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There is limited information on the prevalence of SARS-CoV-2 infection in obstetric settings in Canada, beyond the first wave of the COVID-19 pandemic (February to June 2020). We sought to describe the prevalence of SARS-CoV-2 infection in pregnant people admitted to triage units at a tertiary care hospital in Ottawa, Canada.We conducted a descriptive study of pregnant people admitted to obstetric triage assessment units at The Ottawa Hospital between Oct. 19 and Nov. 27, 2020 (second local wave of the COVID-19 pandemic). Participants underwent SARS-CoV-2 polymerase chain reaction (PCR) (via naso- or oropharyngeal swabs) and serology testing upon admission. We excluded individuals younger than 18 years, those who did not speak English or French, those who enrolled in conflicting studies, those admitted for pregnancy termination and those triaged between 11:31 pm and 7:29 am. Swab and serology samples were analyzed using digital droplet PCR and enzyme-linked immunosorbent assays, respectively. We defined SARS-CoV-2 seropositivity as a positive result for immunoglobulin (Ig) G, either alone or in combination with IgM or IgA.Of the 632 eligible patients, 363 (57.4%) consented to participation and 362 collectively provided 284 swab and 352 blood samples eligible for analysis. Common reasons for declining participation included feeling overwhelmed or anxious, being worried about repercussions of testing, pain or discomfort with testing or disinterest in research. Participants were mostly multiparous (53.9%) and in their third trimester upon admission (88.4%). In all, 18 (4.9%) participants had evidence of SARS-CoV-2 exposure; 2 (0.7%) of 284 were positive for SARS-CoV-2 by PCR and 16 (4.5%) of 352 were positive for IgG antibodies to SARS-CoV-2.During the second local wave of the COVID-19 pandemic, the prevalence of active SARS-CoV-2 infection among obstetric patients in Ottawa was 0.7% and seroprevalence was 4.5%. Our low participation rate highlights the need for improvements in patient education and public health messaging on the benefits of SARS-CoV-2 testing programs.

The neuron-glia cross-talk is critical to brain homeostasis and is particularly affected by neurodegenerative diseases. How neurons manipulate the neuron-astrocyte interaction under pathological conditions, such as hyperphosphorylated tau, a pathological hallmark in Alzheimer’s disease (AD), remains elusive. In this study, we identified excessively elevated neuronal expression of adenosine receptor 1 (Adora1 or A1R) in 3×Tg mice, MAPT P301L (rTg4510) mice, patients with AD, and patient-derived neurons. The up-regulation of A1R was found to be tau pathology dependent and posttranscriptionally regulated by Mef2c via miR-133a-3p. Rebuilding the miR-133a-3p/A1R signal effectively rescued synaptic and memory impairments in AD mice. Furthermore, neuronal A1R promoted the release of lipocalin 2 (Lcn2) and resulted in astrocyte activation. Last, silencing neuronal Lcn2 in AD mice ameliorated astrocyte activation and restored synaptic plasticity and learning/memory. Our findings reveal that the tau pathology remodels neuron-glial cross-talk and promotes neurodegenerative progression. Approaches targeting A1R and modulating this signaling pathway might be a potential therapeutic strategy for AD.

Bistable composite structures have a wide application prospect in the design of deformable structures. In this study, the snap behaviors of unsymmetric cross-ply bistable composites with different ...

Recurrent epidemics of influenza infection and its pandemic potential present a significant risk to global population health. To mitigate hospitalizations and death, local public health relies on clinical surveillance to locate and monitor influenza-like illnesses and/or influenza cases and outbreaks. At an international level, the global integration of clinical surveillance networks is the only reliable method to report influenza types and subtypes and warn of an emergent pandemic strain. During the COVID-19 pandemic, the demonstrated utility of wastewater surveillance (WWS) in complementing or even replacing clinical surveillance, the latter a resource-intensive enterprise, was predicated on the presence of stable viral fragments in wastewater. We show that influenza virus targets are stable in wastewaters and partitions to the solids fraction. We subsequently quantify, type, and subtype influenza virus in municipal wastewater and primary sludge throughout the course of a community outbreak. This research demonstrates the feasibility of applying influenza virus WWS to city and neighbourhood levels; showing a 17-day lead time in forecasting a citywide flu outbreak and providing population-level viral subtyping in near real-time using minimal resources and infrastructure.

