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Diverse entry inhibitors targeting the gp120 subunit of the HIV-1 envelope (Env) trimer have been developed including BMS-626529, also called temsavir, a prodrug version of which is currently in phase III clinical trials. Here we report the characterization of a panel of small-molecule inhibitors including BMS-818251, which we show to be >10-fold more potent than temsavir on a cross-clade panel of 208-HIV-1 strains, as well as the engineering of a crystal lattice to enable structure determination of the interaction between these inhibitors and the HIV-1 Env trimer at higher resolution. By altering crystallization lattice chaperones, we identify a lattice with both improved diffraction and robust co-crystallization of HIV-1 Env trimers from different clades complexed to entry inhibitors with a range of binding affinities. The improved diffraction reveals BMS-818251 to utilize functional groups that interact with gp120 residues from the conserved β20-β21 hairpin to improve potency. Temsavir, a compound that inhibits HIV entry by binding envelope (Env), is currently in clinical development. Here, Lai et al. identify a more than 10-fold improved compound and, using lattice engineering, obtain crystal structures that give insights into improved inhibition between small molecules and Env.

Incidence of kidney failure with replacement therapy During 2022, 1471 new patients entered the KFRT programme at an incidence of 197.5 per million population (pmp), an 0.34% increase compared with 2021. Since the establishment of the Renal Registry in 1995, the number of new patients increased by 139%, from 615 per year (95.1 pmp) in 1996 to a peak of 1471 per year (197.5 pmp) in 2022 (Fig 1). The overall peritonitis rate among patients receiving continuous ambulatory PD has greatly improved, from 0.55 episode per patient-year in 1999 to 0.27 episode per patient-year in 2022. [...]patients receiving automated PD had a peritonitis rate of 0.23 episode per patient-year, which was better than the rate among patients receiving continuous ambulatory PD. Haemodialysis As of 31 December 2022, there were 2452 patients receiving HD in the Renal Registry, representing a prevalence of 329 pmp; this rate constituted a 2.0% increase compared with 2021. The proportion of HD among all KFRT treatment modalities also increased from 11% in 1996 to 17.6% in 2022, resulting in the HD-to-PD ratio of 0.37:1. Since the introduction of the nocturnal home dialysis programme in 2006 and New Generation Home HD in 2020, HA home HD services have expanded. Infection remained the most common cause of death among KFRT patients (46.0% in 2022), followed by cardiovascular disease (26.2%) and cerebrovascular disease (4.1%) [online supplementary Fig 3]. Because of improved hepatitis treatment for transplant recipients, liver failure has caused [lesser than]1% of deaths in recent years.

Objectives: This study aims to examine the rates of anxiety, depression, and posttraumatic stress disorder (PTSD) after hospital discharge among COVID-19 survivors and to determine the associated risk factors. Methods: Adult COVID-19 survivors discharged from hospitals between March 2020 and March 2021 were asked to complete a questionnaire at 4 weeks after discharge. The Chinese version of the 22-item Impact of Event Scale - Revised (IES-R) was used to measure symptoms of PTSD. The 9-item Patient Health Questionnaire (PHQ-9) was used to assess symptoms of major depressive disorder. The 7-item Generalised Anxiety Disorder Scale (GAD-7) was used to measure symptoms of generalised anxiety disorder. The rates of anxiety, depression, and PTSD among discharged patients were determined, as were associations between psychosocial factors and outcome measures and predictors for moderate-tosevere symptoms of anxiety, depression, and PTSD. Results: 96 men and 103 women aged 18 to 81 years returned the completed questionnaire. 12.1% to 20.1% of them reported symptoms of PTSD, anxiety, or depression. Higher symptom severity was associated with higher perceived life threat, lower emotional support, lower disease severity upon admission, and longer hospital stay. Women had more PTSD symptoms than men, particularly when knowing someone under quarantine. Conclusion: COVID-19 survivors with higher perceived life threat, lower emotional support, lower disease severity upon admission, and longer hospital stay were associated with higher severity of symptoms of PTSD, anxiety, and depression. Timely intervention should provide to at-risk survivors.

