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Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg–1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg–1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load., A single dose of a broadly neutralizing, HIV-specific antibody transiently reduces viral load in plasma, and in some individuals is associated with durable virus suppression in the absence of antiretroviral therapy.

BACKGROUND: Zika virus (ZIKV) may cause severe congenital disease after maternal-fetal transmission. No vaccine is currently available. OBJECTIVE: To assess the safety and immunogenicity of Ad26.ZIKV.001, a prophylactic ZIKV vaccine candidate. DESIGN: Phase 1 randomized, double-blind, placebo-controlled clinical study. (ClinicalTrials.gov: NCT03356561). SETTING: United States. PARTICIPANTS: 100 healthy adult volunteers. INTERVENTION: Ad26.ZIKV.001, an adenovirus serotype 26 vector encoding ZIKV M-Env, administered in 1- or 2-dose regimens of 5 × 1010 or 1 × 1011 viral particles (vp), or placebo. MEASUREMENTS: Local and systemic adverse events; neutralization titers by microneutralization assay (MN50) and T-cell responses by interferon-I³ enzyme-linked immunospot and intracellular cytokine staining; and protectivity of vaccine-induced antibodies in a subset of participants through transfer in an exploratory mouse ZIKV challenge model. RESULTS: All regimens were well tolerated, with no safety concerns identified. In both 2-dose regimens, ZIKV neutralizing titers peaked 14 days after the second vaccination, with geometric mean MN50 titers (GMTs) of 1065.6 (95% CI, 494.9 to 2294.5) for 5 × 1010 vp and 956.6 (595.8 to 1535.8) for 1 × 1011 vp. Titers persisted for at least 1 year at a GMT of 68.7 (CI, 26.4-178.9) for 5 × 1010 vp and 87.0 (CI, 29.3 to 258.6) for 1 × 1011 vp. A 1-dose regimen of 1 × 1011 vp Ad26.ZIKV.001 induced seroconversion in all participants 56 days after the first vaccination (GMT, 103.4 [CI, 52.7 to 202.9]), with titers persisting for at least 1 year (GMT, 90.2 [CI, 38.4 to 212.2]). Env-specific cellular responses were induced. Protection against ZIKV challenge was observed after antibody transfer from participants into mice, and MN50 titers correlated with protection in this model. LIMITATION: The study was conducted in a nonendemic area, so it did not assess safety and immunogenicity in a flavivirus-exposed population. CONCLUSION: The safety and immunogenicity profile makes Ad26.ZIKV.001 a promising candidate for further development if the need reemerges. PRIMARY FUNDING SOURCE: Janssen Vaccines and Infectious Diseases.

Recent studies have reported the protective efficacy of both natural1 and vaccine-induced2–7 immunity against challenge with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in rhesus macaques. However, the importance of humoral and cellular immunity for protection against infection with SARS-CoV-2 remains to be determined. Here we show that the adoptive transfer of purified IgG from convalescent rhesus macaques (Macaca mulatta) protects naive recipient macaques against challenge with SARS-CoV-2 in a dose-dependent fashion. Depletion of CD8+ T cells in convalescent macaques partially abrogated the protective efficacy of natural immunity against rechallenge with SARS-CoV-2, which suggests a role for cellular immunity in the context of waning or subprotective antibody titres. These data demonstrate that relatively low antibody titres are sufficient for protection against SARS-CoV-2 in rhesus macaques, and that cellular immune responses may contribute to protection if antibody responses are suboptimal. We also show that higher antibody titres are required for treatment of SARS-CoV-2 infection in macaques. These findings have implications for the development of SARS-CoV-2 vaccines and immune-based therapeutic agents. Adoptive transfer of purified IgG from convalescent macaques protects naive macaques against SARS-CoV-2 infection, and cellular immune responses contribute to protection against rechallenge with SARS-CoV-2.

Viral rebound following antiretroviral therapy (ART) discontinuation in HIV-1-infected individuals is believed to originate from a small pool of CD4+ T cells harboring replication-competent provirus. However, the origin and nature of the rebound virus has remained unclear. Recent studies have suggested that rebound virus does not originate directly from individual latent proviruses but rather from recombination events involving multiple proviruses. Here we evaluate the origin of rebound virus in 16 ART-suppressed, chronically SIV-infected rhesus monkeys following ART discontinuation. We sequence viral RNA and viral DNA in these animals prior to ART initiation, during ART suppression, and following viral rebound, and we compare rebound viral RNA after ART discontinuation with near full-length viral DNA from peripheral blood and lymph node mononuclear cells (PBMC and LNMC) during ART suppression. Sequences of initial rebound viruses closely match viral DNA sequences in PBMC and LNMC during ART suppression. Recombinant viruses are rare in the initial rebound virus populations but arise quickly within 2–4 weeks after viral rebound. These data suggest that intact proviral DNA in PBMC and LNMC during ART suppression is likely the direct origin of viral rebound in chronically SIV-infected rhesus monkeys following ART discontinuation., The origin and nature of rebound HIV-1 virus following antiretroviral therapy (ART) discontinuation still remains unclear. Here, Liu et al. suggest that intact proviral DNA in peripheral blood and lymph node mononuclear cells during ART suppression likely is the source of viral rebound following ART discontinuation.

The recent novel coronavirus disease (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is seeing a rapid increase in infected patients worldwide. The host immune response to SARS-CoV-2 appears to play a critical role in disease pathogenesis and clinical manifestations. SARS-CoV-2 not only activates antiviral immune responses, but can also cause uncontrolled inflammatory responses characterized by marked pro-inflammatory cytokine release in patients with severe COVID-19, leading to lymphopenia, lymphocyte dysfunction, and granulocyte and monocyte abnormalities. These SARS-CoV-2-induced immune abnormalities may lead to infections by microorganisms, septic shock, and severe multiple organ dysfunction. Therefore, mechanisms underlying immune abnormalities in patients with COVID-19 must be elucidated to guide clinical management of the disease. Moreover, rational management of the immune responses to SARS-CoV-2, which includes enhancing anti-viral immunity while inhibiting systemic inflammation, may be key to successful treatment. In this review, we discuss the immunopathology of COVID-19, its potential mechanisms, and clinical implications to aid the development of new therapeutic strategies against COVID-19.

A safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be required to end the coronavirus disease 2019 (COVID-19) pandemic1-8. For global deployment and pandemic control, a vaccine that requires only a single immunization would be optimal. Here we show the immunogenicity and protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccines expressing the SARS-CoV-2 spike (S) protein in non-human primates. Fifty-two rhesus macaques (Macaca mulatta) were immunized with Ad26 vectors that encoded S variants or sham control, and then challenged with SARS-CoV-2 by the intranasal and intratracheal routes9,10. The optimal Ad26 vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs after SARS-CoV-2 challenge. Titres of vaccine-elicited neutralizing antibodies correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate robust single-shot vaccine protection against SARS-CoV-2 in non-human primates. The optimal Ad26 vector-based vaccine for SARS-CoV-2, termed Ad26.COV2.S, is currently being evaluated in clinical trials.

