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ABSTRACT HIV infects long-lived CD4 memory T cells, establishing a latent viral reservoir that necessitates lifelong antiretroviral therapy (ART). How this reservoir is formed so quickly after infection remains unclear. We now show the innate inflammatory response to HIV infection results in CCL2 chemokine release, leading to recruitment of cells expressing the CCR2 receptor, including a subset of central memory CD4 T cells. Supporting a role for the CCL2/CCR2 axis in rapid reservoir formation, we find (i) treatment of humanized mice with anti-CCL2 antibodies during early HIV infection decreases reservoir seeding and preserves CCR2/5+ cells and (ii) CCR2/5+ cells from the blood of HIV-infected individuals on long-term ART contain significantly more integrated provirus than CCR2/5-negative memory or naive cells. Together, these studies support a model where the host’s innate inflammatory response to HIV infection, including CCL2 production, leads to the recruitment of CCR2/5+ central memory CD4 T cells to zones of virus-associated inflammation, likely contributing to rapid formation of the latent HIV reservoir. IMPORTANCE There are currently over 35 million people living with HIV worldwide, and we still have no vaccine or scalable cure. One of the difficulties with HIV is its ability to rapidly establish a viral reservoir in lymphoid tissues that allows it to elude antivirals and the immune system. Thus, it is important to understand how HIV accomplishes this so we can develop preventive strategies. Our current results show that an early inflammatory response to HIV infection includes production of the chemokine CCL2, which recruits a unique subset of CCR2/5+ CD4+ T cells that become infected and form a significant reservoir for latent infection. Furthermore, we show that blockade of CCL2 in humanized mice significantly reduces persistent HIV infection. This information is relevant to the development of therapeutics to prevent and/or treat chronic HIV infections.

During 6–7 June 2003, a Mei-Yu jet/front system over Southern China is characterized by appreciable horizontal temperature contrast below the 850 hPa level (>8 K), where the cold, dry, postfrontal northeasterlies converge with the warm, moist southwesterly flow, and above the 400–hPa level (>18 K) associated with an upper-level front. The frontal baroclinic zone tilts northward with a slope of ~1/100. During the passage of a midlatitude trough, the upper-level jet/front system advances southeastward. The thermally direct circulation across the subsynoptic low-level jet (SLLJ)/Mei-Yu front system, coupled with dynamic forcing aloft on the equatorial side of the entrance region of a subsynoptic upper-level jet (SULJ), provides a favorable environment for the development of a frontal cyclone over Southern China. A southwesterly marine boundary layer jet (MBLJ) develops between the deepening Mei-Yu frontal cyclone and the West Pacific Subtropical High (WPSH). The MBLJ transports moisture from the northern South China Sea (NSCS) to Southern China. All three jets (SULJ, SLLJ, and MBLJ) interact together during the deepening of the Mei-Yu frontal cyclone with positive feedback effects of latent heat release. On 7 June 2003, as the Mei-Yu front arrives near the Taiwan area, the warm, moist, and unstable air associated with the MBLJ decelerates as it approaches the Central Mountain Range (CMR). The warm, moist, and unstable air is orographically lifted by the CMR and enhances the vertical motion already present with the frontal zone. A region of widespread heavy rainfall develops, with a maximum of more than 350 mm/day, over a region extending from the southwestern coast of Taiwan to the windward slopes of the CMR.

The latent reservoir is a major barrier to HIV cure. As latently infected cells cannot be phenotyped directly, the features of the in vivo reservoir have remained elusive. Here, we describe a method that leverages high-dimensional phenotyping using CyTOF to trace latently infected cells reactivated ex vivo to their original pre-activation states. Our results suggest that, contrary to common assumptions, the reservoir is not randomly distributed among cell subsets, and is remarkably conserved between individuals. However, reservoir composition differs between tissues and blood, as do cells successfully reactivated by different latency reversing agents. By selecting 8–10 of our 39 original CyTOF markers, we were able to isolate highly purified populations of unstimulated in vivo latent cells. These purified populations were highly enriched for replication-competent and intact provirus, transcribed HIV, and displayed clonal expansion. The ability to isolate unstimulated latent cells from infected individuals enables previously impossible studies on HIV persistence.

