Protective human monoclonal antibodies target conserved sites of vulnerability on the underside of influenza virus neuraminidase.

Continuously evolving influenza viruses cause seasonal epidemics and pose global pandemic threats. Although viral neuraminidase (NA) is an effective drug and vaccine target, our understanding of the NA antigenic landscape still remains incomplete. Here, we describe NA-specific human antibodies that target the underside of the NA globular head domain, inhibit viral propagation of a wide range of human H3N2, swine-origin variant H3N2, and H2N2 viruses, and confer both pre- and post-exposure protection against lethal H3N2 infection in mice. Cryo-EM structures of two such antibodies in complex with NA reveal non-overlapping epitopes covering the underside of the NA head. These sites are highly conserved among N2 NAs yet inaccessible unless the NA head tilts or dissociates. Our findings help guide the development of effective countermeasures against ever-changing influenza viruses by identifying hidden conserved sites of vulnerability on the NA underside.

AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence.

Inflammasomes are important sentinels of innate immune defence, sensing pathogens and inducing cell death in infected cells1. There are several inflammasome sensors that each detect and respond to a specific pathogen- or damage-associated molecular pattern (PAMP or DAMP, respectively)1. During infection, live pathogens can induce the release of multiple PAMPs and DAMPs, which can simultaneously engage multiple inflammasome sensors2-5. Here we found that AIM2 regulates the innate immune sensors pyrin and ZBP1 to drive inflammatory signalling and a form of inflammatory cell death known as PANoptosis, and provide host protection during infections with herpes simplex virus 1 and Francisella novicida. We also observed that AIM2, pyrin and ZBP1 were members of a large multi-protein complex along with ASC, caspase-1, caspase-8, RIPK3, RIPK1 and FADD, that drove inflammatory cell death (PANoptosis). Collectively, our findings define a previously unknown regulatory and molecular interaction between AIM2, pyrin and ZBP1 that drives assembly of an AIM2-mediated multi-protein complex that we term the AIM2 PANoptosome and comprising multiple inflammasome sensors and cell death regulators. These results advance the understanding of the functions of these molecules in innate immunity and inflammatory cell death, suggesting new therapeutic targets for AIM2-, ZBP1- and pyrin-mediated diseases.

TRF2 inhibition rather than telomerase disruption drives CD4T cell dysfunction during chronic viral infection.

We investigated the role of telomerase and telomere repeat-binding factor 2 (TRF2 or TERF2) in T-cell dysfunction in chronic viral infection. We found that the expression and activity of telomerase in CD4+ T (CD4T) cells from patients with hepatitis C virus (HCV) infections or people living with HIV (PLWH) were intact, but TRF2 expression was significantly inhibited at the post-transcriptional level, suggesting that TRF2 inhibition is responsible for the CD4T cell dysfunction observed during chronic viral infection. Silencing TRF2 expression in CD4T cells derived from healthy subjects induced telomeric DNA damage and CD4T cell dysfunction without affecting telomerase activity or translocation - similar to what we observed in CD4T cells from HCV patients and PLWH. These findings indicate that premature T-cell aging and dysfunction during chronic HCV or HIV infection are primarily caused by chronic immune stimulation and T-cell overactivation and/or proliferation that induce telomeric DNA damage due to TRF2 inhibition, rather than telomerase disruption. This study suggests that restoring TRF2 presents a novel approach to prevent telomeric DNA damage and premature T-cell aging, thus rejuvenating T-cell functions during chronic viral infection.

Nature of partial sigma bond.

This study investigates the formation of partial sigma (σ) covalent bonds in experimentally synthesizable biradicals formed from hydrogenated and fluorinated C8, C20, and C60 cage structures, by assessing their stability, geometry, and bonding character in singlet and triplet states using restricted B3LYP-D3/6-31+G(d,p) theory, natural bond orbital (NBO) analysis, and complete active space self-consistent field (CASSCF) method. The results show that these partial σCC bonds have Wiberg bond orders of 0.38 to 0.48 and bond lengths ranging from 2.62 Å to 5.93 Å. Cage size influences the characteristics of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), with electrons favoring more antibonding orbitals in smaller cages where electrons reside more on the exterior of the cage and favoring bonding orbitals in larger ones where electrons are more in the interior. Fluorination enhances electron density on bonding orbitals. The analysis further clarified that the differentiation between antibonding and bonding features of HOMOs and LUMOs extends beyond merely electron transfer from s- to p-atomic orbitals, also noting possible interactions of the same symmetry repel. The study also introduces hyperconjugation from α-position CH bonds as a factor in stabilizing partial σ-bond formation. The results also caution against the use of broken symmetry methodology in unrestricted SCF wavefunctions for biradicals, such as those in this study as it may cause large spin contamination and thus errors in the calculated electronic properties results.

