurological disorder, have not been analyzed in Asians by genome-wide association study (GWAS). Methods We conducted a two-stage case-control GWAS to identify susceptibility genes for migraine without aura in Han Chinese residing in Taiwan. In the discovery stage, we genotyped 1005 clinic-based Taiwanese migraine patients and 1053 population-based sex-matched controls using Axiom Genome-Wide CHB Array. In the replication stage, we genotyped 27 single-nucleotide polymorphisms with p < 10-4 in 1120 clinic-based migraine patients and 604 sex-matched normal controls by using Sequenom. Variants at LRP1, TRPM8, and PRDM, which have been replicated in Caucasians, were also genotyped. Results We identified a novel susceptibility locus (rs655484 in DLG2) that reached GWAS significance level for migraine risk in Han Chinese ( p = 1.45 × 10-12, odds ratio [OR] = 2.42), and also another locus (rs3781545in GFRA1) with suggestive significance ( p = 1.27 × 10-7, OR = 1.38). In addition, we observed positive association signals with a similar trend to the associations identified in Caucasian GWASs for rs10166942 in TRPM8 (OR = 1.33, 95% confidence interval [CI] = 1.14-1.54, Ppermutation = 9.99 × 10-5; risk allele: T) and rs1172113 in LRP1 (OR = 1.23, 95% CI = 1.04-1.45, Ppermutation = 2.9 × 10-2; risk allele: T). Conclusion The present study is the first migraine GWAS conducted in Han-Chinese and Asians. The newly identified susceptibility genes have potential implications in migraine pathogenesis. DLG2 is involved in glutamatergic neurotransmission, and GFRA1 encodes GDNF receptors that are abundant in CGRP-containing trigeminal neurons. Furthermore, positive association signals for TRPM8 and LRP1 suggest the possibility for common genetic contributions across ethnicities.

Susceptible genes of restless legs syndrome in migraine.

Objective Several genetic variants have been found to increase the risk of restless legs syndrome (RLS). The aim of the present study was to determine if these genetic variants were also associated with the comorbidity of RLS and migraine in patients. Methods Thirteen single-nucleotide polymorphisms (SNPs) at six RLS risk loci ( MEIS1, BTBD9, MAP2K5, PTPRD, TOX3, and an intergenic region on chromosome 2p14) were genotyped in 211 migraine patients with RLS and 781 migraine patients without RLS. Association analyses were performed for the overall cohort, as well as for the subgroups of patients who experienced migraines with and without aura and episodic migraines (EMs) vs. chronic migraines (CMs). In order to verify which genetic markers were potentially related to the incidence of RLS in migraine patients, multivariate regression analyses were also performed. Results Among the six tested loci, only MEIS1 was significantly associated with RLS. The most significant SNP of MEIS1, rs2300478, increased the risk of RLS by 1.42-fold in the overall cohort ( p = 0.0047). In the subgroup analyses, MEIS1 augmented the risk of RLS only in the patients who experienced EMs (odds ratio (OR) = 1.99, p = 0.0004) and not those experiencing CMs. Multivariate regression analyses further showed that rs2300478 in MEIS1 (OR = 1.39, p = 0.018), a CM diagnosis (OR = 1.52, p = 0.022), and depression (OR = 1.86, p = 0.005) were independent predictors of RLS in migraine. Conclusions MEIS1 variants were associated with an increased risk of RLS in migraine patients. It is possible that an imbalance in iron homeostasis and the dopaminergic system may represent a link between RLS incidence and migraines.

Quantitative apical membrane proteomics reveals vasopressin-induced actin dynamics in collecting duct cells.

In kidney collecting duct cells, filamentous actin (F-actin) depolymerization is a critical step in vasopressin-induced trafficking of aquaporin-2 to the apical plasma membrane. However, the molecular components of this response are largely unknown. Using stable isotope-based quantitative protein mass spectrometry and surface biotinylation, we identified 100 proteins that showed significant abundance changes in the apical plasma membrane of mouse cortical collecting duct cells in response to vasopressin. Fourteen of these proteins are involved in actin cytoskeleton regulation, including actin itself, 10 actin-associated proteins, and 3 regulatory proteins. Identified were two integral membrane proteins (Clmn, Nckap1) and one actin-binding protein (Mpp5) that link F-actin to the plasma membrane, five F-actin end-binding proteins (Arpc2, Arpc4, Gsn, Scin, and Capzb) involved in F-actin reorganization, and two actin adaptor proteins (Dbn1, Lasp1) that regulate actin cytoskeleton organization. There were also protease (Capn1), protein kinase (Cdc42bpb), and Rho guanine nucleotide exchange factor 2 (Arhgef2) that mediate signal-induced F-actin changes. Based on these findings, we devised a live-cell imaging method to observe vasopressin-induced F-actin dynamics in polarized mouse cortical collecting duct cells. In response to vasopressin, F-actin gradually disappeared near the center of the apical plasma membrane while consolidating laterally near the tight junction. This F-actin peripheralization was blocked by calcium ion chelation. Vasopressin-induced apical aquaporin-2 trafficking and forskolin-induced water permeability increase were blocked by F-actin disruption. In conclusion, we identified a vasopressin-regulated actin network potentially responsible for vasopressin-induced apical F-actin dynamics that could explain regulation of apical aquaporin-2 trafficking and water permeability increase.