The primary reservoir for HIV is within memory CD4+ T cells residing within tissues, yet the features that make some of these cells more susceptible than others to infection by HIV is not well understood. Recent studies demonstrated that CCR5-tropic HIV-1 efficiently enters tissue-derived memory CD4+ T cells expressing CD127, the alpha chain of the IL7 receptor, but rarely completes the replication cycle. We now demonstrate that the inability of HIV to replicate in these CD127-expressing cells is not due to post-entry restriction by SAMHD1. Rather, relative to other memory T cell subsets, these cells are highly prone to undergoing latent infection with HIV, as revealed by the high levels of integrated HIV DNA in these cells. Host gene expression profiling revealed that CD127-expressing memory CD4+ T cells are phenotypically distinct from other tissue memory CD4+ T cells, and are defined by a quiescent state with diminished NFκB, NFAT, and Ox40 signaling. However, latently-infected CD127+ cells harbored unspliced HIV transcripts and stimulation of these cells with anti-CD3/CD28 reversed latency. These findings identify a novel subset of memory CD4+ T cells found in tissue and not in blood that are preferentially targeted for latent infection by HIV, and may serve as an important reservoir to target for HIV eradication efforts.

Abstract Recent development of artificial intelligence (AI) technology has resulted in the fruition of machine learning-based weather prediction (MLWP) systems. Five prominent global MLWP model, Pangu-Weather, FourCastNet v2 (FCN2), GraphCast, FuXi, and FengWu, emerged. This study conducts a homogeneous comparison of these models utilizing identical initial conditions from ERA5. The performance is evaluated in the Eastern Asia and Western Pacific from June to November 2023. The evaluation comprises Root Mean Square Error and Anomaly Correlation Coefficients within the designated region, typhoon track and intensity predictions, and a case study for Typhoon Haikui. Results indicate that FengWu emerges as the best-performing model, followed by FuXi and GraphCast, with FCN2 and Pangu-Weather ranking lower. A multi-model ensemble, constructed by averaging predictions from the five models, demonstrates superior performance, rivaling that of FengWu. For the 11 typhoons in 2023, FengWu demonstrates the most accurate track prediction; however, it also has the largest intensity errors.

Abstract Introduction Sustained lung inflation (SLI) right after birth to decrease the use of mechanical ventilation of preterm infants is controversial because of potential harm. This randomized controlled trial was conducted to evaluate the effectiveness and safety of delayed SLI in neonatal intensive care unit (NICU). Methods Preterm neonates requiring continuous positive airway pressure after birth were eligible for enrollment. In the experimental group, SLI with 20 cm H2O for 15 s was conducted by experienced staff in the NICU between 30 min and 24 h after birth. Results A total of 45 neonates were enrolled into this study, including 24 in the experimental group and 21 in the control group. There was no significant difference in the birth condition between the experimental and control groups, including gestational age (p = 0.151), birth weight (p = 0.692), and Apgar score at 1 min (p = 0.410) and 5 min (p = 0.518). The results showed the duration of respiratory support was shorter in the experimental group than the control group (p = 0.044). In addition, there was no significant difference in the other outcomes, such as pneumothorax, patent ductus arteriosus, and bronchopulmonary dysplasia. Conclusion Our findings indicate that sustained inflation conducted by experienced staff in the NICU is safe. The data suggest that SLI conducted by experienced staff in the NICU after stabilization could serve as an alternative management for preterm infants with respiratory distress. However, the reduction in use of respiratory support should be interpreted cautiously as a result of limited sample size. Trial registration University hospital Medical Information Network (UMIN) Clinical Trials Registry: UMIN000052797 (retrospectively registered).

Abstract Karyopherin α 2 (KPNA2, importin α1), a transport factor shuttling between the nuclear and cytoplasmic compartments, is involved in the nuclear import of proteins and participates in cellular processes such as cell cycle regulation, apoptosis, and transcriptional regulation. However, it is still unclear which signaling regulates the nucleocytoplasmic distribution of KPNA2 in response to cellular stress. In this study, we report that oxidative stress increases nuclear retention of KPNA2 through alpha serine/threonine‐protein kinase (AKT1)‐mediated reduction of serine 62 (S62) phosphorylation. We first found that AKT1 activation was required for H2O2‐induced nuclear accumulation of KPNA2. Immunoprecipitation and quantitative proteomic analysis revealed that the phosphorylation of KPNA2 at S62 was decreased under H2O2‐induced oxidative stress. We showed that cyclin‐dependent kinase 1 (CDK1), a kinase responsible for KPNA2 S62 phosphorylation, contributes to the localization of KPNA2 in the cytoplasm. AKT1 knockdown increased KPNA2 S62 phosphorylation and inhibited CDK1 activation. Furthermore, H2O2‐induced AKT1 activation promoted nuclear KPNA2 interaction with nucleophosmin 1 (NPM1), resulting in attenuation of NPM1‐mediated cyclin D1 gene transcription. Thus, we infer that the AKT1‐CDK1 axis regulates the nucleocytoplasmic shuttling and function of KPNA2 through spatiotemporal regulation of KPNA2 S62 phosphorylation under oxidative stress conditions.