In this paper, AACGS concrete was prepared by using raw and 700 °C calcined coal gangue as the coarse aggregate and alkali-activated coal gangue-slag (AACGS) as the cementitious material. The variation of compressive strength and durability of AACGS concrete was studied, and the durability damage mechanism of AACGS concrete is analyzed in depth by SEM. The research results showed that coal gangue as coarse aggregate shows high compressive strength and good durability in AACGS concrete. AACGS concrete with calcined CGCA shows great advantages in compressive strength and sulfate attack resistance. Under the condition of large content, its long-term frost resistance durability and chloride ion permeability resistance are not as good as that of raw CGCA. If AACGS concrete is applied to the freeze-thaw environment, the content range of CGCA should be 30%–50%. This study provides an experimental basis for the large-scale utilization of coal gangue.

Zika virus (ZIKV) has caused significant disease, with widespread cases of neurological pathology and congenital neurologic defects. Rapid vaccine development has led to a number of candidates capable of eliciting potent ZIKV-neutralizing antibodies (reviewed in refs. 1–3). Despite advances in vaccine development, it remains unclear how ZIKV vaccination affects immune responses in humans with prior flavivirus immunity. Here we show that a single-dose immunization of ZIKV purified inactivated vaccine (ZPIV)4–7 in a dengue virus (DENV)-experienced human elicited potent cross-neutralizing antibodies to both ZIKV and DENV. Using a unique ZIKV virion-based sorting strategy, we isolated and characterized multiple antibodies, including one termed MZ4, which targets a novel site of vulnerability centered on the Envelope (E) domain I/III linker region and protects mice from viremia and viral dissemination following ZIKV or DENV-2 challenge. These data demonstrate that Zika vaccination in a DENV-experienced individual can boost pre-existing flavivirus immunity and elicit protective responses against both ZIKV and DENV. ZPIV vaccination in Puerto Rican individuals with prior flavivirus experience yielded similar cross-neutralizing potency after a single vaccination, highlighting the potential benefit of ZIKV vaccination in flavivirus-endemic areas., Zika virus vaccination elicits Zika and dengue virus cross-neutralizing antibodies in flavivirus-exposed individuals, potentially enhancing the protective efficacy of the vaccine in flavivirus-endemic regions.

The global COVID-19 pandemic has sparked intense interest in the rapid development of vaccines as well as animal models to evaluate vaccine candidates and to define immune correlates of protection. We recently reported a mouse-adapted SARS-CoV-2 virus strain (MA10) with the potential to infect wild-type laboratory mice, driving high levels of viral replication in respiratory tract tissues as well as severe clinical and respiratory symptoms, aspects of COVID-19 disease in humans that are important to capture in model systems. We evaluated the immunogenicity and protective efficacy of novel rhesus adenovirus serotype 52 (RhAd52) vaccines against MA10 challenge in mice. Baseline seroprevalence is lower for rhesus adenovirus vectors than for human or chimpanzee adenovirus vectors, making these vectors attractive candidates for vaccine development. We observed that RhAd52 vaccines elicited robust binding and neutralizing antibody titers, which inversely correlated with viral replication after challenge. These data support the development of RhAd52 vaccines and the use of the MA10 challenge virus to screen novel vaccine candidates and to study the immunologic mechanisms that underscore protection from SARS-CoV-2 challenge in wild-type mice.ImportanceWe have developed a series of SARS-CoV-2 vaccines using rhesus adenovirus serotype 52 (RhAd52) vectors, which exhibits a lower seroprevalence than human and chimpanzee vectors, supporting their development as novel vaccine vectors or as an alternative Ad vector for boosting. We sought to test these vaccines using a recently reported mouse-adapted SARS-CoV-2 (MA10) virus to i) evaluate the protective efficacy of RhAd52 vaccines and ii) further characterize this mouse-adapted challenge model and probe immune correlates of protection. We demonstrate RhAd52 vaccines elicit robust SARS-CoV-2-specific antibody responses and protect against clinical disease and viral replication in the lungs. Further, binding and neutralizing antibody titers correlated with protective efficacy. These data validate the MA10 mouse model as a useful tool to screen and study novel vaccine candidates, as well as the development of RhAd52 vaccines for COVID-19.

Individuals on immunosuppressive (IS) therapy have increased mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and delayed viral clearance may lead to new viral variants. IS therapy reduces antibody responses following coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccination; however, a comprehensive assessment of vaccine immunogenicity is lacking. Here we show that IS therapy reduced neutralizing, binding, and nonneutralizing antibody functions in addition to CD4 and CD8 T-cell interferon-γ responses following COVID-19 mRNA vaccination compared to immunocompetent individuals. Moreover, IS therapy reduced cross-reactivity against SARS-CoV-2 variants. These data suggest that the standard COVID-19 mRNA vaccine regimens will likely not provide optimal protection in immunocompromised individuals., Individuals on immunosuppression for various indications have impaired neutralizing, binding, and nonneutralizing antibody responses and reduced T-cell activity in response to COVID-19 mRNA vaccination compared to immunocompetent controls. This suggests that standard vaccination may not result in protective immunity in this population.

Live oral vaccines have been explored for their protective efficacy against respiratory viruses, particularly for adenovirus serotypes 4 and 7. The potential of a live oral vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, remains unclear. In this study, we assessed the immunogenicity of live SARS-CoV-2 delivered to the gastrointestinal tract in rhesus macaques and its protective efficacy against intranasal and intratracheal SARS-CoV-2 challenge. Post-pyloric administration of SARS-CoV-2 by esophagogastroduodenoscopy resulted in limited virus replication in the gastrointestinal tract and minimal to no induction of mucosal antibody titers in rectal swabs, nasal swabs, and bronchoalveolar lavage. Low levels of serum neutralizing antibodies were induced and correlated with modestly diminished viral loads in nasal swabs and bronchoalveolar lavage following intranasal and intratracheal SARS-CoV-2 challenge. Overall, our data show that post-pyloric inoculation of live SARS-CoV-2 is weakly immunogenic and confers partial protection against respiratory SARS-CoV-2 challenge in rhesus macaques.ImportanceSARS-CoV-2 remains a global threat, despite the rapid deployment but limited coverage of multiple vaccines. Alternative vaccine strategies that have favorable manufacturing timelines, greater ease of distribution and improved coverage may offer significant public health benefits, especially in resource-limited settings. Live oral vaccines have the potential to address some of these limitations; however no studies have yet been conducted to assess the immunogenicity and protective efficacy of a live oral vaccine against SARS-CoV-2. Here we report that oral administration of live SARS-CoV-2 in non-human primates may offer prophylactic benefits, but that formulation and route of administration will require further optimization.

