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The chemokine co-receptors CXCR4 and CCR5 mediate HIV entry and signal transduction necessary for viral infection. However, to date only the CCR5 antagonist maraviroc is approved for treating HIV-1 infection. Given that approximately 50% of late-stage HIV patients also develop CXCR4-tropic virus, clinical anti-HIV CXCR4 antagonists are needed. Here, we describe a novel allosteric CXCR4 antagonist TIQ-15 which inhibits CXCR4-tropic HIV-1 infection of primary and transformed CD4 T cells. TIQ-15 blocks HIV entry with an IC 50 of 13 nM. TIQ-15 also inhibits SDF-1α/CXCR4-mediated cAMP production, cofilin activation, and chemotactic signaling. In addition, TIQ-15 induces CXCR4 receptor internalization without affecting the levels of the CD4 receptor, suggesting that TIQ-15 may act through a novel allosteric site on CXCR4 for blocking HIV entry. Furthermore, TIQ-15 did not inhibit VSV-G pseudotyped HIV-1 infection, demonstrating its specificity in blocking CXCR4-tropic virus entry, but not CXCR4-independent endocytosis or post-entry steps. When tested against a panel of clinical isolates, TIQ-15 showed potent inhibition against CXCR4-tropic and dual-tropic viruses, and moderate inhibition against CCR5-tropic isolates. This observation was followed by a co-dosing study with maraviroc, and TIQ-15 demonstrated synergistic activity. In summary, here we describe a novel HIV-1 entry inhibitor, TIQ-15, which potently inhibits CXCR4-tropic viruses while possessing low-level synergistic activities against CCR5-tropic viruses. TIQ-15 could potentially be co-dosed with the CCR5 inhibitor maraviroc to block viruses of mixed tropisms.

Increasing evidence suggests that walking while performing a concurrent task negatively influences gait performance. However, it remains unclear how higher-level cognitive processes and coordination of limb movements are altered in challenging walking environments. This study investigated the influence of cognitive task complexity and walking road condition on the neutral correlates of executive function and postural control in dual-task walking. Twenty-four healthy young adults completed a series of overground walks with three walking road conditions (wide, narrow, with obstacles) with and without the concurrent n-back working memory tasks of two complexity levels (1-back and 3-back). Prefrontal brain activation was assessed by functional near-infrared spectroscopy. A three-dimensional motion analysis system was used simultaneously to measure gait performance and lower-extremity kinematics. Repeated measures analysis of variance were performed to examine the differences between the conditions. In comparison with standing still, participants showed lower n-back task accuracy while walking, with the worst performance from the road with obstacles. Spatiotemporal gait parameters, lower-extremity joint movements, and the relative changes in oxygenated hemoglobin (HbO) concentration levels were all significantly different across the task complexity and walking path conditions. While dual-tasking participants were found to flex their hips and knees less, leading to a slower gait speed, longer stride time, shorter step length, and greater gait variability than during normal walking. For narrow-road walking, smaller ankle dorsiflexion and larger hip flexion were observed, along with a reduced gait speed. Obstacle negotiation was mainly characterized by increased gait variability than other conditions. HbO levels appeared to be lower during dual-task walking than normal walking. Compared to wide and obstacle conditions, walking on the narrow road was found to elicit a smaller decrement in HbO levels. The current study provided direct evidence that, in young adults, neural correlates of executive function and dynamic postural control tend to be altered in response to the cognitive load imposed by the walking environment and the concurrent task during ambulation. A shift of brain activation patterns between functionally connected networks may occur when facing challenging cognitive-motor interaction.