Abstract Purpose To enhance the predictive risk model for all-cause mortality in individuals with Type 2 Diabetes (T2DM) and prolonged Atherosclerotic Cardiovascular Disease (ASCVD) risk factors. Despite the utility of the Coronary Artery Calcium (CAC) score in assessing cardiovascular risk, its capacity to predict all-cause mortality remains limited. Methods A retrospective cohort study included 1929 asymptomatic T2DM patients with ASCVD risk factors, aged 40–80. Variables encompassed demographic attributes, clinical parameters, CAC scores, comorbidities, and medication usage. Factors predicting all-cause mortality were selected to create a predictive scoring system. By using stepwise selection in a multivariate Cox proportional hazards model, we divided the patients into three risk groups. Results In our analysis of all-cause mortality in T2DM patients with extended ASCVD risk factors over 5 years, we identified significant risk factors, their adjusted hazard ratios (aHR), and scores: e.g., CAC score > 1000 (aHR: 1.57, score: 2), CAC score 401–1000 (aHR: 2.05, score: 2), and more. These factors strongly predict all-cause mortality, with varying risk groups (e.g., very low-risk: 2.0%, very high-risk: 24.0%). Significant differences in 5-year overall survival rates were observed among these groups (log-rank test

This study employed the new generation Taiwan global forecast system (TGFS) to focus on its performance in forecasting the tracks of western North Pacific typhoons during 2022–2023. TGFS demonstrated better forecasting performance in typhoon track compared to central weather administration (CWA) GFS. For forecasts with large track errors by TGFS at the 120th h, it was found that most of them originated during the early stages of typhoon development when the typhoons were of mild intensity. The tracks deviated predominantly towards the northeast and occasionally towards the southwest, which were speculated to be due to inadequate environmental steering guidance resulting from the failure to capture synoptic environmental features. The tracks could be corrected by replacing the original new simplified Arakawa–Schubert (NSAS) scheme with the new Tiedtke (NTDK) scheme to change the synoptic environmental field, not only for Typhoon Khanun, which occurred in the typhoon season of 2023, but also for Typhoon Bolaven, which occurred after the typhoon season, in October 2023, under atypical circulation characteristics over the western Pacific. The diagnosis of vorticity budget primarily analyzed the periods where divergence in typhoon tracks between control (CTRL) and NTDK experiments occurred. The different synoptic environmental fields in the NTDK experiment affected the wavenumber-1 vorticity distribution in the horizontal advection term, thereby enhancing the accuracy of typhoon translation velocity forecasts. This preliminary study suggests that utilizing the NTDK scheme might improve the forecasting skill of TGFS for typhoon tracks. To gain a more comprehensive understanding of the impact of NTDK on typhoon tracks, further examination for more typhoons is still in need.

The study first proposes the difficult nonlinear convergent radius and convergent rate formulas and the complete derivations of a mathematical model for the nonlinear five-link human biped robot (FLHBR) system which has been a challenge for engineers in recent decades. The proposed theorem simultaneously has very distinctive superior advantages including the stringent almost disturbance decoupling feature that addresses the major deficiencies of the traditional singular perturbation approach without annoying “complete” conditions for the discriminant function and the global exponential stability feature without solving the impractical Hamilton–Jacobi equation for the traditional H-infinity technique. This article applies the feedback linearization technique to globally stabilize the FLHBR system that greatly improved those shortcomings of nonlinear function approximator and make the effective working range be global for whole state space, whereas the traditional Jacobian linearization technique is valid only for areas near the equilibrium point. In order to make some comparisons with traditional approaches, first example of the representative ones, that cannot be addressed well for the pioneer paper, is shown to demonstrate the fact that the effectiveness of the proposed main theorem is better than the traditional singular perturbation technique. Finally, we execute a second simulation example to compare the proposed approach with the traditional PID approach. The simulation results show that the transient behaviors of the proposed approach including the peak time, the rise time, the settling time and the maximum overshoot specifications are better than the traditional PID approach.