To detect sparse small objects in high resolution images at a low cost is significantly more challenging than regular detection tasks. Compared to the overall detection accuracy, the recall rate is much less affected when using properly downsampled images for detection. Based on this fact, we propose a clustering-based coarse-to-fine object detection framework to enhance the object detection of sparse small objects. The first stage is coarse detection on a downsampled image to obtain image chips based on a clustering-baed region generation method. After that, the associated high resolution image clips are sent to a second-stage detector for fine detection. This approach reduces the number of chips for final object detection compared to regular methods, which divide the image into small tiles of the same size, and makes the best use of information in high-resolution images to increase detection accuracy. Experimental results show that our proposed approach achieves promising performance compared with other state-of-the-art detectors.

BackgroundA cluster of over a thousand infections with the SARS-CoV-2 delta variant was identified in a predominantly fully vaccinated population in Provincetown, Massachusetts in July 2021. Immune responses in breakthrough infections with the SARS-CoV-2 delta variant remain to be defined.MethodsHumoral and cellular immune responses were assessed in 35 vaccinated individuals who were tested for SARS-CoV-2 in the Massachusetts Department of Public Health outbreak investigation.ResultsVaccinated individuals who tested positive for SARS-CoV-2 demonstrated substantially higher antibody responses than vaccinated individuals who tested negative for SARS-CoV-2, including 28-fold higher binding antibody titers and 34-fold higher neutralizing antibody titers against the SARS-CoV-2 delta variant. Vaccinated individuals who tested positive also showed 4.4-fold higher Spike-specific CD8+ T cell responses against the SARS-CoV-2 delta variant than vaccinated individuals who tested negative.ConclusionsFully vaccinated individuals developed robust anamnestic antibody and T cell responses following infection with the SARS-CoV-2 delta variant. These data suggest important immunologic benefits of vaccination in the context of breakthrough infections.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that result in increased transmissibility and partial evasion of neutralizing antibodies have recently emerged. Whether natural immunity induced by the original SARS-CoV-2 WA1/2020 strain protects against rechallenge with these SARS-CoV-2 variants remains a critical unresolved question. In this study, we show that natural immunity induced by the WA1/2020 strain leads to partial but incomplete protection against the SARS-CoV-2 variants B.1.1.7 (alpha) and B.1.351 (beta) in rhesus macaques. We challenged rhesus macaques with B.1.1.7 and B.1.351 and showed that infection with these variants resulted in high viral replication in the upper and lower respiratory tract. We then infected rhesus macaques with the WA1/2020 strain and rechallenged them on day 35 with the WA1/2020, B.1.1.7, or B.1.351 variants. Natural immunity to WA1/2020 led to robust protection against rechallenge with WA1/2020 but only partial protection against rechallenge with B.1.351. An intermediate degree of protection was observed in rhesus macaques against rechallenge with B.1.1.7. These data demonstrate partial but incomplete protective efficacy of natural immunity induced by WA1/2020 against SARS-CoV-2 variants of concern. Our findings have important implications for both vaccination and public health strategies in the context of emerging SARS-CoV-2 variants of concern.

The a priori T cell repertoire and immune response against SARS-CoV-2 viral antigens may explain the varying clinical course and prognosis of patients having a mild COVID-19 infection as opposed to those developing more fulminant multisystem organ failure and associated mortality. Using a novel SARS-Cov-2-specific artificial antigen presenting cell (aAPC), coupled with a rapid expansion protocol (REP) as practiced in tumor infiltrating lymphocytes (TIL) therapy, we generate an immune catalytic quantity of Virus Induced Lymphocytes (VIL). Using T cell receptor (TCR)-specific aAPCs carrying co-stimulatory molecules and major histocompatibility complex (MHC) class-I immunodominant SARS-CoV-2 peptide-pentamer complexes, we expand virus-specific VIL derived from peripheral blood mononuclear cells (PBMC) of convalescent COVID-19 patients up to 1000-fold. This is achieved in a clinically relevant 7-day vein-to-vein time-course as a potential adoptive cell therapy (ACT) for COVID-19. We also evaluate this approach for other viral pathogens using Cytomegalovirus (CMV)-specific VIL from donors as a control. Rapidly expanded VIL are enriched in virus antigen-specificity and show an activated, polyfunctional cytokine profile and T effector memory phenotype which may contribute to a robust immune response. Virus-specific T cells can also be delivered allogeneically via MHC-typing and patient human leukocyte antigen (HLA)-matching to provide pragmatic treatment in a large-scale therapeutic setting. These data suggest that VIL may represent a novel therapeutic option that warrants further clinical investigation in the armamentarium against COVID-19 and other possible future pandemics.

Interim immunogenicity and efficacy data for the Ad26.COV2.S vaccine for COVID-19 have recently been reported1–3. We describe here the 8-month durability of humoral and cellular immune responses in 20 individuals who received one or two doses of 5×1010 vp or 1011 vp Ad26.COV2.S and in 5 participants who received placebo2. We evaluated antibody and T cell responses on day 239, which was 8 months after the single-shot vaccine regimen (N=10) or 6 months after the two-shot vaccine regimen (N=10), although the present study was not powered to compare these regimens3. We also report neutralizing antibody responses against the parental SARS-CoV-2 WA1/2020 strain as well as against the SARS-CoV-2 variants D614G, B.1.1.7 (alpha), B.1.617.1 (kappa), B.1.617.2 (delta), P.1 (gamma), B.1.429 (epsilon), and B.1.351 (beta).

Interim immunogenicity and efficacy data for the Ad26.COV2.S vaccine for COVID-19 have recently been reported1-3. We describe here the 8-month durability of humoral and cellular immune responses in 20 individuals who received one or two doses of 5×1010 vp or 1011 vp Ad26.COV2.S and in 5 participants who received placebo2. We evaluated antibody and T cell responses on day 239, which was 8 months after the single-shot vaccine regimen (N=10) or 6 months after the two-shot vaccine regimen (N=10), although the present study was not powered to compare these regimens3. We also report neutralizing antibody responses against the parental SARS-CoV-2 WA1/2020 strain as well as against the SARS-CoV-2 variants D614G, B.1.1.7 (alpha), B.1.617.1 (kappa), B.1.617.2 (delta), P.1 (gamma), B.1.429 (epsilon), and B.1.351 (beta).

