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The present study investigated the association between the presence of periodontitis and aortic calcification (AC) risk among Chinese adults. A total of 6059 individuals who underwent regular health check-ups and received a diagnosis of periodontitis between 2009 and 2016 were included. The outcome was AC, assessed by a chest low-dose spiral CT scan. Cox proportional hazards regression analysis was used to assess the association between periodontitis and AC risk after adjusting for several confounders. After a median follow-up period of 2.3 years (interquartile range: 1.03–4.97 years), 843 cases of AC were identified, with 532 (12.13%) and 311 (18.59%) patients in the non-periodontitis group and periodontitis group, respectively. Multivariate analyses demonstrated that, compared with those without periodontitis, the hazard ratio and 95% confidence interval for AC risk in participants with periodontitis was 1.18 (1.02–1.36) ( P = .025) in the fully adjusted model. Stratified analyses showed that the positive relationship between periodontitis and AC was more evident in males and participants interaction = .005 and .004, respectively). Our results show that the presence of periodontitis was positively associated with AC among Chinese adults, especially among males and younger participants.

Alpha synuclein has a key role in the pathogenesis of Parkinson’s disease (PD), Dementia with Lewy Bodies (LBD) and Multiple System Atrophy (MSA). Immunotherapies aiming at neutralising toxic αSyn species are being investigated in the clinic as potential disease modifying therapies for PD and other synucleinopathies. In this study, the effects of active immunisation against αSyn with the UB-312 vaccine were investigated in the Thy1SNCA/15 mouse model of PD. Young transgenic and wild-type mice received an immunisation regimen over a period of 6 weeks, then observed for an additional 9 weeks. Behavioural assessment was conducted before immunisation and at 15 weeks after the first dose. UB-312 immunisation prevented the development of motor impairment in the wire test and challenging beam test, which was associated with reduced levels of αSyn oligomers in the cerebral cortex, hippocampus and striatum of Thy1SNCA/15 mice. UB-312 immunotherapy resulted in a significant reduction of theαSyn load in the colon, accompanied by a reduction in enteric glial cell reactivity in the colonic ganglia. Our results demonstrate that immunisation with UB-312 prevents functional deficits and both central and peripheral pathology in Thy1SNCA/15 mice. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-021-02381-5.

The SARS-CoV-2 non-Spike (S) structural protein targets of nucleocapsid (N), membrane (M) and envelope (E), critical in the host cell interferon response and memory T-cell immunity, have been grossly overlooked since the inception of COVID vaccine development. To pursue a universal (pan-sarbecovirus) vaccine against ever-emergent future mutants, we explored booster immunogenicity of UB-612, a multitope-vaccine that contains S1-RBD-sFc protein and sequence-conserved rationally designed promiscuous Th and CTL epitope peptides on the Sarbecovirus N, M and S2 proteins. To a subpopulation of infection-free participants (aged 18-85 years) involved in a two-dose Phase-2 trial, a UB-612 booster (third dose) was administered 6-8 months after the second dose. The immunogenicity was evaluated at 14 days post-booster with overall safety monitored until the end of study. The booster induced high viral-neutralizing antibodies against live Wuhan WT (VNT50, 1,711) and Delta (VNT50, 1,282); and against pseudovirus WT (pVNT50, 11,167) vs. Omicron BA.1/BA.2/BA.5 variants (pVNT50, 2,314/1,890/854), respectively. The lower primary neutralizing antibodies in the elderly were uplifted upon boosting to approximately the same high level in young adults. UB-612 also induced potent, durable Th1-oriented (IFN-γ+-) responses (peak/pre-boost/post-boost SFU/106 PBMCs, 374/261/444) along with robust presence of cytotoxic CD8+ T cells (peak/pre-boost/post-boost CD107a+-Granzyme B+, 3.6%/1.8%/1.8%). Booster vaccination is safe and well tolerated without SAEs. By recognition against epitopes on Spike (S1-RBD and S2) and non-Spike (N and M) structure proteins, UB-612 provides potent, broad and long-lasting B-cell and T-cell memory immunity and offers a potential as a universal vaccine to fend off Omicrons and new VoCs.SIGNIFICANCE STATEMENTThe Omicron has swept the globe with a rapid succession of dominating sublineages from BA.1, BA.2, to the current BA.5 with increasing infectivity and antibody evasion. Concerningly, the non-Spike structure proteins that promote T-cell immunity are grossly overlooked in vaccine development. Looking beyond short-interval booster jabs and omicron-updated vaccines, a pragmatic approach to curbing ever-emergent new mutants would be “universal (pan-Sarbecovirus) vaccines” targeting conserved nonmutable epitopes on coronavirus. UB-612, a multitope-vaccine armed with Spike (S1-RBD and S2) and non-Spike targets (Nucleocapsid N and Membrane M), allows booster vaccination to elicit potent, broadly-recognizing, durable B- and T-cell memory immunity. Sequence-conserved epitope peptides were rationally-designed from S2, N and M proteins to synergistically enhance memory helper and cytotoxic T-cell immunity and B-cell immunity.

