Explore the vast range of titles available.

Janus Kinases (JAKs) play a crucial role as therapeutic targets for various cancers. However, the current JAK inhibitors (JAKi) available have limited therapeutic benefits due to their lack of selectivity. This review focuses on the structural analysis to elucidate the molecular determinants of JAKs specificity and the discovery and design of selective JAKi. It includes descriptions and comparison of different JAK structures and their binding sites, a comparative analysis of JAKi and their binding modes, detailed interaction fingerprints (IFPs), and an extensive structure‐selectivity relationship (SSRs). Moreover, the review also explores the challenges and possibilities of using computational structure‐based methods for discovering and designing selective JAKi. Other structure‐based approaches, such as targeting the pseudokinase domain, as well as covalent and allosteric designs, are also covered. Based on this analysis, key determinants corresponding to JAK specificity and rational medicinal chemistry strategies are proposed to facilitate the development of highly selective JAKi. Overall, we aim to enhance the understanding of JAK specificity and explore strategies that can lead to the discovery of effective and selective JAKi in cancer therapy, thus improving the prognosis for cancer patients. Despite their significant efficacy in cancer therapy, current Janus kinases inhibitors (JAKi) are limited for their selectivity, which can cause off‐target effects. This remains a major clinical challenge. This review aims to integrates three‐dimensional structural information with comprehensive pharmacological data to study the determinants of specificity, to develop effective medicinal chemistry strategies for the discovery of selective JAKi.

Root pile is a new type of pile that improves the load carrying capacity by roots penetrating into soils. To carry out the nonlinear settlement analysis of such a root pile in multilayered soils, the hyperbolicity-based load transfer model is in this paper reformulated to account for the discontinuities between the segments with and without roots. The procedure to determine the model parameters for root piles is presented accordingly. The feasibility and reliability of such a proposed modified hyperbolic model for nonlinear settlement analysis of root piles in multilayered soils are verified by a numerical case and two real experimental cases. The numerical case study shows that the root pile does increase the pile load carrying capacity to some extent. In a parametric study based on this numerical case, it can be found that the bearing capacity of root piles increases along with the increase in the root number, size, depth and the elastic modulus of the surrounding soil. The loading test results on two real root piles sited in Chizhou Yangtze River Bridge, China, are used to further verify the proposed method. Comparing with other analytical methods, it is demonstrated that the proposed method incorporated with the proposed modified hyperbolic model can achieve a better agreement with the measured ones especially in a large loading stage.

The open reduction of mandibular condyle neck fractures is difficult due to the limited surgical field and complex facial nerve structures. The most effective fixation method for narrow fractured segments is debated as standard double four-hole plate fixation is often not feasible. This research compared bone stability and force resistance between single-long-plate and double-short-plate fixations using clinical outcomes, a Sawbones mandible model, and finite element analysis. In patients with condyle neck fractures, nine were fixed with single-long-plate and twelve with double-short-plate fixations, with no significant differences in malocclusion and facial palsy rates. In compression tests with a Sawbones model, displacements in the posterior part were similar in both fixation groups. In contrast, the anterior part had significantly higher displacements in the single-long-plate group. Finite element analysis showed higher displacements in both anterior and posterior parts in the single-plate group compared to the double-short-plate group. Maximum stresses were at the second screw hole in single-long-plate fixation and the turning point of the upper plate at the condyle neck in double-short-plate fixation. Double-short-plate fixations demonstrated better stability and force resistance than single-long-plate fixations.

Acute alcoholic liver injury is an important health problem worldwide. Apples are rich in many nutrients and have a variety of biological activities, including antioxidant, anti-inflammatory, and anti-tumor, and therefore have the potential to be a natural protective agent against acute alcoholic liver injury. This study evaluated the protective effect of apples (Malus pumila Mill) on acute alcoholic liver injury in rats. Male Wistar rats were randomly assigned to four groups: a control group (C), a control group that was fed fresh apples (CA), an ethanol-treated group (E), and an ethanol-treated group that was fed fresh apples (EA). Rats were treated with continuous forced gavage with 40° ethanol (4 mL/kg) for one week to simulate human alcoholism. Liver injury was assessed based on changes in the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as histological analysis. The protective effect of apples on alcoholic liver injury was assessed in terms of alcohol metabolism, oxidative stress, inflammation, lipid synthesis, and tissue fibrosis. The results showed that apple consumption protected against alcoholic liver injury, as indicated by the decreased serum ALT and AST levels, reduced liver lipid peroxidation, and improved liver histopathology. Moreover, apple consumption increased antioxidant enzyme activity and reduced inflammatory cytokine levels in the liver. These findings suggest that apple consumption may have a protective effect against acute ethanol-induced liver injury in rats, possibly through its antioxidant and anti-inflammatory properties.

Three new oxoaporphine Co(II), Ni(II) and Zn(II) complexes 1 – 3 have been synthesized and fully characterized. 1 – 3 have similar mononuclear structures with the metal and ligand ratio of 1:2. 1 – 3 exhibited higher cytotoxicity than the OD ligand and cisplatin against HepG2, T-24, BEL-7404, MGC80–3 and SK-OV-3/DDP cells, with IC 50 value of 0.23−4.31 μM. Interestingly, 0.5 μM 1 – 3 significantly caused HepG2 arrest at S-phase, which was associated with the up-regulation of p53, p21, p27, Chk1 and Chk2 proteins, and decrease in cyclin A, CDK2, Cdc25A, PCNA proteins. In addition, 1 – 3 induced HepG2 apoptosis via a caspase-dependent mitochondrion pathway as evidenced by p53 activation, ROS production, Bax up-regulation and Bcl-2 down-regulation, mitochondrial dysfunction, cytochrome c release, caspase activation and PARP cleavage. Furthermore, 3 inhibited tumor growth in HepG2 xenograft model, and displayed more safety profile in vivo than cisplatin.