Modern maize (Zea mays L.) hybrids are generally regarded as strongly population dependent because maximum grain yields (GYs) per area are achieved primarily in high‐density populations. This study was conducted to analyze changes in density independence with plant density based on the response of GY, dry matter (DM) accumulation, and the harvest index (HI) to changes in plant density. Two modern cultivars, ZhengDan958 and ZhongDan909, were planted at 12 densities ranging from 1.5 to 18 plants m−2. The experiment was conducted for 3 yr, with drip irrigation and plastic mulching, at the 71 Group and Qitai Farms located in Xinjiang, China. With increased plant density, DM accumulation per area increased logarithmically, the HI decreased according to a cubic curve, and GY per area increased quadratically; the optimum density was 10.57 plants m−2. Further analysis showed that the response of GY per area, DM per area, and the HI to changes in plant density could be divided into four density ranges: Range I (≤4.7 plants m−2), in which DM per area, the HI, and GY per area were significantly affected by density; Range II (4.7–8.3 plants m−2), in which the HI was unaffected by density but DM per area and GY per area were significantly affected; Range III (8.3–10.75 plants m−2), in which GY per area was unaffected by density but DM per area and the HI were significantly affected; and Range IV (≥10.7 plants m−2), in which DM per area was unaffected by density but the HI and GY per area were significantly affected. These results indicated that Range II is a density‐independent range and Range III is a GY‐stable range.

Background:Systemic sclerosis (SSc) is a chronic immune-mediated autoimmune disease that is characterized by fibrotic changes of the skin and internal organs, which in turn leads to distortion of tissue structure and gradual loss of organ function. So far, there is still no treatment allows full recovery from this severe disorder. Therefore, it is of great social significance to study the pathogenesis of this disease and find new targets for treatment. Interleukin 33 (IL-33), which is a potent inducer of type 2 immune response, has been confirmed to be involved in the development and progression of multiple fibrotic diseases. However, the role and mechanism of IL-33 in SSc-related fibrosis remains unclear.Objectives:To clarify the role of interleukin 33 (IL-33) and its receptor Suppression of tumorigenicity 2 (ST2) in the skin fibrosis of SSc, so to provides a new target for the treatment of fibrosis in patients with SSc.Methods:The levels of IL-33 and ST2 was analysed in human samples, murine models of SSc and in cultured fibroblasts by immunohistochemistry and immunofluorescence. The functional role of IL-33 was evaluated by detecting changes in proliferation, migration, and activation of fibroblasts stimulated with recombinant IL-33 protein. MAPK and NF-κB signallings of fibroblasts were assessed by western blotting and analyses of target genes. The role of IL-33 in skin fibrosis was analysed in IL-33 deficient mice (il33−/−) and wild-type controls injected with bleomycin or NaCl.Results:The expression of IL-33 and its receptor ST2 were up-regulated in skin lesions of SSc patients (Fig 1 A-C) and bleomycin-treated mice(Fig1 D-F). Compared to the healthy skin, the skin from SSc patients expressed more ST2 on fibroblasts membrane(Fig 1 B-C). IL33 induces MAPK and IκBα activation in human dermal fibroblast(Fig 2 A), and promote proliferation, migration and production of collagen of human dermal fibroblasts, but not the release of inflammatory factors(IL-6, MCP-1)(Fig2 B-G). Mice deficient for IL33 are protected from bleomycin-induced dermal fibrosis (Fig3).Fig 1.Increased expression of IL33, ST2 in SSc patients and bleomycin-treated mice.Fig 2.IL33 induces MAPK and IκBα activation in human dermal fibroblast, and and promote proliferation, migration and production of collagen of human dermal fibroblasts.Fig 3.Mice deficient for IL33 are protected from bleomycin-induced dermal fibrosis.Conclusion:IL33 promotes skin fibrosis by activating fibroblasts, and IL33/ST2 may be an important target for the treatment of fibrosis in patients with SSc.References:[1]Ingegnoli F, Ughi N, Mihai C. Update on the epidemiology, risk factors, and disease outcomes of systemic sclerosis. Best practice & research. Clinical rheumatology. 2018;32(2):223-240.[2]Schmitz J, Owyang A, Oldham E, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23(5):479-490.[3]Molofsky AB, Savage AK, Locksley RM. Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation. Immunity. 2015;42(6):1005-1019.Disclosure of Interests:None declared