During early postnatal life, extensive changes in gene expression occur concomitantly in multiple major organs, indicating the existence of a common core developmental genetic program. This program includes hundreds of growth-promoting genes that are downregulated with age in liver, kidney, lung, and heart, and there is evidence that this component of the program drives the widespread decline in cell proliferation that occurs in juvenile life, as organs approach adult sizes. To investigate epigenetic changes that might orchestrate this program, we performed chromatin immunoprecipitation-promoter tiling array to assess temporal changes in histone H3K4 and H3K27 trimethylation (me3) at promoter regions throughout the genome in kidney and lung, comparing 1- to 4-wk-old mice. We found extensive genome-wide shifts in H3K4me3 and H3K27me3 occurring with age in both kidney and lung. The number of genes with concordant changes in the two organs was far greater than expected by chance. Temporal changes in H3K4me3 showed a strong, positive association with changes in gene expression, assessed by microarray, whereas changes in H3K27me3 showed a negative association. Gene ontology analysis indicated that shifts in specific histone methylation marks were associated with specific developmental functions. Of particular interest, genes with decreases in H3K4me3 with age in both organs were strongly implicated in cell cycle and cell proliferation functions. Taken together, the findings suggest that the common core developmental program of gene expression which occurs in multiple organs during juvenile life is associated with a common core developmental program of histone methylation. In particular, declining H3K4me3 is strongly associated with gene downregulation and occurs in the promoter regions of many growth-regulating genes, suggesting that this change in histone methylation may contribute to the component of the genetic program that drives juvenile body growth deceleration.

The level of endothelin-1 (ET-1), a potent vasoconstrictor, was associated with retinopathy under ischemia. The effects of endothelial endothelin-1 (ET-1) over-expression in a transgenic mouse model using Tie-1 promoter (TET-1 mice) on pathophysiological changes of retinal ischemia were investigated by intraluminal insertion of a microfilament up to middle cerebral artery (MCA) to transiently block the ophthalmic artery. Two-hour occlusion and twenty-two-hour reperfusion were performed in homozygous (Hm) TET-1 mice and their non-transgenic (NTg) littermates. Presence of pyknotic nuclei in ganglion cell layer (GCL) was investigated in paraffin sections of ipsilateral (ischemic) and contralateral (non-ischemic) retinae, followed by measurement of the thickness of inner retinal layer. Moreover, immunocytochemistry of glial fibrillary acidic protein (GFAP), glutamine synthetase (GS) and aquaporin-4 (AQP4) peptides on retinal sections were performed to study glial cell reactivity, glutamate metabolism and water accumulation, respectively after retinal ischemia. Similar morphology was observed in the contralateral retinae of NTg and Hm TET-1 mice, whereas ipsilateral retina of NTg mice showed slight structural and cellular changes compared with the corresponding contralateral retina. Ipsilateral retinae of Hm TET-1 mice showed more significant changes when compared with ipsilateral retina of NTg mice, including more prominent cell death in GCL characterized by the presence of pyknotic nuclei, elevated GS immunoreactivity in Müller cell bodies and processes, increased AQP-4 immunoreactivity in Müller cell processes, and increased inner retinal thickness. Thus, over-expression of endothelial ET-1 in TET-1 mice may contribute to increased glutamate-induced neurotoxicity on neuronal cells and water accumulation in inner retina leading to edema.