Importance Pregnant women are at increased risk of morbidity and mortality from COVID-19 but have been excluded from the phase 3 COVID-19 vaccine trials. Data on vaccine safety and immunogenicity in these populations are therefore limited. Objective To evaluate the immunogenicity of COVID-19 messenger RNA (mRNA) vaccines in pregnant and lactating women, including against emerging SARS-CoV-2 variants of concern. Design, setting, and participants An exploratory, descriptive, prospective cohort study enrolled 103 women who received a COVID-19 vaccine from December 2020 through March 2021 and 28 women who had confirmed SARS-CoV-2 infection from April 2020 through March 2021 (the last follow-up date was March 26, 2021). This study enrolled 30 pregnant, 16 lactating, and 57 neither pregnant nor lactating women who received either the mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) COVID-19 vaccines and 22 pregnant and 6 nonpregnant unvaccinated women with SARS-CoV-2 infection. Main outcomes and measures SARS-CoV-2 receptor binding domain binding, neutralizing, and functional nonneutralizing antibody responses from pregnant, lactating, and nonpregnant women were assessed following vaccination. Spike-specific T-cell responses were evaluated using IFN-γ enzyme-linked immunospot and multiparameter intracellular cytokine-staining assays. Humoral and cellular immune responses were determined against the original SARS-CoV-2 USA-WA1/2020 strain as well as against the B.1.1.7 and B.1.351 variants. Results This study enrolled 103 women aged 18 to 45 years (66% non-Hispanic White) who received a COVID-19 mRNA vaccine. After the second vaccine dose, fever was reported in 4 pregnant women (14%; SD, 6%), 7 lactating women (44%; SD, 12%), and 27 nonpregnant women (52%; SD, 7%). Binding, neutralizing, and functional nonneutralizing antibody responses as well as CD4 and CD8 T-cell responses were present in pregnant, lactating, and nonpregnant women following vaccination. Binding and neutralizing antibodies were also observed in infant cord blood and breast milk. Binding and neutralizing antibody titers against the SARS-CoV-2 B.1.1.7 and B.1.351 variants of concern were reduced, but T-cell responses were preserved against viral variants. Conclusion and relevance In this exploratory analysis of a convenience sample, receipt of a COVID-19 mRNA vaccine was immunogenic in pregnant women, and vaccine-elicited antibodies were transported to infant cord blood and breast milk. Pregnant and nonpregnant women who were vaccinated developed cross-reactive antibody responses and T-cell responses against SARS-CoV-2 variants of concern.

The development of low-cost, earth-abundant and highly-efficient cocatalysts is still important to promote the photocatalytic H2 evolution reaction over semiconductors. Herein, a series of Ni nanoclusters (NCs) modified brookite TiO2 quasi nanocubes (BTN) (marked as Ni/BTN) are fabricated via a chemical reduction process. It is found that the loading content and oxidation state of Ni NCs can significantly influence the optical absorption, photocatalytic activity, and stability of Ni/BTN composites. Among the resultant Ni NCs-loaded products, 0.1%Ni/BTN composite delivers the best H2 evolution activity (156 µmol/h), which is 4.3 times higher than that of the BTN alone (36 µmol/h). Furthermore, the Ni NCs with ultrafine size (~2 nm) and high dispersity enable shorter charge transfer distance by quickly capturing the photoexcited electrons of BTN, and thus result in the improved activity even though the oxidization of some Ni NCs on BTN is harmful to the activity for H2 evolution due to the much lower electron capturing capability of NiO than metallic Ni. This study not only clarifies that brookite TiO2 would be a promising high-efficient photo-catalyst for H2 evolution, but also reveals vital clues for further improving its photocatalytic performance using low-cost Ni-based cocatalyst.

Importance Control of the global COVID-19 pandemic will require the development and deployment of safe and effective vaccines. Objective To evaluate the immunogenicity of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in humans, including the kinetics, magnitude, and phenotype of SARS-CoV-2 spike-specific humoral and cellular immune responses. Design, Setting, and Participants Twenty-five participants were enrolled from July 29, 2020, to August 7, 2020, and the follow-up for this day 71 interim analysis was completed on October 3, 2020; follow-up to assess durability will continue for 2 years. This study was conducted at a single clinical site in Boston, Massachusetts, as part of a randomized, double-blind, placebo-controlled phase 1 clinical trial of Ad26.COV2.S. Interventions Participants were randomized to receive 1 or 2 intramuscular injections with 5 × 1010viral particles or 1 × 1011viral particles of Ad26.COV2.S vaccine or placebo administered on day 1 and day 57 (5 participants in each group). Main Outcomes and Measures Humoral immune responses included binding and neutralizing antibody responses at multiple time points following immunization. Cellular immune responses included immunospot-based and intracellular cytokine staining assays to measure T-cell responses. Results Twenty-five participants were randomized (median age, 42; age range, 22-52; 52% women, 44% male, 4% undifferentiated), and all completed the trial through the day 71 interim end point. Binding and neutralizing antibodies emerged rapidly by day 8 after initial immunization in 90% and 25% of vaccine recipients, respectively. By day 57, binding and neutralizing antibodies were detected in 100% of vaccine recipients after a single immunization. On day 71, the geometric mean titers of spike-specific binding antibodies were 2432 to 5729 and the geometric mean titers of neutralizing antibodies were 242 to 449 in the vaccinated groups. A variety of antibody subclasses, Fc receptor binding properties, and antiviral functions were induced. CD4+ and CD8+ T-cell responses were induced. Conclusion and Relevance In this phase 1 study, a single immunization with Ad26.COV2.S induced rapid binding and neutralization antibody responses as well as cellular immune responses. Two phase 3 clinical trials are currently underway to determine the efficacy of the Ad26.COV2.S vaccine. Trial Registration ClinicalTrials.gov Identifier:NCT04436276

We previously reported that a single immunization with an adenovirus serotype 26 (Ad26) vector-based vaccine expressing an optimized SARS-CoV-2 spike (Ad26.COV2.S) protected rhesus macaques against SARS-CoV-2 challenge. To evaluate reduced doses of Ad26.COV2.S, 30 rhesus macaques were immunized once with 1x1011, 5x1010, 1.125x1010, or 2x109 vp Ad26.COV2.S or sham and were challenged with SARS-CoV-2. Vaccine doses as low as 2x109 vp provided robust protection in bronchoalveolar lavage, whereas doses of 1.125x1010 vp were required for protection in nasal swabs. Activated memory B cells and binding or neutralizing antibody titers following vaccination correlated with protective efficacy. At suboptimal vaccine doses, viral breakthrough was observed but did not show enhancement of disease. These data demonstrate that a single immunization with relatively low dose of Ad26.COV2.S effectively protected against SARS-CoV-2 challenge in rhesus macaques, although a higher vaccine dose may be required for protection in the upper respiratory tract., Evaluation of a reduced dosage of the single-shot Ad26.COV2.S reveals protection across different tissues protects against SARS-CoV-2 challenge and enhancement of disease. A higher dosage may be needed for protection in the upper respiratory tract.