Comparisons of disability, quality of life, and resource use between chronic and episodic migraineurs: a clinic-based study in Taiwan.

BACKGROUND: The International Burden of Migraine Study (IBMS) showed chronic migraine (CM) was associated with a higher disease burden than episodic migraine (EM). However, in this study Asians with CM were underrepresented. Objectives We investigated if CM and EM differed in headache-related disability, health-related quality of life (HRQoL) and health care resource utilization in Taiwan. METHODS: This study recruited patients with EM and CM from two headache clinics in Taiwan. Diagnosis was made by physicians based on Silberstein-Lipton criteria. Participants completed a questionnaire including sociodemographics, Migraine Disability Assessment (MIDAS), EuroQol five-dimensions (EQ-5D), Migraine-Specific Quality of Life v2.1 (MSQ), Patient Health Questionnaire-4 (PHQ-4), productivity and health care resource utilization. RESULTS: A total of 331 patients (EM, n = 164 (49.5%); CM, n = 167 (50.5%)) completed the study. CM patients reported a significantly higher MIDAS score, lower generic (EQ-5D visual analogue scale score and EQ-5D index score) and migraine-specific (all three domains of MSQ) HRQoL, higher levels of anxiety and depression (PHQ-4 ≥ 6) and greater health care resource utilization and productivity loss than those with EM. Positive correlations were found between these instruments and levels of anxiety and depression. CONCLUSION: Compared to EM, CM was significantly associated with higher disability, lower HRQoL and greater health care resource utilization and productivity loss.

Free-standing 3D core-shell architecture of Ni3S2@NiCoP as an efficient cathode material for hybrid supercapacitors.

The design and discovery of free-standing hybrid electrode materials with large absolute capacity and high cycling stability for energy storage become desirable and are still challenging. In this work, we demonstrate that the hybrid supercapacitor (HSC) device is assembled by 3D core-shell hierarchical nanorod arrays of Ni3S2@NiCoP nanocomposite for the first time. The Ni3S2@NiCoP nanocomposite is successfully synthesized through a facile stratagem containing hydrothermal process and the subsequent electrodeposition method. The 3D architecture of Ni3S2@NiCoP hybrid electrode composed of vertically aligned "hyperchannel" 1D Ni3S2 nanorods and highly conductive interconnected 2D nanosheets of NiCoP is beneficial to fast electron transfer kinetics, thus leading to enhancing the ionic and electronic conductivity, kinetics of redox reaction, and synergistic behavior of active species. The fabricated HSC device with Ni3S2@NiCoP electrode delivers outstanding areal capacity of 109 µAh cm-2 at a current density of 1 mA cm-2, brilliant energy density of 74.9 Wh kg-1 at a power density of 700 W kg-1, and prominent cyclic performance of 92% capacity retention even after 144-h floating test. This work demonstrates that the core-shell hierarchical nanorod arrays of Ni3S2@NiCoP can be viewed as one of the novel battery-type electrode materials for high-performance HSCs.

[Treatment guidelines for acute and preventive treatment of cluster headache].