Clinical testing has been the cornerstone of public health monitoring and infection control efforts in communities throughout the COVID-19 pandemic. With the extant and anticipated reduction of clinical testing as the disease moves into an endemic state, SARS-CoV-2 wastewater surveillance (WWS) is likely to have greater value as an important diagnostic tool to inform public health. As the widespread adoption of WWS is relatively new at the scale employed for COVID-19, interpretation of data, including the relationship to clinical cases, has yet to be standardized. An in-depth analysis of the metrics derived from WWS is required for public health units/agencies to interpret and utilize WWS-acquired data effectively and efficiently. In this study, the SARS-CoV-2 wastewater signal to clinical cases (WC) ratio was investigated across seven different cities in Canada over periods ranging from 8 to 21 months. Significant increases in the WC ratio occurred when clinical testing eligibility was modified to appointment-only testing, identifying a period of insufficient clinical testing in these communities. The WC ratio decreased significantly during the emergence of the Alpha variant of concern (VOC) in a relatively non-immunized community’s wastewater (40-60% allelic proportion), while a more muted decrease in the WC ratio signaled the emergence of the Delta VOC in a relatively well-immunized community’s wastewater (40-60% allelic proportion). Finally, a rapid and significant decrease in the WC ratio signaled the emergence of the Omicron VOC, likely because of the variant’s greater effectiveness at evading immunity, leading to a significant number of new reported clinical cases, even when vaccine-induced community immunity was high. The WC ratio, used as an additional monitoring metric, complements clinical case counts and wastewater signals as individual metrics in its ability to identify important epidemiological occurrences, adding value to WWS as a diagnostic technology during the COVID-19 pandemic and likely for future pandemics.

In this perspective, we outline that a space borne gravitational wave detector network combining LISA and Taiji can be used to measure the Hubble constant with an uncertainty less than 0.5% in ten years, compared with the network of the ground based gravitational wave detectors which can measure the Hubble constant within a 2% uncertainty in the next five years by the standard siren method. Taiji is a Chinese space borne gravitational wave detection mission planned for launch in the early 2030 s. The pilot satellite mission Taiji-1 has been launched in August 2019 to verify the feasibility of Taiji. The results of a few technologies tested on Taiji-1 are presented in this paper. Gravitational wave astronomy has opened the door to test general relativity and the effect of gravity in the Universe. The authors present the capabilities of an overlap between space gravitational wave detectors LISA and Taiji to constrain the Hubble constant to 0.5%, in 10 years, and what can be learned from the satellite pilot Taiji-1 launched in 2019.

Aim To study the imaging features of leukoaraiosis (LA) and hemorrhage in cerebral amyloid angiopathy (CAA) patients. Methods The earliest MRI images of probable CAA patients and non-CAA patients were collected. The characteristics of LA in the two groups were analyzed. Cerebral micro bleeding (CMB), superficial siderosis (SS), and intracranial hemorrhage (ICH) were recorded in the follow-up study. The space relationship between CMB or SS and ICH was assessed. Results We found that 10/21 (47.6%) patients had occipital prominent LA and 14/21 (66.7%) patients had subcortical punctate LA before the ICH, which was higher than that of the ones in the control group (p = 0.015 and 0.038, respectively). The recurrence rate of ICH was 100% (3/3) in patients with diffuse SS and 36.4% (4/11) in patients without. The recurrence rate of ICH was 60% (3/5) in patients with multiple-lobe CMBs and 44.4% (4/9) in those without. The location of the ICH and CMB was inconsistent. ICH occurred in the ipsilateral cerebral hemisphere of SS in three patients with diffuse SS. Conclusion LA, diffuse SS, and multiple-lobe CMBs are important imaging characteristics of CAA, which may help make early diagnosis and predict the recurrence of ICH.