Combining the characteristics of graded broken stone (GBS) and SRB, a pavement base structure with cement stabilized recycled masonry aggregate (CRMA) and upper base of GBS was adopted in a road project in Cangzhou City (CZC). The indoor test determined that the optimal water content (OWC) of the GBS mixture was 3.2% and the maximum dry density (MDD) was 2.197 g/cm3; OWC of CRMA is 14.3%, and MDD is 1.81 g/cm3. The investigation results of pavement deflection and cracks in the six years of opening to traffic show that the asphalt pavement structure with the lower base (LB) of SRB and the upper base (UB) of GBS has good crack resistance.

Personal neoantigen vaccines have been envisioned as an effective approach to induce, amplify and diversify antitumor T cell responses. To define the long-term effects of such a vaccine, we evaluated the clinical outcome and circulating immune responses of eight patients with surgically resected stage IIIB/C or IVM1a/b melanoma, at a median of almost 4 years after treatment with NeoVax, a long-peptide vaccine targeting up to 20 personal neoantigens per patient ( NCT01970358 ). All patients were alive and six were without evidence of active disease. We observed long-term persistence of neoantigen-specific T cell responses following vaccination, with ex vivo detection of neoantigen-specific T cells exhibiting a memory phenotype. We also found diversification of neoantigen-specific T cell clones over time, with emergence of multiple T cell receptor clonotypes exhibiting distinct functional avidities. Furthermore, we detected evidence of tumor infiltration by neoantigen-specific T cell clones after vaccination and epitope spreading, suggesting on-target vaccine-induced tumor cell killing. Personal neoantigen peptide vaccines thus induce T cell responses that persist over years and broaden the spectrum of tumor-specific cytotoxicity in patients with melanoma. Personalized neoantigen vaccination in patients with melanoma elicits durable and specific memory T cell clones that have cytotoxic gene signatures and can diversify to include nonvaccine neoantigen specificities.

BackgroundTumor relapse due to mutation inCD19can hinder the efficacy of chimeric antigen receptor (CAR)-T cell therapy. Herein, we focused on lymphoma patients whose B cells exhibited a point mutation inCD19of B cells after CAR-T cell infusion.MethodsThe CAR-T and CD19+B cells from peripheral blood or bone marrow were assessed using flow cytometry. Genome sequencing was conducted to identify the molecular characteristics of CAR-T and CD19+B cells from pre-relapse and postrelapse samples. CD19 in CARs comprising single chain fragments variable (scFV) antibody with FMC63 or 21D4 was constructed. The cytotoxic efficacy of CAR-T cells was also evaluated via in vitro and in vivo experiments.ResultsA patient with high-grade B cell lymphoma exhibited complete response, but the lymphoma relapsed in her left breast at 6 months afterCD19CAR (FMC63)-T cell infusion. A mutation was found in exon 3 ofCD19(p.163. R-L) in malignant B cells of the patient. In two lymphoma patients who exhibited resistance to CAR-T cell therapy, a mutation was detected in exon 3 ofCD19(p.174. L-V). Functional analysis revealed that FMC63 CAR-T cells exhibited antitumor ability against wild-type CD19+cells but were unable to eradicate these two types of mutated CD19+cells. Interestingly, 21D4 CAR-T cells were potentially capable of eradicating these mutated CD19+cells and exhibiting high antitumor capacity against CD19+cells with loss of exon 1, 2, or 3.ConclusionsThese findings suggest that point mutation can facilitate immune escape from CAR-T cell therapy and that alternative CAR-T cells can effectively eradicate the mutated B cells, providing an individualized therapeutic approach for lymphoma patients showing relapse.

An understanding of protective immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for vaccine and public health strategies aimed at ending the global coronavirus disease 2019 (COVID-19) pandemic. A key unanswered question is whether infection with SARS-CoV-2 results in protective immunity against reexposure. We developed a rhesus macaque model of SARS-CoV-2 infection and observed that macaques had high viral loads in the upper and lower respiratory tract, humoral and cellular immune responses, and pathologic evidence of viral pneumonia. After the initial viral clearance, animals were rechallenged with SARS-CoV-2 and showed 5 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa compared with after the primary infection. Anamnestic immune responses after rechallenge suggested that protection was mediated by immunologic control. These data show that SARS-CoV-2 infection induced protective immunity against reexposure in nonhuman primates.

The global coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made the development of a vaccine a top biomedical priority. In this study, we developed a series of DNA vaccine candidates expressing different forms of the SARS-CoV-2 spike (S) protein and evaluated them in 35 rhesus macaques. Vaccinated animals developed humoral and cellular immune responses, including neutralizing antibody titers at levels comparable to those found in convalescent humans and macaques infected with SARS-CoV-2. After vaccination, all animals were challenged with SARS-CoV-2, and the vaccine encoding the full-length S protein resulted in >3.1 and >3.7 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, as compared with viral loads in sham controls. Vaccine-elicited neutralizing antibody titers correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate vaccine protection against SARS-CoV-2 in nonhuman primates.

The latent viral reservoir is the critical barrier for the development of a cure for HIV-1 infection. Previous studies have shown direct antiviral activity of potent HIV-1 Env-specific broadly neutralizing antibodies (bNAbs) administered when antiretroviral therapy (ART) was discontinued, but it remains unclear whether bNAbs can target the viral reservoir during ART. Here we show that administration of the V3 glycan-dependent bNAb PGT121 together with the Toll-like receptor 7 (TLR7) agonist vesatolimod (GS-9620) during ART delayed viral rebound following discontinuation of ART in simian-human immunodeficiency virus (SHIV)-SF162P3-infected rhesus monkeys in which ART was initiated during early acute infection. Moreover, in the subset of monkeys that were treated with both PGT121 and GS-9620 and that did not show viral rebound after discontinuation of ART, adoptive transfer studies and CD8-depletion studies also did not reveal virus. These data demonstrate the potential of bNAb administration together with innate immune stimulation as a possible strategy for targeting the viral reservoir.

With the dramatic increase of image data, image clustering algorithms have received extensive attention. Meanwhile, deep learning has shown excellent performance in various fields, while there are few studies on its application in image clustering. Moreover, previous deep clustering frameworks are multistage and difficult to embed the available supervision information. In view of the above, we propose a deep clustering network called CCLN (Clustering and Classification Learning Network), which combines feature learning, clustering, and classification to achieve end-to-end learning. At the same time, we add a branch of the supervisory to utilize multi-Grained supervision information, so as to improve the performance of image clustering. Extensive experiments show that CCLN effectively utilizes available supervision information, and improves clustering performance.