COMPUTATIONAL DESIGN OF 3D LANTERN ORGANIC FRAMEWORK.

This study employed a computational approach, particularly Density Functional Theory at B3LYP-D3/6-31+G(d) level to design two new classes of three-dimensional (3D) Lantern Organic Frameworks (LOFs) materials based on trisilasumanene and porphyrin core building units. Particularly, we detail strategies for transitioning from 1DLOF nanowires to extended 3D structures: first by connecting planar-molecule base units of trisilasumanene or porphyrin using benzene-based linkers, and then connecting silicon anchoring atoms on the bases with other bases that are vertically stacked by sp3-hydrocarbon chains. The 3D-LOF structures are designed to have different pore sizes through the use of various bases, bridges, and linkers. Comparisons of electronic properties of these 3D structures lead to one designing rule. That is, the gap between highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of the 3D materials depends only on its base and is nearly independent of the stack size or the length of the sp3-hydrocarbon bridges. Additionally, connecting base units with linkers also extends π-electron conjugation system leading to a reduction in HOMO-LUMO gap. For instance, linking two trisilasumanene molecules significantly narrows HOMO-LUMO gap by 1.75 eV while stacking these bases vertically and connecting them by linear pentane-based bridges yield insignificant change to the gap.

Harnessing Cooperative Multivalency in Thioguanine for Surface-Enhanced Raman Scattering (SERS)-Based Differentiation of Polyfunctional Analytes Differing by a Single Functional Group.

Small-molecule receptors are increasingly employed to probe various functional groups for (bio)chemical analysis. However, differentiation of polyfunctional analogs sharing multiple functional groups remains challenging for conventional mono- and bidentate receptors because their insufficient number of binding sites limits interactions with the least reactive yet property-determining functional group. Herein, we introduce 6-thioguanine (TG) as a supramolecular receptor for unique tridentate receptor-analyte complexation, achieving ≥97 % identification accuracy among 16 polyfunctional analogs across three classes: glycerol derivatives, disubstituted propane, and vicinal diols. Crucially, we demonstrate distinct spectral changes induced by the tridentate interaction between TG's three anchoring points and all the analyte's functional groups, even the least reactive ones. Notably, hydrogen bond (H-bond) networks formed in the TG-analyte complexes demonstrate additive effects in binding strength originating from good bond linearity, cooperativity, and resonance, thus strengthening complexation events and amplifying the differences in spectral changes induced among analytes. It also enhances spectral consistency by selectively forming a sole configuration that is stronger than the respective analyte-analyte interaction. Finally, we achieve 95.4 % accuracy for multiplex identification of a mixture consisting of multiple polyfunctional analogs. We envisage that extension to other multidentate non-covalent interactions enables the development of interference-free small molecule-based sensors for various (bio)chemical analysis applications.

Synthetic gRNA/Cas9 ribonucleoprotein targeting HBV DNA inhibits viral replication.

The presence of hepatitis B virus (HBV) covalently closed circular (ccc) DNA (cccDNA), which serves as a template for viral replication and integration of HBV DNA into the host cell genome, sustains liver pathogenesis and constitutes an intractable barrier to the eradication of chronic HBV infection. The current antiviral therapy for HBV infection, using nucleos(t)ide analogues (NAs), can suppress HBV replication but cannot eliminate integrated HBV DNA and episomal cccDNA. Clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 is a powerful genetic tool that can edit integrated HBV DNA and minichromosomal cccDNA for gene therapy, but its expression and delivery require a viral vector, which poses safety concerns for therapeutic applications in humans. In the present study, we used synthetic guide RNA (gRNA)/Cas9-ribonucleoprotein (RNP) as a nonviral formulation to develop a novel CRISPR/Cas9-mediated gene therapy for eradicating HBV infection. We designed a series of gRNAs targeting multiple specific HBV genes and tested their antiviral efficacy and cytotoxicity in different HBV cellular models. Transfection of stably HBV-infected human hepatoma cell line HepG2.2.15 with HBV-specific gRNA/Cas9 RNPs resulted in a substantial reduction in HBV transcripts. Specifically, gRNA5 and/or gRNA9 RNPs significantly reduced HBV cccDNA, total HBV DNA, pregenomic RNA, and HBV antigen (HBsAg, HBeAg) levels. T7 endonuclease 1 (T7E1) cleavage assay and DNA sequencing confirmed specific HBV gene cleavage and mutations at or around the gRNA target sites. Notably, this gene-editing system did not alter cellular viability or proliferation in the treated cells. Because of their rapid DNA cleavage capability, low off-target effects, low risk of insertional mutagenesis, and readiness for use in clinical application, these results suggest that synthetic gRNA/Cas9 RNP-based gene-editing can be utilized as a promising therapeutic drug for eradicating chronic HBV infection.