The Treatment Guideline Subcommittee of the Taiwan Headache Society evaluated both the acute and the preventive treatments for cluster headache now being used in Taiwan, based on the principles of evidence- based medicine. We assessed the quality of clinical trials and levels of evidence, and referred to other treatment guidelines proposed by other countries. Throughout several panel discussions, we merged opinions from the subcommittee members and proposed a consensus on the major roles, recommended levels, clinical efficacy, adverse events and cautions of clinical practice regarding acute and preventive treatments of cluster headache. The majority of Taiwanese patients have episodic cluster headaches, because chronic clusters are very rare. Cluster headache is characterized by severe and excruciating pain which develops within a short time and is associated with ipsilateral autonomic symptoms. Therefore, emergency treatment for a cluster headache attack is extremely important. Within the group of acute medications currently available in Taiwan, the subcommittee determined that high-flow oxygen inhalation has the best evidence of effectiveness, followed by intranasal triptans. Both are recommended as first-line medical treatments for acute attacks. Oral triptans were determined to be second-line medications. For transitional prophylaxis, oral corticosteroids are recommended as the first-line medication, and ergotamine as the second-line choice. As for maintenance prophylaxis, verapamil has the best evidence and is recommended as the first-line medication. Lithium, melatonin, valproic acid, topiramate and gabapentin are suggested as the second-line preventive medications. Surgical interventions, including occipital nerve stimulation, deep brain stimulation, radiofrequency block of the sphenopalatine ganglion, percutaneous radiofrequency rhizotomy and trigeminal nerve section, are invasive and their long-term efficacy and adverse events are still not clear in Taiwanese patients; therefore, they are not recommended currently by the subcommittee. The transitional and maintenance prophylactic medications can be used together to attain treatment efficacy. Once the maintenance prophylaxis achieves efficacy, the transitional prophylactic medications can be tapered gradually. We suggest the corticosteroids be used within two weeks, if possible. The duration of maintenance treatment depends on the individual patient's clinical condition, and the medications can be tapered off when the cluster period is over.

Diagnosis and development of screening items for migraine in neurological practice in Taiwan.

BACKGROUND/PURPOSE: The objectives of this study were to: (1) survey migraine diagnoses among neurological outpatients in Taiwan; (2) compare neurologists' migraine diagnoses with the International Classification of Headache Disorders 2nd Edition (ICHD-2) criteria; and (3) evaluate the diagnostic ability of screening items on a patient migraine questionnaire. METHODS: This prospective study surveyed patients who consulted neurologists for the first time with a chief complaint of headache, excluding those experiencing headaches for > or = 15 days/month. Each neurologist interviewed a maximum of 10 patients. Patients were asked to complete a self-administered questionnaire and their physicians completed another questionnaire. The physicians were asked if patients could be diagnosed with migraine. In addition, a diagnosis of ICHD-2 migraine was made by the physician's questionnaire through a computer-generated algorithm. In this study, migraine without aura (code 1.1) or migraine with aura (code 1.2) were designated as "strict migraine", and the combination of strict migraine and ICHD-2 probable migraine (code 1.6) as "any migraine". RESULTS: Among 755 patients who were eligible for analysis, 537 (71%) were diagnosed as having "any migraine", 363 (48%) with "strict migraine", and 451 (60%) with physician-diagnosed migraine. Among the 537 patients diagnosed as having "any migraine", 308 patients (57%) had not been diagnosed by any physician before. A moderate agreement (kappa statistic around 0.5) was found between the physicians' diagnoses and ICHD-2 "strict migraine" or "any migraine". In patients with ICHD-2 probable migraine (n = 174), only 52% were diagnosed with migraine by our physicians. Nausea was the best single item for predicting migraine diagnosis, while any combination of two items among nausea/vomiting, moderate or severe pain and photophobia, provided the optimum screening tool. CONCLUSION: Migraine was the most common headache diagnosis in the neurologists' clinics. Probable migraine was not completely adopted as a migraine spectrum among neurologists. In contrast to ID Migraine(TM), moderate or severe headache intensity replaced headache-related disability as one screening item for migraine in Taiwan.

Homozygous deletion genotype of angiotensin converting enzyme confers protection against migraine in man.

Studies have shown that migraine may have a major genetic component. Meanwhile, angiotensin converting enzyme (ACE) gene has been implicated as a genetic factor associated with migraine. We designed a case-control study to investigate the association between ACE and migraine in 240 migraine patients and 200 healthy controls, matched by age and sex. There was no significant difference in allelic frequency (I and D) and genotype polymorphism (DD, DI and II) of the ACE gene in migraine patients and controls. Analysis of the difference in ACE polymorphism stratified by gender revealed that male migraine patients with the homozygote DD genotype (ACE-DD) were significantly fewer than that of male controls (OR = 0.331, p = 0.045). There was no existence of a difference among the frequency and duration of headache in each subgroup of migraine patients stratified by ACE genotype. Our findings indicate that ACE-DD may have a slight protective effect against migraine in male patients.