Conserved epitopes on the influenza hemagglutinin (HA) stem are an attractive target for universal vaccine strategies as they elicit broadly neutralizing antibodies. Such antibody responses to stem-specific epitopes have been extensively characterized for HA subtypes H1 and H5 in humans. H2N2 influenza virus circulated 50 years ago and represents a pandemic threat due to the lack of widespread immunity, but, unlike H1 and H5, the H2 HA stem contains Phe45 HA2 predicted to sterically clash with HA stem-binding antibodies characterized to date. To understand the effect of Phe45 HA2 , we compared the HA stem-specific B cell response in post hoc analyses of two phase 1 clinical trials, one testing vaccination with an H2 ferritin nanoparticle immunogen ( NCT03186781 ) and one with an inactivated H5N1 vaccine ( NCT01086657 ). In H2-naive individuals, the magnitude of the B cell response was equivalent, but H2-elicited HA stem-binding B cells displayed greater cross-reactivity than those elicited by H5. However, in individuals with childhood H2 exposure, H5-elicited HA stem-binding B cells also displayed high cross-reactivity, suggesting recall of memory B cells formed 50 years ago. Overall, we propose that a one-residue difference on an HA immunogen can alter establishment and expansion of broadly neutralizing memory B cells. These data have implications for stem-based universal influenza vaccination strategies. A bulky residue in the stem domain of the influenza virus H2 hemagglutinin appears pivotal in eliciting broadly cross-reactive antibodies capable of recognizing diverse group 1 influenza subtypes and is informative for universal influenza vaccine development.

Summary Purpose : Sunitinib is a multi-target receptor tyrosine kinase (RTK) inhibitor against vascular endothelial growth factor receptors, platelet-derived growth factor receptors (PDGFR), c-kit and RET. Several of these RTKs are known to be involved in the progression of nasopharyngeal carcinoma (NPC). Here, we evaluated the preclinical activities of sunitinib in NPC. Method : We determined the basal level of total and phosphorylated PDGFR, c-kit and RET by immunoblotting in a panel of five NPC cell lines. The effect of sunitinib on NPC cell proliferation was evaluated by MTT assay. We further studied the effect of sunitinib on NPC cell cycle progression and apoptosis. We investigated the in vitro and in vivo activities of sunitinib as single agent and in combination with cisplatin or docetaxel in NPC cell lines and tumor xenografts. Results : Sunitinib exhibited dose-dependent growth inhibition in all NPC cell lines tested with IC 50 between 2–7.5 μM and maximum inhibition of over 97%. Sunitinib induced apoptosis and cell cycle arrest at G 0 /G 1 phase. In vitro, sunitinib moderately enhanced the growth inhibition of cisplatin or docetaxel. Single agent sunitinib demonstrated significant growth inhibition, reduced microvessel density and caused extensive tumor necrosis in a NPC xenograft model. However, concurrent administration of sunitinib and docetaxel induced severe toxicity in mice without enhanced antitumor effect. Conclusions : Single agent sunitinib demonstrated potent in vitro and in vivo growth inhibition in NPC. When combined with chemotherapy, sequential instead of concurrent administration schedule should be further explored.

Using mAbs as therapeutic molecules is complicated by the propensity of mAbs to aggregate at elevated concentrations, which can lead to a variety of adverse events in treatment. Here, we describe a proof-of-concept for new methodology to detect and quantify mAb aggregation. Assay development included using an aggregated mAb as bait for screening of phage display peptide library and identifying those peptides with random sequence which can recognize mAb aggregates. Once identified, the selected peptides can be used for developing quantitative methods to assess mAb aggregation. Results indicate that a peptide binding method coupled with mass spectrometric detection of bound peptide can quantify mAb aggregation and potentially be useful for monitoring aggregation propensity of therapeutic protein candidates.

Logit models are popular tools for analyzing discrete choice and ranking data. The models assume that judges rate each item with a measurable utility, and the ordering of a judge’s utilities determines the outcome. Logit models have been proven to be powerful tools, but they become difficult to interpret if the models contain nonlinear and interaction terms. We extended the logit models by adding a decision tree structure to overcome this difficulty. We introduced a new method of tree splitting variable selection that distinguishes the nonlinear and linear effects, and the variable with the strongest nonlinear effect will be selected in the view that linear effect is best modeled using the logit model. Decision trees built in this fashion were shown to have smaller sizes than those using loglikelihood-based splitting criteria. In addition, the proposed splitting methods could save computational time and avoid bias in choosing the optimal splitting variable. Issues on variable selection in logit models are also investigated, and forward selection criterion was shown to work well with logit tree models. Focused on ranking data, simulations are carried out and the results showed that our proposed splitting methods are unbiased. Finally, to demonstrate the feasibility of the logit tree models, they were applied to analyze two datasets, one with binary outcome and the other with ranking outcome.