Long-Term Outcomes of Open Versus Laparoscopic Distal Gastrectomy for T4a Gastric Cancer: A Propensity Score-Matched Cohort Study.

BACKGROUND: Laparoscopic gastrectomy for advanced gastric cancer (GC) has been applied more frequently worldwide but is still controversial for patients with serosal invasion (T4a). This study compared short- and long-term outcomes of laparoscopic distal radical gastrectomy (LDG) with open distal gastrectomy (ODG) for T4a GC. PATIENTS AND METHODS: We retrospectively studied 472 patients with T4a gastric adenocarcinoma in the lower or middle third of the stomach: 231 underwent LDG and 241 underwent ODG between 2013 and 2020. Short-term outcomes included operative characteristics and complications. Long-term outcomes included overall survival (OS) and disease-free survival (DFS). Propensity score-matched (PSM) analysis was used to adjust for imbalances in baseline characteristics between groups. RESULTS: The PSM strategy resulted in 294 patients (147 in each group). The LDG group had a significantly longer operating time (mean: 200 vs 190 min, p = 0.001) but reduced blood loss (mean: 50 vs 100 ml, p = 0.001). The LDG group had a higher rate of any postoperative complication (23.1% vs 12.2%, p = 0.021) but most were classified as grades I-II according to Clavien-Dindo classification. Grade III-V complications were similar between groups. Five-year OS was 69% versus 60% (p = 0.109) and 5-year DFS was 58% vs 53% (p = 0.3) in LDG and ODG groups, respectively. For tumor size < 5 cm, LDG was better in reduction of blood loss, postoperative hospital length of stay, and OS. CONCLUSIONS: LDG is feasible and safe for patients with T4a GC and is comparable to ODG regarding short- and long-term outcomes. Furthermore, LDG can be a favorable option for T4a GC smaller than 5 cm.

Validation of Multidimensional Scale of Perceived Social Support (MSPSS) in Vietnamese Among People Living with HIV/AIDS.

Social support plays a vital role in the health of HIV/AIDS patients, but there needs to be a validated instrument to measure social support in Vietnam. This cross-sectional study was to validate a Vietnamese translation of the Multidimensional Perceived Social Support Scale (MSPSS). The study had three stages: [1] translation to Vietnamese, [2] pilot testing, and [3] validation of the translation. Stage 1, including forward and backward translation by four independent translators, resulted in a good content validity translation. Pilot testing was done on 30 HIV/AIDS patients: the translation was understandable, and no change was required. Five hundred HIV/AIDS patients were recruited in stage 3. The translation had excellent internal consistency (Cronbach's alpha: 0.90), good test-retest reliability (intra-class correlation coefficient: 0.95), and good concurrent validity. Construct validity was well established by confirmatory factor analysis. The Vietnamese translation of the MSPSS is reliable and valuable for measuring perceived social support.

Pregnancy and birth outcomes among young women living with perinatally acquired HIV in Thailand and Vietnam.