Optical clock networks play important roles in various fields, such as precise navigation, redefinition of "second" unit, and gravitational tests. To establish a global-scale optical clock network, it is essential to disseminate time and frequency with a stability of $10^{-19}$ over a long-distance free-space link. However, such attempts were limited to dozens of kilometers in mirror-folded configuration. Here, we take a crucial step toward future satellite-based time-frequency disseminations. By developing the key technologies, including high-power frequency combs, high-stability and high-efficiency optical transceiver systems, and efficient linear optical sampling, we demonstrate free-space time-frequency dissemination over two independent links with femtosecond time deviation, $3\times10^{-19}$ at 10,000 s residual instability and $1.6\times10^{-20}\pm 4.3\times10^{-19}$ offset. This level of the stability retains for an increased channel loss up to 89 dB. Our work can not only be directly used in ground-based application, but also firmly laid the groundwork for future satellite time-frequency dissemination., 27 pages, 13 figures, 2 tables

Deregulation of mRNA translation engenders many human disorders, including obesity, neurodegenerative diseases, and cancer, and is associated with pathogen infections. The role of eIF4E-dependent translational control in macrophage inflammatory responses in vivo is largely unexplored. In this study, we investigated the involvement of the translation inhibitors eIF4E-binding proteins (4E-BPs) in the regulation of macrophage inflammatory responses in vitro and in vivo. We show that the lack of 4E-BPs exacerbates inflammatory polarization of bone marrow–derived macrophages and that 4E-BP–null adipose tissue macrophages display enhanced inflammatory gene expression following exposure to a high-fat diet (HFD). The exaggerated inflammatory response in HFD-fed 4E-BP–null mice coincides with significantly higher weight gain, higher Irf8 mRNA translation, and increased expression of IRF8 in adipose tissue compared with wild-type mice. Thus, 4E-BP–dependent translational control limits, in part, the proinflammatory response during HFD. These data underscore the activity of the 4E-BP–IRF8 axis as a paramount regulatory mechanism of proinflammatory responses in adipose tissue macrophages.

Wastewater surveillance (WWS) of SARS-CoV-2 was proven to be a reliable and complementary tool for population-wide monitoring of COVID-19 disease incidence but was not as rigorously explored as an indicator for disease burden throughout the pandemic. Prior to global mass immunization campaigns and during the spread of the wildtype COVID-19 and the Alpha variant of concern (VOC), viral measurement of SARS-CoV-2 in wastewater was a leading indicator for both COVID-19 incidence and disease burden in communities. As the two-dose vaccination rates escalated during the spread of the Delta VOC in Jul. 2021 through Dec. 2021, relations weakened between wastewater signal and community COVID-19 disease incidence and maintained a strong relationship with clinical metrics indicative of disease burden (new hospital admissions, ICU admissions, and deaths). Further, with the onset of the vaccine-resistant Omicron BA.1 VOC in Dec. 2021 through Mar. 2022, wastewater again became a strong indicator of both disease incidence and burden during a period of limited natural immunization (no recent infection), vaccine escape, and waned vaccine effectiveness. Lastly, with the populations regaining enhanced natural and vaccination immunization shortly prior to the onset of the Omicron BA.2 VOC in mid-Mar 2022, wastewater is shown to be a strong indicator for both disease incidence and burden. Hospitalization-to-wastewater ratio is further shown to be a good indicator of VOC virulence when widespread clinical testing is limited. In the future, WWS is expected to show moderate indication of incidence and strong indication of disease burden in the community during future potential seasonal vaccination campaigns.HighlightsNeed to elucidate interpretation of CoV-2 WWS for seasonal vaccination campaigns.WWS to incidence relation weakens with peak natural and vaccination immunization.WWS to hospitalization remains strong with natural and vaccination immunization.WWS as indicator of hospitalization during future seasonal vaccination campaigns.WWS/hospitalization as indicator of VOC virulence with limited clinical testing.

LARP1 is a key repressor of TOP mRNA translation. It binds the m7Gppp cap moiety and the adjacent 5′TOP motif of TOP mRNAs, thus impeding the assembly of the eIF4F complex on these transcripts. mTORC1 controls TOP mRNA translation via LARP1, but the details of the mechanism are unclear. Herein we elucidate the mechanism by which mTORC1 controls LARP1’s translation repression activity. We demonstrate that mTORC1 phosphorylates LARP1 in vitro and in vivo, activities that are efficiently inhibited by rapamycin and torin1. We uncover 26 rapamycin-sensitive phospho-serine and -threonine residues on LARP1 that are distributed in 7 clusters. Our data show that phosphorylation of a cluster of residues located proximally to the m7Gppp cap-binding DM15 region is particularly sensitive to rapamycin and regulates both the RNA-binding and the translation inhibitory activities of LARP1. Our results unravel a new model of translation control in which the La module (LaMod) and DM15 region of LARP1, both of which can directly interact with TOP mRNA, are differentially regulated: the LaMod remains constitutively bound to PABP (irrespective of the activation status of mTORC1), while the C-terminal DM15 ‘pendular hook’ engages the TOP mRNA 5′-end to repress translation, but only in conditions of mTORC1 inhibition.