ICAM1 Is a Potential Cancer Stem Cell Marker of Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancer diagnosed in Asian countries, with its incidence on the rise. Cancer stem cell (CSC; also known as tumor-initiating cells, TIC) is inherently resistant to cytotoxic chemotherapy and radiation and associates with poor prognosis and therapy failure. Targeting therapy against cancer stem cell has emerged as a potential therapeutic approach to develop effective regimens. However, the suitable CSC marker of ESCC for identification and targeting is still limited. In this study, we screened the novel CSC membrane protein markers using two distinct stemness characteristics of cancer cell lines by a comparative approach. After the validation of RT-PCR, qPCR and western blot analyses, intercellular adhesion molecule 1 (ICAM1) was identified as a potential CSC marker of ESCC. ICAM1 promotes cancer cell migration, invasion as well as increasing mesenchymal marker expression and attenuating epithelial marker expression. In addition, ICAM1 contributes to CSC properties, including sphere formation, drug resistance, and tumorigenesis in mouse xenotransplantation model. Based on the analysis of ICAM1-regulated proteins, we speculated that ICAM1 regulates CSC properties partly through an ICAM1-PTTG1IP-p53-DNMT1 pathway. Moreover, we observed that ICAM1 and CD44 could have a compensation effect on maintaining the stemness characteristics of ESCC, suggesting that the combination of multi-targeting therapies should be under serious consideration to acquire a more potent therapeutic effect on CSC of ESCC.

A long-term analysis of the spinal somatosensory evoked potential of rats with sciatic constriction injury.

BACKGROUND: This study was undertaken to evaluate the long-term effect of a peripheral neuropathic pain model, chronic constriction injury (CCI) of the sciatic nerve, through analyses of electrophysiologic change, sciatic nerve function, and pain behavior. METHODS: CCI of the sciatic nerve was induced in twelve rats as described by Bennett and Xie. Three parameters were monitored: spinal somatosensory evoked potential (SSEP) elicited by supramaximal stimulation of the posterior tibial nerve and recorded from the thoracolumbar junctional space; thermal hyperalgesia assessed by measuring paw withdrawal latency (PWL); and sciatic function index (SFI). All the values of these parameters were obtained before the CCI procedure (day 1 as a preoperative baseline, and again on days 5, 12, 19, 26, 33, 47, 61, 75, and 89). SSEP was also measured 3 hr after the CCI operation. Data were also obtained from contralateral limbs. RESULTS: All rats with CCI developed thermal hyperalgesia on day 5, as indicated by a significant reduction in PWL in the CCI limbs and a deterioration of the SFI compared with baseline values. These effects persisted to day 89. In the electrophysiologic study, 3 hrs after the CCI operation, the amplitude significantly decreased and latency significantly increased in all SSEP recordings. The changes persisted and showed no further statistically significant deterioration or recovery. The data demonstrated that the major electrophysiologic change after a constriction injury was the loss of conduction ability across the injury site in the fast-conducting fibers, but in the slow-conducting fibers the conduction ability was still preserved, which occurred immediately after the operation and persisted consistently for 89 days in the rats with behavior manifestations of neuropathic pain. CONCLUSIONS: Our findings suggest that SSEP is simple to obtain and sensitive in the acute phase of electrophysiological changes, but is limited for long-term evaluation after CCI.

Increased risk of developing hepatocellular carcinoma associated with carriage of the TNF2 allele of the -308 tumor necrosis factor-alpha promoter gene.

BACKGROUND AND AIMS: Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that may act as an endogenous tumor promoter. A genetic polymorphism of TNF-alpha at position -308 of the promoter region, which includes TNF1 (-308G) and TNF2 (-308A) alleles, has been found to be associated with susceptibility to various types of cancer. We conducted a study to evaluate the association between this polymorphism and hepatocellular carcinoma (HCC). METHODS: We recruited 74 HCC patients and 289 healthy controls, and determined their -308 TNF-alpha promoter genotypes through polymerase chain reaction followed by electrophoresis. RESULTS: Carriage of the TNF2 allele was associated with an increased risk of HCC (odds ratio [OR] = 3.5; 95% confidence interval [CI]:[2.1, 6.0]), and a trend toward a significant increase in the risk of developing HCC was observed from TNF1/TNF1, TNF1/TNF2, to TNF2/TNF2 genotypes (p < 0.01). After adjustment for gender, age, and markers of hepatitis B and C, the OR of developing HCC associated with TNF2 allele carriage was 5.3 (95% CI: [2.3, 12.1]; p < 0.01) CONCLUSIONS: Carriage of the TNF2 allele is a significant predictor of HCC independent of hepatitis B and C, and therefore it may be used as a biomarker for susceptibility to HCC.