Over the last 2 decades, omalizumab is the only anti-IgE antibody that has been approved for asthma and chronic spontaneous urticaria (CSU). Ligelizumab, a higher-affinity anti-IgE mAb and the only rival viable candidate in late-stage clinical trials, showed anti-CSU efficacy superior to that of omalizumab in phase IIb but not in phase III. This report features the antigenic-functional characteristics of UB-221, an anti-IgE mAb of a newer class that is distinct from omalizumab and ligelizumab. UB-221, in free form, bound abundantly to CD23-occupied IgE and, in oligomeric mAb-IgE complex forms, freely engaged CD23, while ligelizumab reacted limitedly and omalizumab stayed inert toward CD23; these observations are consistent with UB-221 outperforming ligelizumab and omalizumab in CD23-mediated downregulation of IgE production. UB-221 bound IgE with a strong affinity to prevent FcԑRI-mediated basophil activation and degranulation, exhibiting superior IgE-neutralizing activity to that of omalizumab. UB-221 and ligelizumab bound cellular IgE and effectively neutralized IgE in sera of patients with atopic dermatitis with equal strength, while omalizumab lagged behind. A single UB-221 dose administered to cynomolgus macaques and human IgE (ε, κ)-knockin mice could induce rapid, pronounced serum-IgE reduction. A single UB-221 dose administered to patients with CSU in a first-in-human trial exhibited durable disease symptom relief in parallel with a rapid reduction in serum free-IgE level.

The highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has caused high rates of breakthrough infections in those previously vaccinated with ancestral strain coronavirus disease 2019 (COVID-19) vaccines. Here, we demonstrate that a booster dose of UB-612 vaccine candidate delivered 7–9 months after primary vaccination increased neutralizing antibody levels by 131-, 61-, and 49-fold against ancestral SARS-CoV-2 and the Omicron BA.1 and BA.2 variants, respectively. Based on the receptor-binding domain protein binding antibody responses, the UB-612 third-dose booster may lead to an estimated approximately 95% efficacy against symptomatic COVID-19 caused by the ancestral strain. Our results support UB-612 as a potential potent booster against current and emerging SARS-CoV-2 variants.

It is known that Stokes' paradox exhibits in various flow conditions, most notably, in flow past a two-dimensional (2D) circular cylinder. In this study, we provide an example through detailed analytical solution that Stokes' paradox can be lifted by accelerating flow past a stationary cylinder. The analysis is also extended to the case of the accelerating flow past a stationary sphere although in this case, there is no Stokes' paradox. The effects of the acceleration parameter on the flow streamlines, the pressure, and the vorticity distributions, as well as on the drag coefficient, are investigated. The drag comprises the potential component and vorticity component, which are further due to form drag and frictional drag receiving a separate investigation. However, the drag decomposition is also examined the viewpoint of the force decomposition: the total drag = the potential component + surface vorticity component + volume vorticity component.

The highly transmissible Omicron variant has caused high rates of breakthrough infections among vaccinated and convalescent individuals. Here, we demonstrate that a booster dose of UB-612 vaccine candidate delivered 7-9 months after primary vaccination increases neutralizing antibody levels by 131-, 61- and 49-fold against ancestral SARS-CoV-2, Omicron BA.1 and BA.2 variants, respectively. Based on the RBD protein binding antibody responses, we estimated a ∼95% efficacy against symptomatic COVID-19 caused by the ancestral strain after a UB-612 booster. Our results support UB-612 vaccine as a potent booster against current and emerging SARS-CoV-2 variants.

High performance and durable bifunctional oxygen electrocatalysts are of great importance for the commercial application of environmentally friendly and sustainable energy through electrochemical d...