We conducted a retrospective cohort study of pregnancy and infant outcomes in 670 adolescents and young adult women with perinatally acquired HIV (AYAPHIV), aged 15-24 years, in Thailand and Vietnam. Between January 2013 and December 2018, there were 52 pregnancies, for an incidence of 2.49 (95% CI 1.90-3.27) per 100 person-years. The median age at pregnancy was 17.7 years (IQR 16.8-18.9). Pregnant AYAPHIV had been on cART for a lifetime median of 9.8 years (IQR 7.3-12.4). At the time of conception, the median CD4 was 521 cells/mm3 (IQR 213-760), and 76% had HIV RNA ≤400 copies/ml. Of the 51 pregnancies with available outcomes, 90% resulted in live singleton births at a median gestational age of 38 weeks (IQR 37-39); 77% of mothers (n = 27/35) had HIV RNA ≤400 copies/ml at delivery. Among infants with available data, 50% (n = 21/42) were male and 29% (n = 12/42) were reported to be low birthweight (<2,500gm); none (n = 0/41) were breastfed. One infant was diagnosed with HIV. Our findings emphasize that efforts to strengthen reproductive health education, including contraception, pregnancy-related psychosocial support services, and prevention of vertical HIV transmission interventions, in our region are needed for adolescents with perinatally acquired HIV as they transition to young adults.

Disclosure of HIV status and associated clinical outcomes of children and adolescents living with HIV in Asia.

Disclosure of HIV status is an important part of pediatric care. We studied disclosure and clinical outcomes in a multi-country Asian cohort of children and adolescents with HIV. Those 6-19 years of age who initiated combination antiretroviral therapy (cART) between 2008 and 2018, and who had at least one follow-up clinic visit were included. Data up to December 2019 were analyzed. Cox and competing risk regression analyses were used to assess the effect of disclosure on disease progression (WHO clinical stage 3 or 4), loss to follow-up (LTFU; > 12 months), and death. Of 1913 children and adolescents (48% female; median [IQR] age 11.5 [9.2-14.7] years at last clinic visit), 795 (42%) were disclosed to about their HIV status at a median age of 12.9 years (IQR: 11.8-14.1). During follow-up, 207 (11%) experienced disease progression, 75 (3.9%) were LTFU, and 59 (3.1%) died. There were lower hazards of disease progression (adjusted hazard ratio [aHR] 0.43 [0.28-0.66]) and death (aHR 0.36 [0.17-0.79]) for those disclosed to compared with those who were not. Disclosure and its appropriate implementation should be promoted in pediatric HIV clinics in resource-limited settings.

Long Noncoding RNA RUNXOR Promotes Myeloid-Derived Suppressor Cell Expansion and Functions via Enhancing Immunosuppressive Molecule Expressions during Latent HIV Infection.

RUNX1 overlapping RNA (RUNXOR) is a long noncoding RNA and a key regulator of myeloid-derived suppressor cells (MDSCs) via targeting runt-related transcription factor 1 (RUNX1). We and others have previously reported MDSC expansion and inhibition of host immune responses during viral infections; however, the mechanisms regulating MDSC differentiation and suppressive functions, especially the role of RUNXOR-RUNX1 in the regulation of MDSCs in people living with HIV (PLHIV), remain unknown. In this study, we demonstrate that RUNXOR and RUNX1 expressions are upregulated in MDSCs that expand and accumulate in human PBMCs derived from PLHIV. We found that the upregulation of RUNXOR and RUNX1 is associated with the expressions of several key immunosuppressive molecules, including arginase 1, inducible NO synthase, STAT3, IL-6, and reactive oxygen species. RUNXOR and RUNX1 could positively regulate each other's expression and control the expressions of these suppressive mediators. Specifically, silencing RUNXOR or RUNX1 expression in MDSCs from PLHIV attenuated MDSC expansion and immunosuppressive mediator expressions, whereas overexpressing RUNXOR in CD33+ myeloid precursors from healthy subjects promoted their differentiation into MDSCs and enhanced the expression of these mediators. Moreover, loss of RUNXOR-RUNX1 function in MDSCs improved IFN-γ production from cocultured autologous CD4 T cells derived from PLHIV. These results suggest that the RUNXOR-RUNX1 axis promotes the differentiation and suppressive functions of MDSCs via regulating multiple immunosuppressive signaling molecules and may represent a potential target for immunotherapy in conjunction with antiviral therapy in PLHIV.

Toward sustainable development goals in gender inequality: an analysis of gender preferences among urban pregnant women in a Southeast Asian country.

