HIV-1 gp41 Fusion Intermediate: A Target for HIV Therapeutics

Human immunodeficiency virus (HIV)-1 infection is initiated by the binding of gp120 envelope glyco-protein to its cell receptor (CD4) and a coreceptor (CXCR4 or CCR5), followed by a series of conformational changes in the gp41 transmembrane subunit. These changes include insertion of fusion peptide into the target cell membrane and association of C-heptad repeat (CHR) peptide with the N-heptad repeat (NHR) trimer, a pre-hairpin fusion intermediate. A stable six-helix bundle core is then formed, bringing the viral envelope and target cell membrane into close proximity for fusion. Peptides derived from the CHR region, such as T20 and C34, inhibit HIV-1 fusion by interacting with the gp41 fusion intermediate. A number of anti-HIV-1 peptides and small molecule compounds targeting the gp41 NHR-trimer have been identified. By combining HIV fusion/entry inhibitors targeting different sites in the gp41 fusion intermediate, a potent synergistic effect takes place, resulting in a potential new therapeutic strategy for the HIV infection/AIDS. Here, we present an overview of the current development of anti-HIV drugs, particularly those targeting the gp41 fusion intermediate

An integrated decision making model for dynamic pricing and inventory control of substitutable products based on demand learning

Purpose: This paper focuses on the PC industry, analyzing a PC supply chain system composed of onelarge retailer and two manufacturers. The retailer informs the suppliers of the total order quantity, namelyQ, based on demand forecast ahead of the selling season. The suppliers manufacture products accordingto the predicted quantity. When the actual demand has been observed, the retailer conducts demandlearning and determines the actual order quantity. Under the assumption that the products of the twosuppliers are one-way substitutable, an integrated decision-making model for dynamic pricing andinventory control is established.Design/methodology/approach: This paper proposes a mathematical model where a large domestichousehold appliance retailer decides the optimal original ordering quantity before the selling season and theoptimal actual ordering quantity, and two manufacturers decide the optimal wholesale price.Findings:By applying this model to a large domestic household appliance retail terminal, the authors canconclude that the model is quite feasible and effective. Meanwhile, the results of simulation analysis showthat when the product prices of two manufacturers both reduce gradually, one manufacturer will often waittill the other manufacturer reduces their price to a crucial inflection point, then their profit will show aqualitative change instead of a real-time profit-price change.Practical implications: This model can be adopted to a supply chain system composed of one largeretailer and two manufacturers, helping manufacturers better make a pricing and inventory controldecision.Originality/value: Previous research focuses on the ordering quantity directly be decided. Limited workhas considered the actual ordering quantity based on demand learning. However, this paper considers boththe optimal original ordering quantity before the selling season and the optimal actual ordering quantityfrom the perspective of the retailerPeer Reviewe

Change Profiles and Functional Targets of MicroRNAs in Type 2 Diabetes Mellitus Patients with Obesity

Background MicroRNAs (miRNAs) exert an essential contribution to obesity and type 2 diabetes mellitus (T2DM). This study aimed to investigate the differences of miRNAs in the presence and absence of T2DM in patients with obesity, as well as before and after bariatric surgery in T2DM patients with obesity. Characterization of the common changes in both was further analyzed. Methods We enrolled 15 patients with obesity but without T2DM and 15 patients with both obesity and T2DM. Their preoperative clinical data and serum samples were collected, as well as 1 month after bariatric surgery. The serum samples were analyzed by miRNA sequencing, and the miRNAs profiles and target genes characteristics were compared. Results Patients with T2DM had 16 up-regulated and 32 down-regulated miRNAs compared to patients without T2DM. Improvement in metabolic metrics after bariatric surgery of T2DM patients with obesity was correlated with changes in miRNAs, as evidenced by the upregulation of 20 miRNAs and the downregulation of 30 miRNAs. Analysis of the two miRNAs profiles identified seven intersecting miRNAs that showed opposite changes. The target genes of these seven miRNAs were substantially enriched in terms or pathways associated with T2DM. Conclusion We determined the expression profiles of miRNAs in the obese population, with and without diabetes, before and after bariatric surgery. The miRNAs that intersected in the two comparisons were discovered. Both the miRNAs discovered and their target genes were closely associated with T2DM, demonstrating that they might be potential targets for the regulation of T2DM

Geochronology, geochemistry, and tectonic significance of the Shirenshan gneiss in the southern margin of the North China Block