In this study, we present an analysis of a Stokes micropump comprising a periodic array of parallel finite belts moved by rotating shafts. The geometry of the mechanical micropump is uniquely determined by the ratio of the length of the belts to the width between two neighboring belts (i.e., the aspect ratio a). The method of eigenfunction expansions with collocation is applied to solve the Stokes equation for the pumping rate, the stream function, and the velocity field as well as for the pressure gradient, which are all normalized by proper scales. It is found that with increasing a, the normalized pumping rate per unit micropump (or, simply abbreviated as a unit channel) first increases drastically and then decreases exponentially until it becomes a constant for large a, indicating that there exists a critical aspect ratio ( ac = 0.035) at which the maximum pumping rate ( qmax = 0.861) occurs, while the limiting value of q at large a is 0.5. The steady flow is driven by the moving belts against the established pressure gradient, and the pressure gradient at the centerline reaches its maximum value at the channel center and vanishes at distances from the micropump. Moreover, it is shown that the average flow velocity component perpendicular to the moving direction of the belts is relatively small, so that the flow field in the channel is approximately a unidirectional laminar flow, and therefore, the results are not necessarily limited to very low Reynolds numbers.

SARS-CoV-2 breakthrough infection occurs due to waning immunity time-to-vaccine, to which the globally-dominant, highly-contagious Delta variant is behind the scene. In the primary 2-dose and booster series of clinical Phase-1 trial, UB-612 vaccine, which contains S1-RBD and synthetic Th/CTL peptide pool for activation of humoral and T-cell immunity, induces substantial, prolonged viral-neutralizing antibodies that goes parallel with a long-lasting T-cell immunity; and a booster (3rd ) dose can prompt recall of memory immunity to induce profound, striking antibodies with the highest level of 50% viral-neutralizing GMT titers against live Delta variant reported for any vaccine. The unique design of S1-RBD only plus multitope T-cell peptides may have underpinned UB-612’s potent anti-Delta effect, while the other full S protein-based vaccines are affected additionally by mutations in the N-terminal domain sequence which contains additional neutralizing epitopes. UB-612, safe and well-tolerated, could be effective for boosting other vaccine platforms that have shown modest homologous boosting. [Funded by United Biomedical Inc., Asia; ClinicalTrials.gov ID: NCT04967742 and NCT04545749]

Objective:Previous studies have shown that the Dietary Approaches to Stop Hypertension (DASH) diet might contribute to managing risk factors of non-alcoholic fatty liver disease (NAFLD), but evidence is limited. We examined the association of DASH diet score (DASH-DS) with NAFLD, as well as the intermediary effects of serum retinol-binding protein-4 (RBP4), serum high-sensitivity C-reactive protein (hs-CRP), serum TAG, homeostasis model assessment of insulin resistance (HOMA-IR) and BMI.Design:We performed a cross-sectional analysis of a population-based cohort study. Dietary data and lifestyle factors were assessed by face-to-face interviews and the DASH-DS was then calculated. We assessed serum RBP4, hs-CRP and TAG and calculated HOMA-IR. The presence and degree of NAFLD were determined by abdominal sonography.Setting:Guangzhou, China.Participants:Guangzhou Nutrition and Health Study participants, aged 40–75 years at baseline (n3051).Results:After adjusting for potential covariates, we found an inverse association between DASH-DS and the presence of NAFLD (Ptrend= 0·009). The OR (95 % CI) of NAFLD for quintiles 2–5 were 0·78 (0·62, 0·98), 0·74 (0·59, 0·94), 0·69 (0·55, 0·86) and 0·77 (0·61, 0·97), respectively. Path analyses indicated that a higher DASH-DS was associated with lower serum RBP4, hs-CRP, TAG, HOMA-IR and BMI, which were positively associated with the degree of NAFLD.Conclusions:Adherence to the DASH diet was independently associated with a marked lower prevalence of NAFLD in Chinese adults, especially in women and those without abdominal obesity, and might be mediated by reducing RBP4, hs-CRP, TAG, HOMA-IR and BMI.