BACKGROUND: Gender-biased discrimination and preferences are global phenomena, particularly son preferences. However, updated evidence about this issue in Vietnam has not yet been provided. Therefore, this study aimed to examine the gender preferences among pregnant women and identify associated factors of such preferences. METHODS: A cross-sectional survey was conducted in two hospitals in Vietnam with 732 pregnant women. Gender preferences for their child were asked, along with socio-demographic (e.g., education, occupation) and pregnancy characteristics (e.g., pressure to have a son, gender of first child, the importance to have a son of family members, and information sources on pregnancy care) by using face-to-face interviews and a structured questionnaire. Multinomial logistic regression was performed to determine factors associated with gender preferences. RESULTS: About 51.9% of the participants had no gender preference, while, among those who had a gender preference, 26.5% preferred sons, and 21.6% preferred daughters. Only 6.2% had pressure to have a son. Having the first child who was female (OR = 4.16, 95%CI = 1.54-11.25), having the pressure to have a son (OR = 6.77, 95%CI = 2.06-22.26), and higher self-perceived importance to have a son (OR = 3.05, 95%CI = 1.85-5.02) were positively associated with son preference. Otherwise, women having partners with high school education or above (OR = 2.04, 95%CI = 1.06-3.91), living with parents-in-law (OR = 2.33; 95%CI = 1.25-4.34), the higher number of pregnancies, and a higher degree of importance in having a son regarding parents-in-law (OR = 2.15, 95%CI = 1.38-3.35) associated with higher odds of preferring daughter. CONCLUSION: This study showed that gender preference was common among pregnant women, but the pressure to have a son was low. Further education programs and legal institutions should be implemented to improve gender inequality and gender preference in society.

Traditional Vietnamese medicine Kovir capsule for non-severe COVID-19 patients: A phase III double-blind randomized controlled trial.

The number of COVID-19 infections is still increasing with the omicron variant. Although vaccination has shown its effectiveness, efficacious treatments are still required. Kovir, a Vietnamese herbal medicine, has shown potential effects for non-severe COVID-19 patients in terms of symptom resolution and prevention of disease progression in previous studies. This phase-3 trial evaluated the safety and efficacy of Kovir for non-severe COVID-19 adults. Participants were randomized to the Kovir (381 patients) or placebo (192 patients) groups. Outcomes were progression to severe/critical COVID-19, a daily symptom score based on 11 pre-defined symptoms, time to symptom resolution, a negative reverse transcription polymerase chain reaction, an EQ-5D-5L quality of life (QOL) score, and serious adverse events. Only one patient (in the placebo group) progressed to severe COVID-19, thus we could not conclude the effect of Kovir on the prevention of disease progression. Kovir significantly reduced time to symptom resolution (median: 7 vs. 11 days, hazard ratio [95% confidence interval]: 2.03 [1.66-2.48]) compared to placebo. Kovir also increased the QOL score on days 7 and 14. No safety concerns were observed. To conclude, Kovir is safe and facilitates symptom relief for non-severe COVID-19 patients. We advocate using Kovir in the early phase of COVID-19 for non-severe adult patients.

Classification of COPD as ABCD according to GOLD 2011 and 2017 versions in COPD patients at University Medical Center in Ho Chi Minh City, Vietnam.

In 2017, Global Initiative for Chronic Lung Disease (GOLD) made substantial changes to its ABCD group categorization. Although several studies had been conducted to assess the impact of the new GOLD category, there was no research on the change of the GOLD classification in Vietnam. This retrospective analysis was conducted at Asthma and COPD clinic at the University Medical Center in Ho Chi Minh City, Vietnam. Our study population comprised patients visiting Medical Center from January 2018 to January 2020. We categorized patients' demographic, clinical characteristics and pharmacotherapy based on GOLD 2011 and 2017 guidelines. A comparison between the two versions was also determined. A total of 457 patients were included in this study. The percentage of groups A, B, C and D according to GOLD 2011 was 5%, 20.8%, 13.1% and 61.1%; and according to GOLD 2017 was 6.1%, 34.1%, 12% and 47.8%, respectively. In terms of gender, male patients constituted nearly 95% of the study's population (433/457 patients). Regarding pharmacotherapy, approximately 20% of the low-risk group (group A-B) was overtreated with ICS components: LABA+ICS (15.8%) and LAMA+LABA+ICS (3.8%). There were 13.3% and 1.1% of patients transferred from D to B and from C to A, respectively. All of them had lower FVC% pred, FEV1% pred and FEV1/FVC than the patients remained in group B or A (p<0.005). This is the first research in Vietnam to show the distribution of COPD patients using both the GOLD 2011 and GOLD 2017 criteria. There was 14% of patients reclassified from high-risk groups to low-risk groups when changing from 2011 to 2017 version and discordance of medications between guidelines and real-life practice. Therefore, clinicians should use their clinical competence to consider patients' conditions before deciding the appropriate therapeutic approach. Consequently, further studies were required to evaluate the effect of the change in GOLD classification.