Good canopy structure is essential for optimal maize (Zea mays L.) production. However, creating appropriate maize canopy structure can be difficult, because the characteristics of individual plants are altered by changes in plant age, density and interactions with neighbouring plants. The objective of the current study was to find a reliable method for building good maize canopy structure by analysing changes in canopy structure, light distribution and grain yield (GY). A modern maize cultivar (ZhengDan958) was planted at 12 densities ranging from 1.5 to 18 plants/m2 at two field locations in Xinjiang, China. At the silking stage (R1), plant and ear height increased with plant density as well as leaf area index (LAI), whereas leaf area per plant decreased logarithmically. The fraction of light intercepted by the plant (F) increased with increasing plant density, but the light extinction coefficient (K) decreased linearly from 0.61 to 0.39. Taking the optimum value of F (95%) as an example, and using measured values of K for each plant density at R1 and the equation from Beer's law, the corresponding (theoretical) LAI for each plant density was calculated and optimum plant density (9.72 plants/m2) obtained by calculating the difference between theoretical LAIs and actual observations. Further analysis showed that plant density ranging from 10.64 to 11.55 plants/m2 yielded a stable GY range. Therefore, taking into account the persistence time for maximum LAI, the plant density required to obtain an ideal GY maize canopy structure should be increased by 10–18% from 9.72 plants/m2.

The characteristic traits of maize (Zea mays L.) leaves affect light interception and photosynthesis. Measurement or estimation of individual leaf area has been described using discontinuous equations or bell-shaped functions. However, new maize hybrids show different canopy architecture, such as leaf angle in modern maize which is more upright and ear leaf and adjacent leaves which are longer than older hybrids. The original equations and their parameters, which have been used for older maize hybrids and grown at low plant densities, will not accurately represent modern hybrids. Therefore, the aim of this paper was to develop a new empirical equation that captures vertical leaf distribution. To characterize the vertical leaf profile, we conducted a field experiment in Jilin province, Northeast China from 2015 to 2018. Our new equation for the vertical distribution of leaf profile describes leaf length, width or leaf area as a function of leaf rank, using parameters for the maximum value for leaf length, width or area, the leaf rank at which the maximum value is obtained, and the width of the curve. It thus involves one parameter less than the previously used equations. By analysing the characteristics of this new equation, we identified four key leaf ranks (4, 8, 14 and 20) for which leaf parameter values need to be quantified in order to have a good estimation of leaf length, width and area. Together, the method of leaf area estimation proposed here adds versatility for use in modern maize hybrids and simplifies the field measurements by using the four key leaf ranks to estimate vertical leaf distribution in maize canopy instead of all leaf ranks.

The spatio-temporal variation of leaf chlorophyll content is an important crop phenotypic trait that is of great significance for evaluating crop productivity. This study used a soil-plant analysis development (SPAD) chlorophyll meter for non-destructive monitoring of leaf chlorophyll dynamics to characterize the patterns of spatio-temporal variation in the nutritional status of maize (Zea mays L.) leaves under three nitrogen treatments in two cultivars. The results showed that nitrogen levels could affect the maximum leaf SPAD reading (SPADmax) and the duration of high SPAD reading. A rational model was used to measure the changes in SPAD readings over time in single leaves. This model was suitable for predicting the dynamics of the nutrient status for each leaf position under different nitrogen treatments, and model parameter values were position dependent. SPADmax at each leaf decreased with the reduction of nitrogen supply. Leaves at different positions in both cultivars responded differently to higher nitrogen rates. Lower leaves (8th–10th positions) were more sensitive than the other leaves in response to nitrogen. Monitoring the SPAD reading dynamic of lower leaves could accurately characterize and assess the nitrogen supply in plants. The lower leaves in nitrogen-deficient plants had a shorter duration of high SPAD readings compared to nitrogen-sufficient plants; this physiological mechanism should be studied further. In summary, the spatio-temporal variation of plant nitrogen status in maize was analysed to determine critical leaf positions for potentially assisting in the identification of appropriate agronomic management practices, such as the adjustment of nitrogen rates in late fertilization.