Administration of a single broadly neutralizing human immunodeficiency virus (HIV)-specific antibody to HIV-infected persons leads to the development of antibody-resistant virus in the absence of antiretroviral therapy (ART). It is possible that monotherapy with UB-421, an antibody that blocks the virus-binding site on human CD4+ T cells, could induce sustained virologic suppression without induction of resistance in HIV-infected persons after analytic treatment interruption.We conducted a nonrandomized, open-label, phase 2 clinical study evaluating the safety, pharmacokinetics, and antiviral activity of UB-421 monotherapy in HIV-infected persons undergoing analytic treatment interruption. All the participants had undetectable plasma viremia (20 copies of HIV RNA per milliliter) at the screening visit. After discontinuation of ART, participants received eight intravenous infusions of UB-421, at a dose of either 10 mg per kilogram of body weight every week (Cohort 1) or 25 mg per kilogram every 2 weeks (Cohort 2). The primary outcome was the time to viral rebound (≥400 copies per milliliter).A total of 29 participants were enrolled, 14 in Cohort 1 and 15 in Cohort 2. Administration of UB-421 maintained virologic suppression (20 copies per milliliter) in all the participants (94.5% of measurements at study visits 2 through 9) during analytic treatment interruption, with intermittent viral blips (range, 21 to 142 copies per milliliter) observed in 8 participants (28%). No study participants had plasma viral rebound to more than 400 copies per milliliter. CD4+ T-cell counts remained stable throughout the duration of the study. Rash, mostly of grade 1, was a common and transient adverse event; one participant discontinued the study drug owing to a rash. A decrease in the population of CD4+ regulatory T cells was observed during UB-421 monotherapy.UB-421 maintained virologic suppression (during the 8 to 16 weeks of study) in participants in the absence of ART. One participant discontinued therapy owing to a rash. (Funded by United Biomedical and others; ClinicalTrials.gov number, NCT02369146.).

Background Alpha-synuclein (α-Syn) aggregation is the primary characteristic of synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Immunotherapy targeting α-Syn has shown promising results in animal models of the disease. This study investigates the target specificity of three different active vaccines for pathological α-Syn aggregates found in human brain tissue from synucleinopathies. Methods Guinea pigs were immunised with 3 vaccines developed by United Neuroscience, and IgG fractions purified from the resulting immune sera (IGG-1, IGG-2 or IGG-3) were used to perform immunohistochemical staining of human cases of PD, DLB and MSA. The resulting immunoreactivity was compared to a commercially available α-Syn antibody from Novacastra (NOV) commonly used for diagnostic purposes. Images were captured from the substantia nigra (SN), temporal lobe, internal capsule, insular cortex and putamen and quantified for the percentage area with α-Syn immunoreactivity. Lewy bodies (LB) and Lewy neurites (LN) were further analysed in PD and DLB cases. Results Vaccine-generated antibodies detected more α-Syn pathology compared to NOV. The levels of α-Syn immunoreactivity varied between brain region and disease type with IGG-3 recognising the highest levels of α-Syn in most cases and in all brain regions that are affected early in disease progression. IGG-3 had a high recognition for glial inclusions found in MSA which are known to have a more compact conformation. Slot blot analysis confirmed the specificity of IGG-3 for native oligomers and fibrillar α-Syn. Higher levels of α-Syn were recognised by IGG-2 in cortical regions, and by IGG-3 in SN of PD and DLB cases. This was due to increased immunolabelling of LNs in these brain regions suggesting that IGG-2 and IGG-3 recognised additional α-Syn pathology compared to IGG-1 and NOV. Whether the unique binding properties of the antibodies produced in guinea pigs will translate in the clinic remains to be addressed, which is the main limitation of this study. Conclusions These vaccines induce antibodies that bind α-Syn oligomers and aggregates in the human brain and specifically support the choice of the vaccine generating IGG-3 (i.e. UB-312) as a candidate for clinical trials for synucleinopathies.

A novel multitope protein-peptide vaccine against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and disease is described in this report. The initial development and characterization experiments are presented along with proof-of-concept studies for the vaccine candidate UB-612. UB-612 consists of eight components rationally designed for induction of potently neutralizing antibodies and broad T cell responses against SARS-CoV-2: the S1-RBD-sFc fusion protein, six synthetic peptides (one universal peptide and five SARS-CoV-2-derived peptides), a proprietary CpG TLR-9 agonist at low concentration as an excipient, and aluminum phosphate adjuvant. Through immunogenicity studies in Guinea pigs and rats, we optimized the design of protein/peptide immunogens and selected an adjuvant system, yielding a vaccine that provides excellent S1-RBD binding and high neutralizing antibody responses, robust cellular responses, and a Th1-oriented response at low doses. In challenge studies, UB- 612 vaccination reduced viral load and prevented development of disease in mouse and non-human primate challenge models. With a Phase 1 trial completed, a Phase 2 trial ongoing in Taiwan, and additional trials planned to support global authorizations, UB-612 is a highly promising and differentiated vaccine candidate for prevention of SARS-CoV-2 infection and COVID-19 disease.Author SummarySARS-CoV-2 virus, the causative agent of Coronavirus Disease 2019 (COVID-19), has spread globally since its origin in 2019, causing an unprecedented public health crisis that has resulted in greater than 4.7 million deaths worldwide. Many vaccines are under development to limit disease spread and reduce the number of cases, but additional candidates that promote a robust immune response are needed. Here, we describe a multitope protein-peptide vaccine platform that is unique among COVID-19 vaccines. The advantages of our approach are induction of both high levels of neutralizing antibodies as well as a Th/CTL response in the vaccinated host, which mimics the immune response that occurs after natural infection with SARS-CoV-2. We demonstrate that our vaccine is immunogenic and effective in preventing disease in several animal models, including AAV- hACE-2 transduced mice, and both rhesus and cynomolgus macaques. Importantly, no immunopathology was observed in the lungs of immunized animals, therefore showing that antibody-dependent enhancement (ADE) does not occur. Our study provides an additional, novel vaccine candidate for advancement in clinical trials to treat and prevent SARS-CoV-2 infection and COVID-19 disease.