In order to investigate human impact in the Changjiang – East China Sea source to sink conveying system, we analyze the siltation and erosion state of the estuary-shelf deposition systems, and discuss the response intensity and timing of the depositional system of the Changjiang subaqueous delta and the related Changjiang distal mud. Results show that after the Three Gorges Dam was put into operation in 2003, the abrupt reduction of the sediment discharge to the estuary disturbed the equilibrium between the estuary-coast-shelf deposition systems, modifying the siltation-erosion balance and seabed sediment types. From the Changjiang subaqueous delta to its distal mud areas, the degree of response to catchment changes diminishes, with a larger response lag from north to south of the distal muds. Influenced by dam emplacements, the change of the Changjiang – East China Sea source to sink conveying system can be divided into three stages, i.e., pre-1950, 1950–2002 and post-2003. Before 1950, the source to sink system remained relatively stable. Between 1950 and 2002, man-made fluvial impoundments created an important sink for terrigenous sediment of the upstream regions, but without profound system changes. In contrast, after 2003, the morphodynamic patterns for the entire mid-lower reaches of the Changjiang River, the subaqueous delta and the distal muds shifted rapidly from siltation to erosion within a short period of time. Furthermore, the upper reaches of the river became disconnected from the source to sink conveying system, and the mid-lower reaches of the river, together with its subaqueous delta and northern distal mud area were converted into net sediment sources. As such, the sink area has shrunk while the source area expanded for the Changjiang – East China Sea source to sink conveying system.

Highlights • RT-ddPCR is more sensitive to inhibitors than RT-qPCR for primary clarified sludge. • Primary clarified sludge has elevated frequency of SARS-CoV-2 RNA detection. • Primary clarified sludge allows detection of RNA during low COVID-19 incidence. • PMMoV normalization of RNA data reduces noise and increases precision. • PMMoV normalization of RNA shows strongest correlation to epidemiological metrics., In the absence of an effective vaccine to prevent COVID-19 it is important to be able to track community infections to inform public health interventions aimed at reducing the spread and therefore reduce pressures on health-care, improve health outcomes and reduce economic uncertainty. Wastewater surveillance has rapidly emerged as a potential tool to effectively monitor community infections through measuring trends of RNA signal in wastewater systems. In this study SARS-CoV-2 viral RNA N1 and N2 gene regions are quantified in solids collected from influent post grit solids (PGS) and primary clarified sludge (PCS) in two water resource recovery facilities (WRRF) serving Canada's national capital region, i.e., the City of Ottawa, ON (pop. ≈ 1.1M) and the City of Gatineau, QC (pop. ≈ 280K). PCS samples show signal inhibition using RT-ddPCR compared to RT-qPCR, with PGS samples showing similar quantifiable concentrations of RNA using both assays. RT-qPCR shows higher frequency of detection of N1 and N2 gene regions in PCS (92.7, 90.6%, n = 6) as compared to PGS samples (79.2, 82.3%, n = 5). Sampling of PCS may therefore be an effective approach for SARS-CoV-2 viral quantification, especially during periods of declining and low COVID-19 incidence in the community. The pepper mild mottle virus (PMMoV) is determined to have a less variable RNA signal in PCS over a three month period for two WRRFs, regardless of environmental conditions, compared to Bacteroides 16S rRNA or human 18S rRNA, making PMMoV a potentially useful biomarker for normalization of SARS-CoV-2 signal. PMMoV-normalized PCS RNA signal from WRRFs of two cities correlated with the regional public health epidemiological metrics, identifying PCS normalized to a fecal indicator (PMMoV) as a potentially effective tool for monitoring trends during decreasing and low-incidence of infection of SARS-Cov-2 in communities., Graphical abstract Image, graphical abstract