Background/purpose: Matrix metalloproteinases (MMPs) and tissue inhibitor of MMPs (TIMPs) have been shown to play an important role in the pathogenesis of tissue destruction in periodontitis. The associations between single nucleotide polymorphisms (SNPs) in the promoter regions of MMP-2, MMP-9, and TIMP-2 genes and the risk of aggressive periodontitis (AgP) and chronic periodontitis (CP) were investigated in a Taiwanese population. Materials and methods: MMP-2 C-1306T, C-735T, T-790G, and MMP-9 C-1562T and TIMP-2 G-418C SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis in 69 patients and 129 patients with AgP and CP, respectively, and 117 periodontal healthy individuals who served as healthy controls (HC). Chi-square test and logistic regression analysis were used to investigate the possible association of genotypes with periodontitis. Results: No significant differences in the distributions of the C-1306T and C-735T variants between periodontitis and HC were detected. Patients with genotype of MMP-2 -790 TT or T allele of MMP-2-790T/G as compared to genotypes of GT + GG genotypes or G allele, were less susceptible to CP [odds ratio (OR) = 0.50, 95% confidence interval (CI) = 0.25–1.00 and OR = 0.52, 95% CI = 0.28–0.96, respectively]. The frequencies of TIMP-2 G-418C gene polymorphisms in nonsmokers were statistically significantly different among AgP, CP, and HC groups (P = 0.024). The nonalcohol drinking participants with C allele of MMP-9 C-1562T as compared to T allele, were less susceptible to AgP (adjusted OR = 0.4; 95% CI, 0.18–0.90). Conclusion: It is suggested that MMP-2 T-790G, MMP-9 C-1562T, and TIMP-2 G-418C gene polymorphisms might be associated with periodontitis in the Taiwanese Han population.

Typhoon WRF (TWRF) based on the Advanced Research Weather Research and Forecasting Model (ARW WRF) was operational at the Central Weather Bureau (CWB) for tropical cyclone (TC) predictions since 2010 (named TWRF V1). CWB has committed to improve this regional model, aiming to increase the model predictability toward typhoons over East Asia. In 2016, an upgraded version designed to replace TWRF V1 became operational (named TWRF V2). Compared with V1, which has triple-nested meshes with coarser resolution (45/15/5 km), V2 increased the model resolution to 15/3 km. Since V1 and V2 were maintained in parallel from 2016 to 2018, this study utilized the real-time forecasts to investigate the impact of model resolution on TC prediction. Statistical measures pointed out the superiority of the high-resolution model on TC prediction. The forecast performance was also found competitive with that of two leading global models. The case study further pointed out, with the higher resolution, the model not only advanced the prediction on the TC track and inner core structure but also improved the representativeness of the complex terrain. Overall, the high-resolution model can better handle the so-called terrain phase-lock effect and, therefore, improve the TC quantitative precipitation forecast over the complex Taiwanese terrain.

Noninvasive positive pressure ventilation has been regarded as a strategy for improving exercise performance. Whether an increase in the ventilatory support level improves exercise performance in patients who have received invasive ventilation is unknown. The purpose of this study is to examine the effects of an additional level of pressure support (PS) ventilation on exercise tolerance in patients undergoing prolonged mechanical ventilation (PMV). Methods: This study examined 15 patients who were undergoing PMV. All patients performed an upper-arm exercise test at three PS levels: the baseline PS level (PS), a level 2 cmH2O higher than the baseline level (PS+2), and a level 4 cmH2O higher than the baseline level (PS+4). The physiological response, reasons for discontinuing the exercise test, and exercise duration were recorded and analyzed. Results: The tidal volume increased significantly from 271.7 ± 54.7 mL to 398.3 ± 88.7 mL at the PS+4 level (p = 0.01). Significant differences in exercise duration were observed at different PS levels. The exercise duration was significantly longer at the PS+4 level than at the PS and PS+2 levels (146.3 ± 139.9 seconds vs. 108.5 ± 85.9 seconds vs. 72.8 ± 43.9 seconds, p = 0.038) as their corresponding order. There were significant relationships between resting respiratory rate and exercise duration at the PS (r = −0.639, p = 0.034) and PS+2 levels (r = −0.668, p = 0.025). Conclusion: In patients undergoing PMV, an additional PS level of up to 4 cmH2O compared with the baseline setting may help to improve exercise tolerance by prolonging exercise duration.