Introduction A novel amyloid β (Aβ) synthetic peptide vaccine (UB-311) has been evaluated in a first-in-human trial with patients of mild-to-moderate Alzheimer's disease. We describe translational research covering vaccine design, preclinical characterization, and phase-I clinical trial with supportive outcome that advances UB-311 into an ongoing phase-II trial. Methods UB-311 is constructed with two synthetic Aβ1–14–targeting peptides (B-cell epitope), each linked to different helper T-cell peptide epitopes (UBITh®) and formulated in a Th2-biased delivery system. The hAPP751 transgenic mouse model was used to perform the proof-of-concept study. Baboons and macaques were used for preclinical safety, tolerability, and immunogenicity evaluation. Patients with mild-to-moderate Alzheimer's disease (AD) were immunized by intramuscular route with 3 doses of UB-311 at weeks 0, 4, and 12, and monitored until week 48. Safety and immunogenicity were assessed per protocol, and preliminary efficacy was analyzed by Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), Mini–Mental State Examination (MMSE), and Alzheimer's Disease Cooperative Study–Clinician's Global Impression of Change (ADCS-CGIC). Results UB-311 covers a diverse genetic background and facilitates strong immune response with high responder rate. UB-311 reduced the levels of Aβ1–42 oligomers, protofibrils, and plaque load in hAPP751 transgenic mice. Safe and well-tolerated UB-311 generated considerable site-specific (Aβ1–10) antibodies across all animal species examined. In AD patients, UB-311 induced a 100% responder rate; injection site swelling and agitation were the most common adverse events (4/19 each). A slower rate of increase in ADAS-Cog from baseline to week 48 was observed in the subgroup of mild AD patients (MMSE ≥ 20) compared with the moderate AD subgroup, suggesting that UB-311 may have a potential of cognition improvement in patients with early stage of Alzheimer's dementia. Discussion The UBITh® platform can generate a high-precision molecular vaccine with high responder rate, strong on-target immunogenicity, and a potential of cognition improvement, which support UB-311 for active immunotherapy in early-to-mild AD patients currently enrolled in a phase-II trial (NCT02551809).

Highly efficient and durable anode electrocatalysts are the key to boost the performance of direct organic-molecule fuel cells (DOMFCs), yet there are still many challenges need to be solved. The PdPt alloy nanocrystals have been regarded as the most promising anode catalysts of DOMFCs, and the further improvement of their catalytic performance has attracted much attention. The effective routes includes tailoring the surface structure and optimizing the alloy composition of PdPt nanocatalysts. The high-index faceted structures possess high density of terraces and atomic steps which are efficient for electrooxidation reactions of small organic-molecule fuels, such as formic acid and ethanol. In particular, electrochemically-controlled synthesis methods present unique advantages in achieving such high-index faceted nanostructures. The current paper reports a direct electrodeposition of PdPt concave nanocubes on carbon paper (denoted as PdPt-CNC/CP). The prepared PdPt-CNC/CP has high-index faceted surface structures varying from {610} to {830}. When served as electrocatalysts, the PdPt-CNC/CP brings in outstanding mass specific activity and durability towards both formic acid oxidation reaction (FAOR) and ethanol oxidation reaction (EOR). More importantly, the selectivity of complete oxidation pathway through the cleavage of C-C bond on PdPt-CNC/CP during EOR in alkaline solution has been confirmed through NMR analysis. Based on the convenient method of direct electrodeposition of PdPt concave nanocubes on carbon paper and their excellent catalytic activity and durability, the PdPt-CNC/CP catalysts have potential advantages in being used as catalyst layers directly for membrane electrode assembly (MEA) in fuel cells, due to the reduced catalyst loading and simplified assembly process in comparison with traditional preparation procedure.