In the absence of an effective vaccine to prevent COVID-19 it is important to be able to track community infections to inform public health interventions aimed at reducing the spread and therefore reduce pressures on health-care units, improve health outcomes and reduce economic uncertainty. Wastewater surveillance has rapidly emerged as a potential tool to effectively monitor community infections for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), through measuring trends of viral RNA signal in wastewater systems. In this study SARS-CoV-2 viral RNA N1 and N2 genes are quantified in solids collected from influent post grit solids (PGS) and primary clarified sludge (PCS) in two water resource recovery facilities (WRRF) serving Canada’s national capital region, i.e., the City of Ottawa, ON (pop. ≈ 1.1M) and the City of Gatineau, QC (pop. ≈ 280K). PCS samples show signal inhibition using RT-ddPCR compared to RT-qPCR, with PGS samples showing similar quantifiable concentrations of RNA using both assays. RT-qPCR shows higher frequency of detection of N1 and N2 genes in PCS (92.7, 90.6%) as compared to PGS samples (79.2, 82.3%). Sampling of PCS may therefore be an effective approach for SARS-CoV-2 viral quantification, especially during periods of declining and low COVID-19 incidence in the community. The pepper mild mottle virus (PMMV) is determined to have a less variable RNA signal in PCS over a three month period for two WRRFs, regardless of environmental conditions, compared to Bacteroides 16S rRNA or human eukaryotic 18S rRNA, making PMMV a potentially useful biomarker for normalization of SARS-CoV-2 signal. PMMV-normalized PCS RNA signal from WRRFs of two cities correlated with the regional public health epidemiological metrics, identifying PCS normalized to a fecal indicator (PMMV) as a potentially effective tool for monitoring trends during decreasing and low-incidence of infection of SARS-Cov-2 in communities.

Microwave-based satellite–ground links are used to transfer time and frequency in various applications such as metrology, navigation, positioning, and very long baseline interferometers. The existing approaches, however, cannot fully satisfy the requirements of these applications. In this study, we investigated the possibility of an optical-based satellite–ground link, where the transferred carriers are pulsed lasers, resulting in a link with a high time resolution and a large ambiguous range. First, we analyzed the parameters of satellites in different orbits and concluded that high-orbit links enable more stable time–frequency comparison or dissemination by taking advantage of the long duration, a large common view range, and the lower relativistic effects. Subsequently, we performed a 16 km free-space transfer experiment to simulate links in the loss, noise, and delay effects. The link exhibits an instability of 4 × 10 − 18 at 3,000 s and an approximately 10 fs time deviation with an average loss of 72 dB, corresponding to the loss of a satellite–ground link at geostationary earth orbit (GEO). Based on these results, we expect that the instability of the time–frequency transfer via a GEO link might reach 10 − 18 at 10,000 s.

With the increasing application of barium titanate (BaTiO3) in polyvinylidene fluoride (PVDF), the evaluation of its dielectric properties has attracted the attention of many frontier scholars. In this paper, from the theoretical point of view, the effects of the aspect ratio and the concentrations of BaTiO3 nanowires on macroscopic dielectric properties were studied by the finite element method. Depending on the calculation results, some conclusions had been obtained: First, it was found that the effect of higher aspect ratios of nanowires on the effective permittivity of the composites was not significant when the aspect ratio of the nanowire filler exceeded 20. Second, when the permittivity of the BaTiO3 nanowires reaches about 3000, as the permittivity of the filler increases, the rate of change of the effective permittivity of the composite material gradually slows down, which indicates that nanowires with higher permittivity have little influence on the effective permittivity of the composites. Finally, by comparing with permittivity data of BT/PVDF composites in the literature, it was found that the simulation results have good consistency with the experimentally measured values. The above-mentioned results have shown that the composite may exhibit good dielectric properties at a low concentration (

Deregulation of mRNA translation engenders many human disorders, including obesity, neurodegenerative diseases, and cancer, and is associated with pathogen infections. The role of eIF4E-dependent translational control in macrophage inflammatory responses in vivo is largely unexplored. In this study, we investigated the involvement of the translation inhibitors eIF4E-binding proteins (4E-BPs) in the regulation of macrophage inflammatory responses in vitro and in vivo. We show that the lack of 4E-BPs exacerbates inflammatory polarization of bone marrow-derived macrophages and that 4E-BP-null adipose tissue macrophages display enhanced inflammatory gene expression following exposure to a high-fat diet (HFD). The exaggerated inflammatory response in HFD-fed 4E-BP-null mice coincides with significantly higher weight gain, higher