The Shirenshan Block is a complex geological body located in the southern margin of the North China Block (NCB). From south to north, it can be divided into the Taihua Group migmatite, and the Shirenshan gneiss and magmatic rocks. The petrographic features, tectonic setting, provenance, and geological age of the Shirenshan gneiss using comprehensive field investigations, microstructural analysis, zircon U-Pb radioactive dating, and geochemical analyses were investigated for this study. The petrology, geochemistry, and geochronology of the Shirenshan gneiss suggests that it is mainly a felsic rock and its protolith was a high-K calc-alkaline series A-type granite. The protolith is high in SiO2, Al2O3, K2O, Na2O, and low in CaO and MgO. Overall, the Sr-Nd isotope composition of the samples showed no significant difference, indicating that the Taihua Group migmatite and the Shirenshan gneiss have the same source material. The Shirenshan block may be partially melted from the Taihua group and formed during activity of the Luo-Luan Fault. By the method of zircon dating analysis, the protolith age of the Shirenshan block was determined as 1559±16Ma (Early Proterozoic). Then, the crystallization age of the syntectonic migmatite is 439.2±7.6Ma, which was formed by subduction of the Taihua Group. During the early Cretaceous (119.5±1.3Ma), the Shirenshan gneiss may have experienced regional migmatization and formed the zircon rims age of the Yanshanian period. Litho-geochemical features of the Shirenshan block are similar to A1-type granites indicating that they are post-orogenic. Therefore, the metamorphic deformation of the Shirenshan gneiss reflects the tectonics in the southern margin of the NCB.</p

Maleic anhydride-modified chicken ovalbumin as an effective and inexpensive anti-HIV microbicide candidate for prevention of HIV sexual transmission

<p>Abstract</p> <p>Background</p> <p>Previous studies have shown that 3-hydroxyphthalic anhydride (HP)-modified bovine milk protein, β-lactoglobulin (β-LG), is a promising microbicide candidate. However, concerns regarding the potential risk of prion contamination in bovine products and carcinogenic potential of phthalate derivatives were raised. Here we sought to replace bovine protein with an animal protein of non-bovine origin and substitute HP with another anhydride for the development of anti-HIV microbicide for preventing HIV sexual transmission.</p> <p>Results</p> <p>Maleic anhydride (ML), succinic anhydride (SU) and HP at different conditions and variable pH values were used for modification of proteins. All the anhydrate-modified globulin-like proteins showed potent anti-HIV activity, which is correlated with the percentage of modified lysine and arginine residues in the modified protein. We selected maleic anhydride-modified ovalbumin (ML-OVA) for further study because OVA is easier to obtain than β-LG, and ML is safer than HP. Furthermore, ML-OVA exhibited broad antiviral activities against HIV-1, HIV-2, SHIV and SIV. This modified protein has no or low <it>in vitro </it>cytotoxicity to human T cells and vaginal epithelial cells. It is resistant to trypsin hydrolysis, possibly because the lysine and arginine residues in OVA are modified by ML. Mechanism studies suggest that ML-OVA inhibits HIV-1 entry by targeting gp120 on HIV-1 virions and also the CD4 receptor on the host cells.</p> <p>Conclusion</p> <p>ML-OVA is a potent HIV fusion/entry inhibitor with the potential to be developed as an effective, safe and inexpensive anti-HIV microbicide.</p

The gut metabolite indole-3-propionic acid activates ERK1 to restore social function and hippocampal inhibitory synaptic transmission in a 16p11.2 microdeletion mouse model

Background: Microdeletion of the human chromosomal region 16p11.2 (16p11.2+/−) is a prevalent genetic factor associated with autism spectrum disorder (ASD) and other neurodevelopmental disorders. However its pathogenic mechanism remains unclear, and efective treatments for 16p11.2+/− syndrome are lacking. Emerging evidence suggests that the gut microbiota and its metabolites are inextricably linked to host behavior through the gut-brain axis and are therefore implicated in ASD development. Despite this, the functional roles of microbial metabo‑ lites in the context of 16p11.2+/− are yet to be elucidated. This study aims to investigate the therapeutic potential of indole-3-propionic acid (IPA), a gut microbiota metabolite, in addressing behavioral and neural defcits associated with 16p11.2+/−, as well as the underlying molecular mechanisms. // Results: Mice with the 16p11.2+/− showed dysbiosis of the gut microbiota and a signifcant decrease in IPA levels in feces and blood circulation. Further, these mice exhibited signifcant social and cognitive memory impairments, along with hyperactivation of hippocampal dentate gyrus neurons and reduced inhibitory synaptic transmission in this region. However, oral administration of IPA efectively mitigated the histological and electrophysiological alterations, thereby ameliorating the social and cognitive defcits of the mice. Remarkably, IPA treatment signifcantly increased the phosphorylation level of ERK1, a protein encoded by the Mapk3 gene in the 16p11.2 region, with‑ out afecting the transcription and translation of the Mapk3 gene. // Conclusions: Our study reveals that 16p11.2+/− leads to a decline in gut metabolite IPA levels; however, IPA supple‑ mentation notably reverses the behavioral and neural phenotypes of 16p11.2+/− mice. These fndings provide new insights into the critical role of gut microbial metabolites in ASD pathogenesis and present a promising treatment strategy for social and cognitive memory defcit disorders, such as 16p11.2 microdeletion syndrome