After decades of de-prioritizing shareholders' economic interests and low corporate profitability, Japan introduced the JPX-Nikkei400 in 2014. The index highlighted the country's “best-run" companies by annually selecting the 400 most profitable of its large and liquid firms. We find that managers competed for inclusion in the index by significantly increasing ROE, and they did so at least in part due to their reputational or status concerns. The ROE increase was predominantly driven by improvements in margins, which were in turn partially driven by cutting R&D intensity. Our findings suggest that indexes can affect managerial behavior through reputational or status incentives.

article i nfo Background: Accumulating data suggest that hyperhomocysteinemia is associated with the risk of ischemic stroke (IS) and coronary heart disease (CHD) in the general population, but the relationship remains unclear in hypertensive patients. We examined the association of total homocysteine (tHcy) with IS and CHD in hyper- tensive patients. Methods: A total of 5935 Chinese hypertensive patients were recruited in a community-based cross-sectional study from 60 communities in Shenzhen, China. Plasma tHcy was quantitatively measured using the enzyme cycle method. Conventional risk factors for IS and CHD were obtained through questionnaire interviews and physicalexaminations. We includedcerebralinfarction, embolismandsmall-vesseldiseaseasIS; and myocardial infarction,anginapectoris,coronary revascularization, and cardiac arrestas CHD. ISand CHD wereretrospective- ly adjudicated by specialists via interviews, hospital records or relevant tests. Results: Significantly higher values of tHcy were observed in IS patients than in non-IS controls among both men and women.GreatertHcy level wasdosedependentlyassociatedwith anincreasedrisk of ISpresenceinwomen, men and them combined (p-trend: 0.002, 3.8 × 10 −4 and 0.001). The odds ratios (95% CI) of IS for tHcy ≥30 (vs. b15) μmol/L were 2.84 (1.73-4.34) in men, 4.41 (1.62-9.15) in women, and 2.86 (1.72-4.75) in their combination after adjusting for other main risk factors of IS. We did not find any significant association be- tween tHcy and presence of CHD after the adjustment for covariates. Conclusions:Plasma homocysteine level is positively associated with the presence of IS, but not CHD, in Chi- nese hypertensive patients.

To machine precision, a micro-duct cannot be fabricated without producing surface roughness. It is of essential importance to examine the effects and predict the level of roughness on electro-osmotic (EO) pumping for ducts of fundamental shapes. In this study, we consider a bumpy microtube with its wall shape modeled by the product of two sinusoidal functions. Boundary perturbation is carried out with respect to the amplitude roughness e (relative to the Debye length) up to the second-order by considering the Debye-Huckel approximation and viscous Stokes equation for the electrolyte transport. Besides the amplitude roughness e, the key parameters include the azimuthal wave number n and the axial wave number α of the bumpiness, as well as the non-dimensional electrokinetic width K. It is shown that the EO pumping rate Q is modified by a second-order term −e2πχ, namely, Q = Q0 − e2πχ, where Q0 denotes the pumping rate through the smooth tube. The net effect χ = χ1 + χ2 comprises two components: χ1 = χ1(K) 1), χ decreases with increasing n at large K (>20). For a given number of oscillations Ac = nα (>1), there exists an intermediate n at which the EO pumping rate is maximized at small K (

Eight-stranded β-barrel outer membrane proteins can confer bacterial virulence via resistance to host innate defenses. This resistance function of OmpW, which was recently identified as an eight-stranded β-barrel protein, was investigated in this study. Our results demonstrated that upregulation of OmpW correlated with increased bacterial survival during phagocytosis. Bacterial mutants harboring a deletion of ompW exhibited a significantly increased phagocytosis rate. Both observations suggest that the OmpW protein protects bacteria against host phagocytosis. In addition, expression of ompW is regulated by iron, which implies that the resistance provided by OmpW may be an important factor in iron-related infectious diseases. Furthermore, OmpW has been identified as a protective antigen that protects mice against bacterial infection and is therefore a promising target for vaccine development against infectious diseases.