With the rapid development of artificial intelligence (AI), ethical issues surrounding AI have attracted increasing attention. In particular, autonomous vehicles may face moral dilemmas in accident scenarios, such as staying the course resulting in hurting pedestrians or swerving leading to hurting passengers. To investigate such ethical dilemmas, recent studies have adopted preference aggregation, in which each voter expresses her/his preferences over decisions for the possible ethical dilemma scenarios, and a centralized system aggregates these preferences to obtain the winning decision. Although a useful methodology for building ethical AI systems, such an approach can potentially violate the privacy of voters since moral preferences are sensitive information and their disclosure can be exploited by malicious parties. In this paper, we report a first-of-its-kind privacy-preserving crowd-guided AI decision-making approach in ethical dilemmas. We adopt the notion of differential privacy to quantify privacy and consider four granularities of privacy protection by taking voter-/record-level privacy protection and centralized/distributed perturbation into account, resulting in four approaches VLCP, RLCP, VLDP, and RLDP. Moreover, we propose different algorithms to achieve these privacy protection granularities, while retaining the accuracy of the learned moral preference model. Specifically, VLCP and RLCP are implemented with the data aggregator setting a universal privacy parameter and perturbing the averaged moral preference to protect the privacy of voters' data. VLDP and RLDP are implemented in such a way that each voter perturbs her/his local moral preference with a personalized privacy parameter. Extensive experiments on both synthetic and real data demonstrate that the proposed approach can achieve high accuracy of preference aggregation while protecting individual voter's privacy., This paper has been published as a full paper in ACM International Conference on Information and Knowledge Management (CIKM) 2019, held in November 3-7, 2019, Beijing, China

With massive real-world networks added with spatial attributes, query processing in spatial networks has been widely used in real-life applications. Considering the high costs of spatial network queries, outsourcing querying services to cloud provides a cost-effective way for data owners. However, directly outsourcing such services may cause serious privacy concerns. To address this privacy problem, existing studies apply anonymous or differential privacy techniques on spatial network queries, which are not under the semi-trusted secure model. Other existing works primarily focus on query processing over either encrypted spatial or network data, which cannot directly be applied to work out the secure spatial network query problem. To this end, we define and study Secure Spatial Network kNN Query (SSNQ) problem on cloud platform. We first present Basic Secure Spatial Network kNN Query (BSSNQ) method, in which we compute secure kNN for the query node to construct candidate sequences using secure subprotocols. With pre-encrypted network distances, we then compute shortest paths between the query node and each candidate, and securely update the candidate sequences according to Euclidean restriction to derive final query results. To improve the efficiency of BSSNQ, we further propose Heuristic Secure Spatial Network kNN Query (HSSNQ) method, which securely calculates shortest paths from the query node to the visiting nodes iteratively, and use optimistic estimate distances as the key to lead the heuristic search within a priority queue. Thorough analysis shows the security and complexity of the proposed methods, and extensive experimental results on real datasets demonstrate the efficiency of the query performance.

The development of immunologic interventions that can target the viral reservoir in HIV-1-infected individuals is a major goal of HIV-1 research. However, little evidence exists that the viral reservoir can be sufficiently targeted to improve virologic control following discontinuation of antiretroviral therapy. Here we show that therapeutic vaccination with Ad26/MVA (recombinant adenovirus serotype 26 (Ad26) prime, modified vaccinia Ankara (MVA) boost) and stimulation of TLR7 (Toll-like receptor 7) improves virologic control and delays viral rebound following discontinuation of antiretroviral therapy in SIV-infected rhesus monkeys that began antiretroviral therapy during acute infection. Therapeutic vaccination with Ad26/MVA resulted in a marked increase in the magnitude and breadth of SIV-specific cellular immune responses in virologically suppressed, SIV-infected monkeys. TLR7 agonist administration led to innate immune stimulation and cellular immune activation. The combination of Ad26/MVA vaccination and TLR7 stimulation resulted in decreased levels of viral DNA in lymph nodes and peripheral blood, and improved virologic control and delayed viral rebound following discontinuation of antiretroviral therapy. The breadth of cellular immune responses correlated inversely with set point viral loads and correlated directly with time to viral rebound. These data demonstrate the potential of therapeutic vaccination combined with innate immune stimulation as a strategy aimed at a functional cure for HIV-1 infection.

In order to solve multi-tag collision problem in radio frequency identification system, many anti-collision algorithms have been proposed, such as query tree algorithm, bi-slotted collision tracking tree algorithm (BSCTTA). In this paper, an enhanced collision tracking tree algorithm is proposed to improve the performance of BSCTTA. The proposed algorithm generates prefix depending on the first collided bit, and then eliminates the idle timeslots and reduces the collided timeslots. Moreover, the proposed algorithm can identify two tags in a timeslot if there is only one collided bit in the response data, and can truncate unvalued data when two collided bits are detected. The simulation results show that the proposed algorithm reduces the communication bits and query cycles than other algorithms, therefore enhances the identification efficiency and identification speed of radio frequency identification system.

Preference elicitation is a challenging activity in any decision-making process, yet preferences are fundamental since the recommendations are meaningful and acceptable only if the Decision Maker's values are taken into account. This study proposes an ex-post application of a recent ranking method named Simple Ranking with Multiple Points (S-RMP) to support a participatory decision-making process. The method has been tested on a real-world case study simulating the selection of the most suitable site for locating a new landfill. The purpose of the research is twofold: (i) to explore the applicability and relevance of the S-RMP method to support environmental decision-making processes and (ii) to provide guidelines for the elicitation of preference parameters of the S-RMP ranking method. The results highlight that the proposed method opens a promising line of research in the environmental decision-making domain, thanks to its ability to use heterogeneous information consistently with the increasing amount of qualitative data embedded in real decision-making processes.

Background: Tumoural infiltration of T lymphocytes is determined by local patterns of specific chemokine expression. In this report, we examined the roles of CCL4 and CCL20 in the accumulation of CD8+ cytotoxic T lymphocytes (CTLs) and regulatory T (Treg) lymphocytes in oesophageal squamous cell carcinoma (ESCC), and determined the correlations between chemokine expressions and ESCC patients' survival. Methods: Reverse transcriptase–PCR and immunohistochemistry (IHC) staining were performed to examine the expressions of interested genes. Flow cytometry was adopted to check the expressions of CCL4- and CCL6-specific receptors, CCR5 and CCR6, on CTLs and Treg cells. In addition, transwell assay was carried on. Results: The CCL4 expression was significantly correlated with the expression of CTL markers (CD8 and Granzyme B), whereas CCL20 was positively correlated with Treg markers (FoxP3 and IL-10). Consistently, CCR5 was found to be mainly expressed on CD8+ T lymphocytes, while CCR6 showed prevalence on Treg lymphocytes and the frequencies of CCR5+CD8+ CTLs and CCR6+ Treg cells were higher in TIL compared with PBMC. Respectively, CCL4 and CCL20 recruited CD8+ and regulatory T cells in vitro. Importantly, high levels of CCL4 in the lesions of ESCC patients predicted prolonged survival. Furthermore, CCL4high/CCL20low group demonstrated better overall survival, whereas CCL4low/CCL20low and CCL4low/CCL20high groups showed the worst overall survival. Conclusions: Our data showed that CCL4 and CCL20 recruit functionally different T lymphocyte subsets into oesophageal carcinoma, indicating CCL4 and CCL20 are potential predictors of ESCC patients' survival.