Hyperinflammatory Syndrome, Natural Killer Cell Function, and Genetic Polymorphisms in the Pathogenesis of Severe Dengue.

BACKGROUND: Severe dengue, characterized by shock and organ dysfunction, is driven by an excessive host immune response. We investigated the role of hyperinflammation in dengue pathogenesis. METHODS: Patients recruited into an observational study were divided into 3 plasma leak severity grades. Hyperinflammatory biomarkers were measured at 4 time points. Frequencies, activation, and cytotoxic potential of natural killer (NK) cells were analyzed by flow cytometry. RNA was extracted from sorted CD56+ NK cells and libraries were prepared using SMART-Seq and sequenced using HiSeq3000 (Illumina). RESULTS: Sixty-nine patients were included (grade 0, 42 patients; grade 1, 19 patients; grade 2, 8 patients). Patients with grade 2 leakage had higher biomarkers than grade 0, including higher peak ferritin levels (83.3% vs 45.2%) and H-scores (median, 148.5 vs 105.5). NK cells from grade 2 patients exhibited decreased expression of perforin and granzyme B and activation markers. RNA sequencing revealed 3 single-nucleotide polymorphisms in NK cell functional genes associated with more severe leakage-NK cell lectin-like receptor K1 gene (KLRK1) and perforin 1 (PRF1). CONCLUSIONS: Features of hyperinflammation are associated with dengue severity, including higher biomarkers, impaired NK cell function, and polymorphisms in NK cell cytolytic function genes (KLRK1 and PRF1). Trials of immunomodulatory therapy in these patients is now warranted.

Surgical outcomes and quality of life assessment of esophagectomy for cancer with colon conduit via retrosternal route.

PURPOSE: Colon conduit is an alternative to a gastric conduit for esophagectomy in patients that stomach is not available. Surgical technique is complex and has a high risk of morbidities and mortality. Outcomes of patients are still lacking in the literature, thus aims of this study are to evaluate the safety, feasibility and long-term functional outcomes of patients who underwent esophagectomy for cancer with colon conduit via retrosternal route. METHODS: Twenty-six patients underwent operation between August 2016 and June 2021 for malignancies. Minimally invasive esophagectomy and laparotomy were performed in accordance with the 2017 Japan Esophageal Society's guidelines. Colonic interposition was used for esophageal replacement. Outcomes were technical success, complications assessed using Clavien-Dindo classification, and patient's quality of life (QOL) based on EORTC-QOL-OES18 questionnaire. RESULTS: Mean age was 56.0 ± 9.9 years and 21 patients (80.8%) were men. Mean operating time was 432 ± 66 min. Technical success was 100%. The average number of resected lymph nodes was 26 ± 14. Twelve patients (46.2%) experienced postoperative complications: 7/12 were classified as grade I-II, 3/12 as grade III, 1/12 as grade IV, and 1/12 as grade V (death). Patient's QOL improved during the follow-up period with median (25-75th percentiles) global EORTC-QOL-OES18 score was 29 (17-34); 13 (9-21), and 9 (6-16) at 3, 6, and 12 months, respectively. During the follow-up period, there were 4 late complications, 3 lymphatic recurrences, 5 distant metastases, and 6 deaths. CONCLUSIONS: Colon conduit via retrosternal route after esophagectomy is feasible, safe, and could provide acceptable long-term functional outcomes.

Immune Activation Induces Telomeric DNA Damage and Promotes Short-Lived Effector T Cell Differentiation in Chronic HCV Infection.