There are large amounts of unfolding or misfolding protein accumulation in the endoplasmic reticulum in patients with type 2 diabetes (T2D), which in turn induces the expression of the glucose-regulated protein 78 (GRP78) that plays a key role in influencing insulin secretion and maintaining glucose homeostasis in pancreatic beta cells. The aim in the study is to analyze the potential association between single-nucleotide polymorphisms (SNPs) of GRP78 and the risk of T2D. To assess the association between GRP78 polymorphisms and T2D, a case-control study was conducted among 1058 consecutive unrelated subjects. Of the 1058 subjects, 523 of them were diagnosed with T2D and 535 of them were healthy controls. Four SNPs with R(2)0.8 and the minor allele frequency0.05 (rs391957, rs17840761, rs17840762, and rs11355458) in the GRP78 gene promoter were analyzed. Overall, no associations of GRP78 polymorphisms with T2D were observed in genotypic analyses. In addition, haplotypes combining those SNPs in the promoter in high linkage disequilibrium were also not associated with a T2D risk. However, the levels of fasting plasma glucose and HbA1c in patients with the -415AA/-180GG genotype were significantly lower than those of the patients with -415GG/-180deldel and -415AG/-180Gdel genotypes, and the level of fasting insulin in patients with the -415AA/-180GG genotype was significantly lower than that of the patients with -415GG/-180deldel. The study does not support a role for promoter polymorphisms of GRP78 in T2D in a Chinese Han population, but it does provide a clue for association between low levels of fasting plasma glucose, HbA1c and fasting insulin, and the -415AA/-180GG model.

Summary Aim Alzheimer's disease (AD) is a multifactor disease that has been reported to have a close association with endoplasmic reticulum (ER) stress response. In the response, the regulator factor human X-box-binding protein 1 (XBP1) has been shown to facilitate the refolding and degradation of misfolded proteins, prevent neurotoxicity of amyloid-beta (Aβ) and tau, and play an important role in the survival of neurons. The aim in the study was to analyze the potential association between the −116C/G polymorphism of XBP1 and the risk of AD. Methods The association between −116C/G polymorphism of XBP1 promoter and possible risk of AD was assessed among 276 patients with AD and 254 matched healthy individuals in a case–control study. Results Overall, there was a significantly statistical difference in genotype (P = 0.0354) and allele frequencies (P = 0.0150, OR = 1.3642, 95% CI = 1.0618–1.7528) between the AD subjects and control subjects, showing that the −116C/G polymorphism of XBP1 might lead to increased susceptibility for AD in a Chinese Han population. In addition, the −116CG and −116GG genotypes were significantly associated with increased AD risk in female (P = 0.0217) and in subjects with APOE є4 (−) (P = 0.0070) in stratified analyses, and the −116CC genotype was significantly associated with fast cognitive deterioration in the AD patients (P = 0.0270). Conclusion The study supports a role for the −116C/G polymorphism of XBP1 gene in the pathogenesis of AD, and further studies with a larger sample size and detailed data should be performed in other populations.

Standard principal-agent models suggest that boards design incentive contracts that filter out common shocks in performance to motivate costly effort from the CEO ― a process entailing the judicious selection of benchmarks for relative performance evaluation (RPE). We evaluate the efficacy of firms' chosen RPE benchmarks and document that, relative to a normative benchmark, index-based benchmarks perform 14% worse in their time-series return-regression R2 and 16% worse in measurement error variance; firms choosing specific peers only modestly under-perform. Structural estimates suggest that, absent frictions, the underperformance of index-based benchmarks imply a performance penalty of 106-277 basis points in annual returns. Consistent with these estimates, firms choosing index-based benchmarks exhibit lower annual returns and ROA. Finally, reduced-form analyses suggest that the inefficient benchmarking is associated with governance-related frictions. Collectively, these findings provide new evidence on the explicit practice of RPE and its implications for corporate governance and firm performance.

In the presence of managerial short-termism and asymmetric information about skill and effort provision, firms may opportunistically shift earnings from uncertain to more certain times. We document that firms report more negative discretionary accruals when financial markets are less certain about their future prospects. Stock-price responses to earnings surprises are moderated when firm-level uncertainty is high, consistent with performance being attributed more to luck rather than skill and effort, which can create incentives to shift earnings toward lower-uncertainty periods. We show that the resulting opportunistic earnings management is concentrated in CEOs, firms, and periods where such incentives are likely to be strongest: (1) where CEO wealth is sensitive to change in the share price, (2) where announced earnings are particularly likely to be an important source of information about managerial ability and effort, and (3) before implementation of Sarbanes-Oxley made opportunistic earnings management more challenging. Our evidence highlights a novel channel through which uncertainty affects managerial decision making in the presence of agency conflicts.