The collinear holographic data storage system (CHDSS) is a very promising storage system due to its large storage capacities and high transfer rates in the era of big data. The digital micro-mirror device (DMD) as a spatial light modulator is the key device of the CHDSS due to its high speed, high precision, and broadband working range. To improve the system stability and performance, an optimal micro-mirror tilt angle was theoretically calculated and experimentally confirmed by analyzing the relationship between the tilt angle of the micro-mirror on the DMD and the power profiles of diffraction patterns of the DMD at the Fourier plane. In addition, we proposed a novel chess board sync mark design in the data page to reduce the system bit error rate in circumstances of reduced aperture required to decrease noise and median exposure amount. It will provide practical guidance for future DMD based CHDSS development.

The power MOSFETs are one of the widely used core components in power electronics, automotive electronics, consumer electronics, aerospace and other fields generally. There is a high requirement for stabilization performance of MOSFETs. The breakdown voltage which is the most important electrical parameter of MOSFETs is usually reduced by the punch-through or reach-through phenomena, which leads the system circuits not to work functionally. In this paper, the basic principle of them are introduced and analyzed respectively. In a p-n junction with the doping concentration distribution fixed, certain width of the semiconductor is depleted in the n-side and p-side respectively when avalanche breakdown occurs. As the designed geometry thickness of the lightly doped side is less than the corresponding depletion width, punch-though phenomenon comes up. It often happens in P+NP+ and P+N-N+ sandwich structure In numerical simulation for a typical P+NP+ sandwich structure with a breakdown voltage of 226.3 V in non-through case, the breakdown voltage of punch-through case is reduced to 100.5 V and decreased by 55.6%. The reach-through effect appears when the designed geometry thickness of the heavily doped side is less than the corresponding depletion width. Its sandwich structure is defined N+P+NN+ style for the convenience of simulation. And the breakdown voltage of reach-through case is reduced to 50.99 V which is just only 22.5% of breakdown voltage of non-through structure. The simulation results are obtained by SSE (Sentaurus Structure Editor) software.

A coplanar waveguide (CPW) feeding circularly polarized (CP) ferrite antenna with rectangular slot and a microstrip feeding CP annular-ring antenna with a pair of identical meandered strips (U-shaped strip) are proposed in this paper They use the same ferrite substrate with e r = 7.5 (tanδ e = 0.01) and µ r = 7.2 (tanδ µ = 0.2). Ferrite can efficiently reduce the dimension of the antenna with respect to the dielectric substrate. Not only that, ferrite can also make the bandwidth of the antenna become wider and energy easier radiate. The rectangular slot antenna and annular-ring antenna can achieve CP easily by embedding arc-shaped strip and a pair of diagonal U-shaped strips, respectively. Electromagnetic simulation software Ansoft HFSS based on the finite element method has been used to make simulation and optimization for the proposed two designs. We contain the simulated results of two different designs in multiple parameters which include return loss, 3 dB axial ratio, radiation patterns and the gain. We found that the rectangular slot antenna has a wider 3 dB axis ratio bandwidth (from 865 MHz to 982 MHz, 12.7% @ 920 MHz) and larger peak gain (2.42 dBi) than annular-ring ferrite antenna (from 901MHz to 940MHz, 4% @ 920MHz; −23.5dBi). The annular-ring ferrite antenna has a wider return loss bandwidth (from 815 MHz to 1.29 GHz) than rectangular slot ferrite antenna (from 825 MHz to 1.0GHz, 18.9% @ 925MHz). The dimensions of the rectangular slot antenna and annular-ring antenna are 106∗94.5 mm2 and 60∗36 mm2 respectively, so annular-ring antenna has a smaller size. They both can be used for UHF RFID applications.

In some RFID applications, the reader needs to identify the staying tags within its interrogation zone repeatedly. Meanwhile, there are some arriving tags continually moving into the interrogation zone of the reader. For these scenes, the adaptive query splitting (AQS) algorithm, the semi-blocking AQS (SBA), and the slot allocated blocking anti-collision (SABA) algorithm are proposed. However, these algorithms all use query tree algorithm to identify arriving tags, which leads to lower identification efficiency. Therefore, the blocking collision tracking tree (BCTT) algorithm is proposed in this paper. BCTT allocates a unique slot number for each identified tag. The identification process of BCTT is divided into two phases. The staying tags are identified in the first phase according to the slot number, which reduce the bits transmitted by tags. In the second phase, the staying tags are blocked to respond the reader's query, so the collision between staying tags and arriving tags are thoroughly avoid. The arriving tags are identified by adopting collision tracking tree algorithm. The query prefix is generated according to the first collided bit, so BCTT can completely eliminate the idle slots, and also significantly reduce the number of collision slots. Especially, if there is only one collided bit in the response, BCTT can identify two tags in a slot. The simulation results indicate that the identification efficiency, identification speed, and communication load of BCTT are obviously superior to other similar algorithms such as SABA.

We address the problem of providing shared-path protection for a set of connection requests in a flexible bandwidth optical network under the constraint that the joint failure probability of the primary path and backup path of each request is below a given maximum joint failure probability threshold. The overall objective of the problem is to minimize spectrum consumption while meeting the maximum joint failure probability requirements. We propose the minimum free spectrum–block consumption algorithm (MFSB) for providing shared-path protection with joint failure probability requirements in flexible bandwidth optical networks, and we introduce two additional algorithms, named the conventional shared spectrum–block (CSSB) consumption algorithm and the maximum shared spectrum–block (MSSB) consumption algorithm, for comparison. Simulation results show that MFSB not only achieves better performance in terms of blocking probability, spectrum consumption, spectrum redundancy, and hop counts compared to the CSSB and MSSB algorithms, but also guarantees a joint failure probability that is lower than the MSSB algorithm. Furthermore, the spectrum efficiency of these three algorithms increases with the growth of the maximum shared degree, especially for the MFSB algorithm. Therefore, the MFSB algorithm provides a better tradeoff between the minimum spectrum–block consumption and the average joint failure probability.