Graphene oxide/cellulose-poly(butylene succinate) (GO/CE-PBS) films with excellent mechanical properties were prepared via the help of ionic liquid. During the process of preparation of the composite films, PBS as the toughening material was added to the composite with the dissolution of CE. The X-ray diffraction results showed that GO was completely exfoliated in the CE-PBS matrix. Fourier-transform infrared spectroscopy verified that new hydrogen bonds were formed between CE chains and GO sheets because of the hydrophilic groups on the GO sheets. Morphological analysis of composite films showed that PBS existed in the CE matrix in the form of microparticles, leading to a rough fractured surface. Tensile tests indicated that the elongation at break of CE was significantly improved with a low PBS content. The tensile strength and Young’s modulus of GO/CE-PBS ternary composite films with only 1 wt% GO were increased by 188 and 320 % compared to the pure CE films, respectively; meanwhile, the elongation at break of the composite films was 9.3, which was also higher than that of pure CE films. SEM and Halpin-Tsai model analysis showed that GO sheets were likely to be arranged parallel to the film because of the large lateral thickness ratio, which may determine the orientation of CE chains and result in significant improvement of the mechanical properties of CE films.

Background. Lupus nephritis (LN) remains a major cause of morbidity and end-stage renal disease. Dysfunction of B lymphocytes is thought to be important in the pathogenesis of SLE/LN. Intrarenal B cells have been found in several forms of inflammatory kidney diseases although their role in LN renal is not well defined. Methods. Intrarenal B cells were analyzed in 192 renal biopsies from patients diagnosed with lupus nephritis. Immunohistochemical staining of serial sections was performed for each LN patient using CD20, CD3, and CD21 antibodies. Results. Intrarenal B cells were more likely to be associated with class IV LN and were mainly distributed in the renal interstitium, with very few in the glomerulus. The systemic lupus erythematosus disease activity index (SLEDAI), blood urea nitrogen, and serum creatinine levels were all significantly greater in the LN-B cell groups (all P<0.05). LN renal activity and chronicity indices correlated with B-cells infiltrates (all P<0.0001). Renal biopsies were classified into four distinct categories according to the organizational grade of inflammatory cell infiltrates. Germinal center- (GC-) like structures were not identified in any LN biopsies. Conclusion. It is hypothesized that intrarenal B cells enhance immunological responses and exaggerate the local immune response to persisting autoimmune damage in the tubulointerstitium.

Introduction. Dysfunction of the B lymphocyte is considered to be involved in the pathogenesis of lupus nephritis (LN). Intrarenal B cells have been found in several forms of inflammatory kidney disease. B-cell activating factor (BAFF) regulates B lymphocyte proliferation and survival, and contributes to human autoimmune disease. Their role in renal inflammation is not well defined. Methods. Clinical parameters and renal biopsies from 62 LN patients were prospectively analyzed. We performed standard immunohistochemistry on serial paraffin tissue sections using monoclonal antibodies to CD20 and BAFF to investigate the characteristics and significance of locally infiltrating B cells and local BAFF expression in patients with LN. Results. Intrarenal B cells and/or BAFF were mainly distributed in the renal interstitium. Compared to the LN-non-B-cell/BAFF expression group, proteinuria (g/24 hour), blood urea nitrogen, serum creatinine levels, LN renal activity, and chronicity indices, were all significantly greater in the LN-B-cell/BAFF expression groups. The expression of BAFF was strongly associated with the quantity of B-cell infiltrate in the interstitium. Conclusion. As BAFF expression was strongly associated with B-cell infiltration, we hypothesize that altered B-cell differentiation and tolerance induced by excess BAFF may be central to the pathogenesis of LN.

The article titled “The Characteristics and Significance of Locally Infiltrating B Cells in Lupus Nephritis and Their Association with Local BAFF Expression” [1] listed the corresponding author incorrectly. The corresponding author of this paper is supposed to be Cheng-De Yang (yangchengde@hotmail.com) rather than Yu-ChengYan. The corrected author information is presented above.

Introduction Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Currently, numerous genetic loci of SLE have been confirmed. Here we try to further explore additional genes contributing to SLE susceptibility in this study. Methods Forty nine single nucleotide polymorphisms (SNPs) with moderate-risk for SLE in previous study were genotyped in a large-scale replication study with a total of 3,522 cases and 8,252 controls using the Sequenom Massarray system. Association analyses were performed using logistic regression with gender or sample cohorts as a covariate through PLINK 1.07 software. Results This replication effort confirmed five reported SLE susceptibility loci reaching genome-wide levels of significance ( P meta <5.00 × 10 −08 ): TNFSF4 (rs1418190, odds ratio (OR) = 0.81, P meta  = 1.08 × 10 −08 ; rs4916219, OR = 0.80, P meta  = 7.77 × 10 −09 ), IRF8 (rs2934498, OR = 1.25, P meta  = 4.97 × 10 −09 ), miR-146a (rs2431697, OR = 0.69, P meta  = 1.15 × 10 −22 ), CD44 (rs2732547, OR = 0.82, P meta  = 1.55 × 10 −11 ), and TMEM39A (rs12494314, OR = 0.84, P meta  = 1.01 × 10 −09 ). Further logistic regression analysis indicated that the genetic effects within TNFSF4 detected in this study are independent from our previously reported signals. Conclusions This study increases the number of established susceptibility loci for SLE in Han Chinese population and highlights the contribution of multiple variants of modest effect. Although further studies will be required to identify the causal alleles within these loci, the findings make a significant step forward in our understanding of the genetic contribution to SLE in Chinese population.