The starting flow due to a suddenly applied pressure gradient in a parallel plate channel which is rotating as a system is studied. Exact analytic series solutions to the unsteady Navier-Stokes equations are found by both the Laplace transform method and the separation of parameters method, the latter is shown to be superior. Rotation not only induces a secondary transverse flow but also alters the character of the transient flow rate and velocity profiles. Back flow and inertial oscillations occur, especially at higher rotation rates.

In this paper, exact vibration frequencies of circular, annular and sector membranes with a radial power law density are presented for the first time. It is found that in general, the sequence of modes may not correspond to increasing az-imuthal mode number n. The normalized frequency increases with the absolute value of the power index |ν|. For a circular membrane, the fundamental frequency occurs at n = 0 where n is the number of nodal diameters. For an annular membrane, the frequency increases with respect to the inner radius b. When b is close to one, the width 1 – b is the dominant factor and the differences in frequencies are small. For a sector membrane, n – 1 is the number of internal radial nodes and the fundamental frequency occurs at n = 1. Increased opening angle β increases the frequency.

This subject is proposed based on the conflict between the heavy workload for maintenance personnel and few personnel at the geological survey automated master station at present, and the purpose is to solve the problem that the SCADA real-time monitoring system, UPS power supply system, automated support system as well as the automated computer room environment and equipment cannot achieve the real-time monitoring, fault diagnosis and accident processing of the remote unified platform. It proposes the remote online automatic monitoring and intelligent diagnosis and processing system on the basis of the OPEN3000 system platform. It uses the distributed network architecture in the network design to protect the security of database and the video records in the video system; it adopts the modular structure design, and combined with the expert system and the rule database design of database knowledge, thereby solving the technical problem that the real-time monitoring and fault diagnosis of SCADA, UPS, video and many other systems and equipment are being integrated into a unified platform.

The present study is concerned with unsteady electroosmotic flow (EOF) in a microchannel with the electric charge distribution described by the Poisson-Boltzmann (PB) equation. The nonlinear PB equation is solved by a systematic perturbation with respect to the parameter λ which measures the strength of the wall zeta potential relative to the thermal potential. In the small λ limits (λ<

The dynamic deformation behavior of an as-extruded Mg-Gd-Y magnesium alloy was studied by using Split Hopkinson Pressure Bar (SHPB) apparatus under high strain rates of 102 s-1 to 103s-1 in the present work, in the mean while the microstructure evolution after deformation were inspected by OM and SEM. The results demonstrated that the material is not sensitive to the strain rate and with increasing the strain rate the yield stress of as-extruded Mg-Gd-Y magnesium alloy has a tendency of increasing. The microstructure observation results shown that several deformation localization areas with the width of 10mm formed in the strain rates of 465s-1 and 2140s-1 along the compression axis respectively, and the grain boundaries within the deformation localization area are parallel with each other and are perpendicular to the compression axis. While increasing the strain rate to 3767s-1 the deformation seems become uniform and all the grains are compressed flat in somewhat. The deformation mechanism of as-extruded Mg-Gd-Y magnesium alloy under high strain rate at room temperature was also discussed.

The high strain rate compression behavior of extruded Mg-Gd-Y magnesium alloy was tested by split Hopkinson pressure bar (SHPB) under the strain rates of 465s-1，2140s-1and 3767s-1. As comparison the quasi-static compression behavior was tested in the meanwhile. The results show that the quasi-static yield stress is equivalent to that of high strain rates, but the flow stress at high strain rates are higher than that of quasi-static stain rate at the same strain. When the strain rate is increase from quasi-static to high strain rates the deformation stresses increase obviously but within the present testing high strain rates, increasing the strain rate the stress has a slight increasing, indicating that at high strain rate the stress of Mg-Gd-Y magnesium alloy is not sensitive to the strain rate. The constitutive equation between deformation stress, strain and strain rate was build based on the tested compression stress strain curves. The calculated stress strain data were compared with tested stress strain curves. The results demonstrate that when the strain rates are 0.001s-1，465s-1，2140s-1respectively the calculated and experimental data are fit very well. The calculated stress is higher than that of tested stress if the strain rate is increase to 3767s-1and the strain is more than 0.15. The discrepancy was explained through the physical soundness of Johnson-Cook model.