Residual cell-intrinsic innate immunity in cancer cells hampers infection with oncolytic viruses. mRNA translation is an important component of innate immunity, yet the targeted cellular mRNAs remain ill-defined. We characterized the translatome of resistant murine “4T1” breast cancer cells infected with three of the most clinically advanced oncolytic viruses: Herpes Simplex virus 1, Reovirus and Vaccinia virus. Common among all three infections were translationally de-repressed mRNAs involved in ciliary homeostasis including Inpp5e, encoding an inositol 5-phosphatase that modifies lipid second messenger signalling. Translationally repressed in the uninfected condition, viral infection induced expression of an Inpp5e mRNA variant that lacks repressive upstream open reading frames (uORFs) within its 5’ leader and is consequently efficiently translated. Furthermore, we show that INPP5E contributes to antiviral immunity by altering virus attachment. These findings uncover a role for translational control through alternative 5’ leader expression and assign ciliary proteins such as INPP5E to the cellular antiviral response.

Residual cell-intrinsic innate immunity in cancer cells hampers infection with oncolytic viruses. mRNA translation is an important component of innate immunity, yet the targeted cellular mRNAs remain ill-defined. We characterized the translatome of resistant murine “4T1” breast cancer cells infected with three of the most clinically advanced oncolytic viruses: Herpes Simplex virus 1, Reovirus and Vaccinia virus. Common among all three infections were translationally de-repressed mRNAs including Inpp5e, encoding an inositol 5-phosphatase that modifies lipid second messenger signalling. We found that viral infection induced expression of an Inpp5e mRNA variant that lacks repressive upstream open reading frames (uORFs) within its 5’ leader and is efficiently translated. Furthermore, we show that INPP5E contributes to antiviral immunity by altering virus attachment. These findings uncover a role for translational control through alternative 5’ leader expression and assign an antiviral function to the ciliopathy gene INPP5E.

The mammalian target of rapamycin complex 1 (mTORC1) controls critical cellular functions such as protein synthesis, lipid metabolism, protein turnover and ribosome biogenesis through the phosphorylation of multiple substrates. In this study, we examined the phosphorylation of a recently identified target of mTORC1: La-related protein 1 (LARP1), a member of the LARP superfamily. Previously, we and others have shown that LARP1 plays an important role in repressing TOP mRNA translation downstream of mTORC1. LARP1 binds the 7-methylguanosine triphosphate (m7Gppp) cap moiety and the adjacent 5’terminal oligopyrimidine (5’TOP) motif of TOP mRNAs, thus impeding the assembly of the eIF4F complex on these transcripts. mTORC1 plays a critical role in the control of TOP mRNA translationviaLARP1 but the precise mechanism by which this occurs is incompletely understood. The data described herein help to elucidate this process. Specifically, it show that: (i) mTORC1 interacts with LARP1, but not other LARP superfamily members,viathe C-terminal region that comprises the DM15 domain, (ii) mTORC1 pathway controls the phosphorylation of multiple (up to 26) serine and threonine residues on LARP1in vivo, (iii) mTORC1 regulates the binding of LARP1 to TOP mRNAs and (iv) phosphorylation of S689 by mTORC1 is particularly important for the association of the DM15 domain of LARP1 with the 5’UTR of RPS6 TOP mRNA. These data reveal LARP1 as a major substrate of mTORC1.