Background. Extracellular vesicles (EVs) are membrane bound, secreted by cells, and detected in bodily fluids, including urine, and contain proteins, RNA, and DNA. Our goal was to identify HIV and human proteins (HPs) in urinary EVs from HIV+ patients and compare them to HIV− samples. Methods. Urine samples were collected from HIV+ ( n = 35 ) and HIV− ( n = 12 ) individuals. EVs were isolated by ultrafiltration and characterized using transmission electron microscopy, tandem mass spectrometry (LC/MS/MS), and nanoparticle tracking analysis (NTA). Western blots confirmed the presence of HIV proteins. Gene ontology (GO) analysis was performed using FunRich and HIV Human Interaction database (HHID). Results. EVs from urine were 30–400 nm in size. More EVs were in HIV+ patients, P < 0.05 , by NTA. HIV+ samples had 14,475 HPs using LC/MS/MS, while only 111 were in HIV−. HPs in the EVs were of exosomal origin. LC/MS/MS showed all HIV+ samples contained at least one HIV protein. GO analysis showed differences in proteins between HIV+ and HIV− samples and more than 50% of the published HPs in the HHID interacted with EV HIV proteins. Conclusion. Differences in the proteomic profile of EVs from HIV+ versus HIV− samples were found. HIV and HPs in EVs could be used to detect infection and/or diagnose HIV disease syndromes.

The extent of the reduction of maize (Zea mays L.) kernel moisture content through drying is closely related to field temperature (or accumulated temperature; AT) following maturation. In 2017 and 2018, we selected eight maize hybrids that are widely planted in Northeastern China to construct kernel drying prediction models for each hybrid based on kernel drying dynamics. In the traditional harvest scenario using the optimal sowing date (OSD), maize kernels underwent drying from 4th September to 5th October, with variation coefficients of 1.0–1.9. However, with a latest sowing date (LSD), drying occurred from 14th September to 31st October, with variation coefficients of 1.3–3.0. In the changed harvest scenario, the drying time of maize sown on the OSD condition was from 12th September to 9th November with variation coefficients of 1.3–3.0, while maize sown on the LSD had drying dates of 26th September to 28th October with variation coefficients of 1.5–3.6. In the future harvest scenario, the Fengken 139 (FK139) and Jingnongke 728 (JNK728) hybrids finished drying on 20th October and 8th November, respectively, when sown on the OSD and had variation coefficients of 2.7–2.8. Therefore, the maize kernel drying time was gradually delayed and was associated with an increased demand for AT ⩾ 0°C late in the growing season. Furthermore, we observed variation among different growing seasons likely due to differences in weather patterns, and that sowing dates impact variations in drying times to a greater extent than harvest scenarios.

Objective To assess long‐term follow‐up evaluations for the treatment of femoral intertrochanteric fractures with the “three‐finger method” assisted by proximal femoral nail antirotation (PFNA). Methods From January 2010 to January 2017, 123 patients were selected and followed for the treatment of femoral intertrochanteric fractures with PFNA assisted by the “three‐finger method” (application of the index finger, middle finger, and ring finger in the process of surgery to assist PFNA). There were 56 male patients and 67 female patients aged 52–93 years with an average age of 75.6 years, and 88 cases were due to a fall and 35 due to a traffic accident injury. The femoral necks were fixed with PFNA assisted by the “three‐finger method” applying the following procedure: traction reduction, determining the incision, inserting the needle, and placing screw. The Harris hip score, postoperative complications, hip pain and function status were statistically analyzed to evaluate the surgical efficacy and to discuss the surgical technique of the “three‐finger method” assisted by PFNA. Results According to the Harris scoring criteria, patients were followed for 1, 2, 4, 6, and 8 years, and the good outcomes of patients were recorded. The excellent and good rate of 87% was the highest in the second year of follow‐up. Then, the rate decreased following the eighth year of follow‐up. The excellent and good rate of 82.7% was the lowest. The patients with incisions healed well, there were no instances of fat liquefaction or infection. There were three cases of effusion, the rate was 2.4%. The secretions were cultured, and no bacterial growth was found. After treatment of the wound, it healed, and the spiral blade used for the femoral head did not wear out. There was one case of femoral head necrosis. There was no significant correlation between hip pain and sex and age (P > 0.05), and the function of the hip joint was significantly correlated with the age of the patients (P < 0.05). Conclusion The “three‐finger method” in the process of surgery to assist PFNA for the treatment of patients with intertrochanteric fractures of the femur simplified the operation steps, reduced the operation difficulty, shortened the operation time, improved the operation efficiency, and reduced the incidence of postoperative complications.