BACKGROUND AND AIMS: Hepatitis C virus (HCV) leads to a high rate of chronic infection and T cell dysfunction. Although it is well known that chronic antigenic stimulation is a driving force for impaired T cell functions, the precise mechanisms underlying immune activation-induced T cell dysfunctions during HCV infection remain elusive. APPROACH AND RESULTS: Here, we demonstrated that circulating CD4+ T cells from patients who are chronically HCV-infected exhibit an immune activation status, as evidenced by the overexpression of cell activation markers human leukocyte antigen-antigen D-related, glucose transporter 1, granzyme B, and the short-lived effector marker CD127- killer cell lectin-like receptor G1+ . In contrast, the expression of stem cell-like transcription factor T cell factor 1 and telomeric repeat-binding factor 2 (TRF2) are significantly reduced in CD4+ T cells from patients who are chronically HCV-infected compared with healthy participants (HP). Mechanistic studies revealed that CD4+ T cells from participants with HCV exhibit phosphoinositide 3-kinase/Akt/mammalian target of rapamycin signaling hyperactivation on T cell receptor stimulation, promoting proinflammatory effector cell differentiation, telomeric DNA damage, and cellular apoptosis. Inhibition of Akt signaling during T cell activation preserved the precursor memory cell population and prevented inflammatory effector cell expansion, DNA damage, and apoptotic death. Moreover, knockdown of TRF2 reduced HP T cell stemness and triggered telomeric DNA damage and cellular apoptosis, whereas overexpression of TRF2 in CD4 T cells prevented telomeric DNA damage. CONCLUSIONS: These results suggest that modulation of immune activation through inhibiting Akt signaling and protecting telomeres through enhancing TRF2 expression may open therapeutic strategies to fine tune the adaptive immune responses in the setting of persistent immune activation and inflammation during chronic HCV infection.

Subwavelength-resolution imaging of surface plasmon polaritons with up-conversion fluorescence microscopy.

Imaging and characterization of surface plasmon polaritons (SPPs) are crucial for the research and development of the plasmonic devices and circuits. Here, we report on direct imaging of SPPs propagation on SiO2/metal interface with subwavelength spatial resolution using up-conversion fluorescence microscopy, that exploits rare-earth ions, such as Er3+, Yb3+, and Nd3+, doped nanoparticles as the fluorophores. We demonstrated that by further taking the intensity ratio of the image obtained with fluorescent emission at different wavelengths, we are able to substantially enhance the features associated to the SPP wavefronts in the image for quantitative analysis, such as the wavevector and propagation direction of the SPPs. Our results agree with the theoretic prediction of the SPP wavelengths quantitatively. We further demonstrate the evolution of the SPP wavefronts due to refraction SPPs, and reproduced the experiment with finite difference time domain (FDTD) method simulations. The relative refractive index of SPP estimated from the experiment also agrees quantitatively with those extracted from the theory and the simulation.

Clinical and laboratory factors associated with coronavirus disease 2019 (Covid-19): A systematic review and meta-analysis.

SARS Coronavirus-2 is one of the most widespread viruses globally during the 21st century, whose severity and ability to cause severe pneumonia and death vary. We performed a comprehensive systematic review of all studies that met our standardised criteria and then extracted data on the age, symptoms, and different treatments of Covid-19 patients and the prognosis of this disease during follow-up. Cases in this study were divided according to severity and death status and meta-analysed separately using raw mean and single proportion methods. We included 171 complete studies including 62,909 confirmed cases of Covid-19, of which 148 studies were meta-analysed. Symptoms clearly emerged in an escalating manner from mild-moderate symptoms, pneumonia, severe-critical to the group of non-survivors. Hypertension (Pooled proportion (PP): 0.48 [95% Confident interval (CI): 0.35-0.61]), diabetes (PP: 0.23 [95% CI: 0.16-0.33]) and smoking (PP: 0.12 [95% CI: 0.03-0.38]) were highest regarding pre-infection comorbidities in the non-survivor group. While acute respiratory distress syndrome (PP: 0.49 [95% CI: 0.29-0.78]), (PP: 0.63 [95% CI: 0.34-0.97]) remained one of the most common complications in the severe and death group respectively. Bilateral ground-glass opacification (PP: 0.68 [95% CI: 0.59-0.75]) was the most visible radiological image. The mortality rates estimated (PP: 0.11 [95% CI: 0.06-0.19]), (PP: 0.03 [95% CI: 0.01-0.05]), and (PP: 0.01 [95% CI: 0-0.3]) in severe-critical, pneumonia and mild-moderate groups respectively. This study can serve as a high evidence guideline for different clinical presentations of Covid-19, graded from mild to severe, and for special forms like pneumonia and death groups.