International audience; Herpes Simplex Virus 1 (HSV1) is amongst the most clinically advanced oncolytic virus platforms. However, efficient and sustained viral replication within tumours is limiting. Rapamycin can stimulate HSV1 replication in cancer cells, but active-site dual mTORC1 and mTORC2 (mammalian target of rapamycin complex 1 and 2) inhibitors (asTORi) were shown to suppress the virus in normal cells. Surprisingly, using the infected cell protein 0 (ICP0)-deleted HSV1 (HSV1-dICP0), we found that asTORi markedly augment infection in cancer cells and a mouse mammary cancer xenograft. Mechanistically, asTORi repressed mRNA translation in normal cells, resulting in defective antiviral response but also inhibition of HSV1-dICP0 replication. asTORi also reduced antiviral response in cancer cells, however in contrast to normal cells, transformed cells and cells transduced to elevate the expression of eukaryotic initiation factor 4E (eIF4E) or to silence the repressors eIF4E binding proteins (4E-BPs), selectively maintained HSV1-dICP0 protein synthesis during asTORi treatment, ultimately supporting increased viral replication. Our data show that altered eIF4E/4E-BPs expression can act to promote HSV1-dICP0 infection under prolonged mTOR inhibition. Thus, pharmacoviral combination of asTORi and HSV1 can target cancer cells displaying dysregulated eIF4E/4E-BPs axis.

Background We investigated the clinical value of serum levels of neuron-specific enolase (NSE) and human soluble protein-100β (S-100β) in acute cerebral infarction (ACI) patients. Material and methods A literature search of electronic databases identified relevant case-control studies that examined the correlations between NSE and S-100β serum levels, and ACI. The retrieved studies were screened based on our strict inclusion and exclusion criteria, and high-quality studies were subsequently selected for meta-analysis. STATA software (Version 12.0, Stata Corporation, College Station, TX, USA) was utilized for statistical analysis. Results A total of 13 case-control studies, containing 911 ACI patients and 686 healthy controls, were enrolled in this meta-analysis. The results of the meta-analysis showed that serum levels of NSE and S-100β in ACI patients were significantly higher than the control group. Subgroup analysis based on ethnicity revealed that the serum levels of NSE and S-100β in ACI patients were significantly higher than the control group in Asian population. In Caucasian population, the serum levels of NSE in case group was significantly higher than the control group, but no significant differences in serum levels of S-100β were observed between ACI patients and the control group. Conclusions Based on our results, we conclude that serum levels of NSE and S-100β strongly correlate with ACI in Asian population, and may be important clinical markers for diagnosis and treatment of ACI.

The 5’terminal oligopyrimidine (5’TOP) motif is a cis-regulatory RNA element located immediately downstream of the 7-methylguanosine [m7G] cap of TOP mRNAs, which encode ribosomal proteins and translation factors. In eukaryotes, this motif coordinates the synchronous and stoichiometric expression of the protein components of the translation machinery. La-related protein 1 (LARP1) binds TOP mRNAs, regulating their stability and translation. We present crystal structures of the human LARP1 DM15 region in complex with a 5’TOP motif, a cap analog (m7GTP), and a capped cytidine (m7GpppC), resolved to 2.6, 1.8 and 1.7 Å, respectively. Our binding, competition, and immunoprecipitation data corroborate and elaborate on the mechanism of 5’TOP motif binding by LARP1. We show that LARP1 directly binds the cap and adjacent 5’TOP motif of TOP mRNAs, effectively impeding access of eIF4E to the cap and preventing eIF4F assembly. Thus, LARP1 is a specialized TOP mRNA cap-binding protein that controls ribosome biogenesis. DOI: http://dx.doi.org/10.7554/eLife.24146.001

Aiming at the precision generating cutting problem of rectangle spline shaft, the multi-parameter fusion method to modified cutting edge of rectangle spline hob is presented. The method based on the analysis of workpiece machining errors to establish a fusion model about the rectangle spline hob cutting parameters and the rectangle spline shaft deformation quantity, the model can indicate the connection between rectangle spling hob theoretics profile and actual cutting profile, therefore, the rectangle spline hob’s profile is modified and to simulate by polynomials. The simulation experiment indicates that the method exact approximation the hob’s modified profile. Compare with the methods of the double-circular-arc and the least square fitting, the multi-parameter fusion method can enhance both design precision and design efficiency.