The early research found that the spiderlings of black widow spider (Latrodectus tredecimguttatus) exhibited obvious toxicity to animals. The present work performed a systematical analysis of the aqueous extract of newborn black widow spiderlings. The extract was shown to contain 69.42% of proteins varying in molecular weights and isoelectric points. Abdominal injection of the extract into mice and cockroaches caused obvious poisoning symptoms as well as death, with LD50 being 5.30 mg/kg in mice and 16.74 µg/g in Periplaneta americana. Electrophysiological experiments indicated that the extract at a concentration of 10 µg/mL could completely block the neuromuscular transmission in isolated mouse nerve-hemidiaphragm preparations within 21 ± 1.5 min, and 100 µg/mL extract could inhibit a certain percentage of voltage-activated Na(+) , K(+) , and Ca(2+) channel currents in rat dorsal root ganglion neurons. These results demonstrate that the spiderlings are rich in neurotoxic components, which play important roles in the spiderling toxicity. Language: en

The aim of this study was to explore the etiology and diagnosis of multiple intracranial hemorrhages (ICHs) following severe burns, with a retrospective review of 16 cases of severe burns further complicated by multiple ICHs. Using cranial CT scans of the brains, we identified that all patients presented with low platelet counts and coagulation abnormalities prior to intracranial hemorrhaging. Following conventional treatment and various supporting treatments, five cases succumbed following a progressive reduction in blood platelet levels and the ICHs were cured in 11 cases following the restoration of normal platelet levels. We conclude that low platelet counts and coagulation abnormalities may cause multiple ICHs following severe burns and early diagnosis and treatment is the key to successful treatment.

A supervised class-preserving Laplacian eigenmaps (SCPLE) algorithm is proposed. In this algorithm, two neighbor graphs, intra-class graph and inter-class graph, are constructed, whose edge weights determined by class label information and adaptive thresholds. By maximizing the weighted neighbor distances between heterogeneous samples and minimizing the weighted neighbor distances between homogeneous samples, this algorithm maps homogeneous samples closer and heterogeneous samples farther in the low dimensional space. Experiments demonstrate the superiority of the proposed algorithm against the classical LE, DVE and S-LE algorithms.

Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment and improve innate and adaptive antitumor immunity. Here we show that chloroquine (CQ), a proven anti-malarial drug, can function as an antitumor immune modulator that switches TAMs from M2 to tumor-killing M1 phenotype. Mechanistically, CQ increases macrophage lysosomal pH, causing Ca2+ release via the lysosomal Ca2+ channel mucolipin-1 (Mcoln1), which induces the activation of p38 and NF-κB, thus polarizing TAMs to M1 phenotype. In parallel, the released Ca2+ activates transcription factor EB (TFEB), which reprograms the metabolism of TAMs from oxidative phosphorylation to glycolysis. As a result, CQ-reset macrophages ameliorate tumor immune microenvironment by decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and Treg cells, thus enhancing antitumor T-cell immunity. These data illuminate a previously unrecognized antitumor mechanism of CQ, suggesting a potential new macrophage-based tumor immunotherapeutic modality., Tumour-associated macrophages (TAMs) display an M2 phenotype that promote tumour immune escape. Here the authors show that Chloroquine (CQ), a lysosome inhibitor used against malaria, inhibits tumour growth by switching TAMs into an M1 tumor-killing phenotype by repolarizing macrophages metabolism.

We propose four-level phase pair encoding and decoding with single interferometric phase retrieval for holographic data storage. Inherent with phase pair encoding, phase shifting is generated by assigning a certain phase difference between two pixels of the phase pair. Multiple phase shifting operations are not required. In addition, a phase-readout reference beam can be a plane beam with an arbitrary phase in our method because phase shifting can be encoded on the phase-only spatial light modulator easily and accurately. Therefore, our method can not only increase the data transfer rate, but also improve the robustness of the holographic data storage system. Although the code rate of our method needs to be sacrificed by half, the code rate is still twice that of amplitude code when four-level phase encoding is used. We demonstrated experimentally that there is only a 1×10−2 order of bit error rate before error correcting, which is acceptable. We believe our method will further advance the phase-modulated holographic data storage technique.

Transcutaneous drug delivery from planar skin patches is effective for small-molecule drugs and skin-permeable vaccine adjuvants. However, to achieve efficient delivery of vaccines and other macromolecular therapeutics into the skin, penetration of the stratum corneum is needed. Topically applied skin patches with micron-scale projections ('microneedles') pierce the upper layers of the skin and enable vaccines that are coated on or encapsulated within the microneedles to be dispersed into the skin. Although millimeter-scale syringes have shown promise for vaccine delivery in humans and technologies, such as the Dermaroller (Dermaroller, Wolfenbüttel, Germany), exist for creating microscale punctures in the skin for delivery of solutions of therapeutics, solid microprojection microneedles coated with dry vaccine formulations offer a number of valuable features for vaccination, including reduced risk of blood-borne pathogen transmission or needle-stick injury, the potential for vaccine administration by minimally trained personnel or even self administration and the use of solid-state vaccine formulations that may reduce or eliminate cold-chain requirements in vaccine distribution. Recent studies in mice have demonstrated the ability of microneedles to effectively deliver vaccines to the skin, eliciting protective immunity to influenza, hepatitis C and West Nile virus., Ragon Institute of MGH, MIT and Harvard, Massachusetts Institute of Technology, Harvard University, National Institutes of Health (U.S.) (AI095109), National Institutes of Health (U.S.) (AI096040), National Institutes of Health (U.S.) (AI095985), National Institutes of Health (U.S.) (AI078526), National Institutes of Health (U.S.) (AI060354), United States. Dept. of Defense (Contract W911NF-07-D-0004)

We define a new index named Service Failure Probability (SFP) with Probabilistic SRLG. An algorithm named SFP-oriented shared-path protection is proposed to provide differentiated Quality-of-Protection. Simulations show the algorithm works well in providing differentiated SFP.

We propose a minimum-free-spectrum-block-consumption algorithm (MFSB) for shared-path protection with joint failure probability requirements in flexible bandwidth optical networks. Compared with conventional algorithms, MFSB efficiently decreases the spectrum block consumption and achieves higher spectrum utilization.

A multilink failures model, i.e., probabilistic-shared risk link group (PSRLG), is adopted to investigate the problem of differentiated quality-of-protection (QoP) provisioning for flexi-grid optical networks. As a metric, service failure probability (SFP) is introduced to exactly examine the feasibility of differentiated QoP schemes, which denotes the failure probability of a connection during transmission. According to different reliability require- ments, connection requests are divided into three classes, i.e., class high, class middle, and class low. Then two differentiated QoP provisioning schemes are proposed based on the class division, i.e., intraclass-shared re- source scheme (ICSR scheme) and cross-class-shared resource scheme (CCSR scheme). The former allows a connection to share backup resources only with those connections in the same class, whereas the latter enables the connections in different classes to share backup resources. Simulation results show that our proposed schemes could well provide differentiated reliability with PSRLG constraint and achieve a good balance between reliability and resource efficiency. Moreover, the CCSR scheme achieves lower blocking probability, lower re- source redundancy, and higher spectrum utilization without sacrificing reliability compared to the ICSR scheme. © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in