Knowledge and Attitudes Towards Obesity and Bariatric Surgery in Chinese Nurses

Abstract Background Obesity has become a global epidemic. Surgical treatment of obesity and metabolic disorders in China is increasing rapidly, but it is still a new discipline even to health professionals. As an important member of the multidisciplinary team, the knowledge and attitudes of nurses provide crucial health care to the patients and support to surgeons. Objectives To study the Chinese nurses' knowledge of obesity and metabolic disorders, and attitudes towards bariatric surgery and to improve their capability of work in this new discipline. Methods This is a multicenter study, with the questionnaire distributed to cooperative hospitals in the form of an electronic questionnaire by the First Affiliated Hospital of Jinan University in April 2018. A questionnaire was designed to investigate nurses' demographic, knowledge, and attitude towards obesity, weight loss, and bariatric surgery. Results A total of 5311 questionnaires were received, with an effective rate of 91.8% (4878 questionnaires); 65.2% of nurses had a normal BMI. Nurses generally had a high knowledge of obesity and related cardiovascular diseases (98.6%) and type 2 diabetes mellitus (90.2%). However, there was a lack of knowledge in other related aspects, for example its relations to carcinoma (49.5%), gastroesophageal reflux disease (40.1%), and psychological disorders (49.1%), which are controversial issues in bariatric surgery. It was found that education (p < 0.05) had an important influence to nurses' knowledge about the comorbidities of obesity. Female nurses had a higher tendency to choose weight loss than males, but male nurses did physical exercise more frequently than females (p < 0.05). Their acceptance of safety (25.1%) and efficacy (22.9%) of bariatric surgery is low, with concerns predominantly about postoperative complications and adverse effects. Surgical nurses had a more optimistic attitude towards surgery (p < 0.05). Conclusions Chinese nurses have poor knowledge of obesity-related metabolic disorders and also have poor acceptance of surgical treatment modalities. Our findings suggest that it is crucial to enhance the continuing education of Chinese nurses for obesity, metabolic disorders, and bariatric surgery

3-Hydroxyphthalic Anhydride- Modified Rabbit Anti-PAP IgG as a Potential Bifunctional HIV-1 Entry Inhibitor

Several studies have reported that amyloid fibrils in human semen formed from a naturally occurring peptide fragment of prostatic acidic phosphatase (PAP248-286), known as semen-derived enhancer of viral infection (SEVI), could dramatically enhance human immunodeficiency virus type 1 (HIV-1) infection. Accordingly, SEVI might serve as a novel target for new antiviral drugs or microbicide candidates for the prevention of sexually transmitted HIV. Theoretically, a special anti-PAP or anti-SEVI antibody could reduce the enhancement of viral infection by blocking the binding of HIV and SEVI fibrils. Here, 3-hydroxyphthalic anhydride modified anti-PAP248-286 antibody, named HP-API, exhibited broad-spectrum and highly effective anti-HIV-1 activities on different subtypes and tropism. By using time-of-addition, cell–cell fusion and a single-cycle HIV-1 infection assays, we demonstrated that HP-API is an HIV-1 entry/fusion inhibitor. Mechanism studies suggest that HP-API inhibited HIV-1 entry/fusion by targeting both HIV-1 gp120 envelop and CD4 receptor on the host cell specifically. It is noteworthy that HP-API abrogated the formation of SEVI fibrils and partially interfered with SEVI-mediated enhancement of HIV-1 infection. Based on these findings, HP-API could be considered a bifunctional HIV-1 entry/fusion inhibitor with high potential

Emerging roles and potential application of PIWI-interacting RNA in urological tumors

The piRNA (PIWI-interacting RNA) is P-Element induced wimpy testis (PIWI)-interacting RNA which is a small molecule, non-coding RNA with a length of 24-32nt. It was originally found in germ cells and is considered a regulator of germ cell function. It can interact with PIWI protein, a member of the Argonaute family, and play a role in the regulation of gene transcription and epigenetic silencing of transposable factors in the nucleus. More and more studies have shown that piRNAs are abnormally expressed in a variety of cancer tissues and patient fluids, and may become diagnostic tools, therapeutic targets, staging markers, and prognostic evaluation tools for cancer. This article reviews the recent research on piRNA and summarizes the structural characteristics, production mechanism, applications, and its role in urological tumors, to provide a reference value for piRNA to regulate urological tumors