ObjectiveTo observe the curative effect of combined Chinese medicine, acupuncture and rehabilitation therapy on vascular dementia (VD), and to compare the Western medicine piracetam.MethodsTotal 134 VD patients screened in reference to the standard for VD diagnosis in DSM-IV were randomly divided into a Chinese medicine plus rehabilitation group (32 cases), a Chinese medicine plus acupuncture group (33 cases), a Chinese medicine and acupuncture plus rehabilitation group (37 cases) and a Western medicine piracetam group (32 cases). Mini Mental State Examination (MMSE) and Bless Behavior Scale (BBS) were used to assess changes in intelligence disorder before treatment and after 12-week treatment.ResultsBBS score, living ability and daily habit were enhanced after treatment in all groups. Cognitive function and behavioral ability were improved with similar total curative effects in all the 4 groups. Directional ability and short-term memory ability were significantly enhanced after treatment (P < 0.05) in both the Chinese medicine plus rehabilitation group and the Chinese medicine plus acupuncture group groups. Living ability was significantly improved after treatment in the Chinese medicine and acupuncture plus rehabilitation group (P < 0.01). However, no obvious difference was shown before and after treatment in the piracetam group.ConclusionThe improvement of living ability in the comprehensive treatment group is better than that in the other groups. Chinese medicine and acupuncture plus rehabilitation treatment can improve intelligence and living ability of senile VD patients.

The mammalian target of rapamycin complex 1 (mTORC1) is a critical regulator of protein synthesis. The best studied targets of mTORC1 in translation are the eukaryotic initiation factor-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). In this study, we identify the La-related protein 1 (LARP1) as a key novel target of mTORC1 with a fundamental role in terminal oligopyrimidine (TOP) mRNA translation. Recent genome-wide studies indicate that TOP and TOP-like mRNAs compose a large portion of the mTORC1 translatome, but the mechanism by which mTORC1 controls TOP mRNA translation is incompletely understood. Here, we report that LARP1 functions as a key repressor of TOP mRNA translation downstream of mTORC1. Our data show the following: (i) LARP1 associates with mTORC1 via RAPTOR; (ii) LARP1 interacts with TOP mRNAs in an mTORC1-dependent manner; (iii) LARP1 binds the 5′TOP motif to repress TOP mRNA translation; and (iv) LARP1 competes with the eukaryotic initiation factor (eIF) 4G for TOP mRNA binding. Importantly, from a drug resistance standpoint, our data also show that reducing LARP1 protein levels by RNA interference attenuates the inhibitory effect of rapamycin, Torin1, and amino acid deprivation on TOP mRNA translation. Collectively, our findings demonstrate that LARP1 functions as an important repressor of TOP mRNA translation downstream of mTORC1.

Background: With the aging of the global population, an increasing number of people are at risk of developing Alzheimer's disease. There is currently no effective treatment to hinder or postpone the progression of Alzheimer's disease. Cholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist Memantine are the commonly prescribed drugs for this disease, but their therapeutic effects are still unsatisfactory. Therefore, there is an urgent need to investigate novel treatment methods. Many animal experiments have suggested that deep brain stimulation benefits Alzheimer's disease, but clinical trials investigating this are still in their infancy. This study aims to investigate the safety and effectiveness of deep brain stimulation in the treatment of severe Alzheimer's disease. Methods/Design: This study is a prospective, self-controlled, phase I trial (case observation), which will be performed in the Department of Neurosurgery, Chinese PLA General Hospital (Beijing, China). Six patients with severe Alzheimer's disease will be enrolled to receive continuous bilateral deep brain stimulation of the fornix. Evaluations will be performed at baseline (prior to surgery) and at 1, 6, and 12 months after surgery. The primary outcome measures are disability and mortality rates during the 12-month deep brain stimulation trial period. Secondary outcome measures include the incidence of complications and Clinical Dementia Rating scale, Zarit Caregiver Burden Interview, Mini-Mental State Examination, and Barthel Index of Activities of Daily Living Scale scores. Patient recruitment will begin in August 2017, the analysis of primary outcome measures will be completed in October 2018, and the study will finish in June 2019. Discussion: The results of this study will help to determine the safety of deep brain stimulation for the treatment of severe Alzheimer's disease. We will also assess whether deep brain stimulation can improve the cognition, symptoms, and activities of daily living of patients with Alzheimer's disease. If the study succeeds, a novel option for patients with Alzheimer's disease who respond poorly to current treatments may be provided. Trial registration: The study protocol is registered with ClinicalTrials.gov (identifier: NCT03115814). Ethics: The study protocol was approved by the Ethics Committee of Chinese PLA General Hospital (approval No. S2015-013-02) and will be performed in accordance with the Declaration of Helsinki formulated by the World Medical Association in 2013. Informed consent: Written informed consent will be obtained from each patient's legal representative.