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Lentiviral vectors (LV) have been developed upon knowledge accumulated in the virology field, in particular intensive research on HIV biology since its discovery in 1983 [...].Lentiviral vectors (LV) have been developed upon knowledge accumulated in the virology field, in particular intensive research on HIV biology since its discovery in 1983 [...].

The human integral membrane protein SERINC5 potently restricts HIV-1 infectivity and sensitizes the virus to antibody-mediated neutralization. Here, using cryo-EM, we determine the structures of human SERINC5 and its orthologue from Drosophila melanogaster at subnanometer and near-atomic resolution, respectively. The structures reveal a novel fold comprised of ten transmembrane helices organized into two subdomains and bisected by a long diagonal helix. A lipid binding groove and clusters of conserved residues highlight potential functional sites. A structure-based mutagenesis scan identified surface-exposed regions and the interface between the subdomains of SERINC5 as critical for HIV-1-restriction activity. The same regions are also important for viral sensitization to neutralizing antibodies, directly linking the antiviral activity of SERINC5 with remodeling of the HIV-1 envelope glycoprotein.Cryo-EM structures of human SERINC5 and its fly orthologue, along with extensive functional analyses, reveal the protein architecture and identify regions important for HIV-1 restriction.

We study the basic age-structured population model describing the HIV infection process, which is defined by PDEs. The model allows the production rate of viral particles and the death rate of productively infected cells to vary and depend on the infection age. By using the direct Lyapunov method and constructing suitable Lyapunov functions, dynamical properties of the agestructured model without (or with) drug treatment are established. The results show that the global asymptotic stability of the infection-free steady state and the infected steady state depends only on the basic reproductive number determined by the burst size. Further, we establish mathematically that the typical ODE and DDE (delay differential equation) models of HIV infection are equivalent to two special cases of the above PDE models.

Accumulating evidence has shown that patients with lifestyle diseases such as type 2 diabetes mellitus, chronic kidney disease, and chronic obstructive pulmonary disease are at increased risk of osteoporotic fracture. Fractures deteriorate quality of life, activities of daily living, and mortality as well as a lifestyle disease. Therefore, preventing fracture is an important issue for those patients. Although the mechanism of the lifestyle diseases-induced bone fragility is still unclear, not only bone mineral density (BMD) reduction but also bone quality deterioration are involved in it. Because fracture predictive ability of BMD and FRAX® is limited, especially for patients with lifestyle diseases, the optimal management strategy should be established. Thus, when the intervention of the lifestyle diseases-induced bone fragility is initiated, the deterioration of bone quality should be taken into account. We here review the association between lifestyle diseases and fracture risk and proposed an algorism of starting anti-osteoporosis drugs for patients with lifestyle diseases.

Background Carotid webs are increasingly recognized as potential sources of ischemic stroke among young patients without conventional cardiovascular risk factors. However, its pathophysiological mechanism remains unclear. We report a case in which a carotid web was resected via carotid endarterectomy (CEA), allowing for histological analysis. Patient presentation In a 49-year-old male, stenosis of the left internal carotid artery occurred via magnetic resonance imaging for medical examination. Carotid ultrasonography revealed turbulent blood flow around a flap-like lesion, which was consistent with a carotid web. Because this hemodynamic disturbance may increase the risk of ischemic stroke, CEA was performed. Histopathological examination revealed intimal hyperplasia with the accumulation of myofibroblast-like cells. Conclusion Our pathological findings revealed intimal thickening and fibrosis and proliferation of SMA-positive, desmin-negative myofibroblast-like cells, suggesting that the dysregulation of myofibroblasts may underlie the pathogenesis of carotid webs.

A delay differential equation model of an infectious disease is considered and analyzed. In this model, the impact of information due to the presence of infection is considered explicitly. As information propagation is dependent on the prevalence of the disease, the delay in reporting the prevalence is an important factor. Further, the time lag in waning immunity related to protective measures (such as vaccination, self-protection, responsive behaviour etc.) is also accounted. Qualitative analysis of the equilibrium points of the model is executed and it is observed that when the basic reproduction number is less unity, the local stability of the disease free equilibrium (DFE) depends on the rate of immunity loss as well as on the time delay for the waning of immunity. If the delay in immunity loss is less than a threshold quantity, the DFE is stable, whereas, it loses its stability when the delay parameter crosses the threshold value. When, the basic reproduction number is greater than unity, the unique endemic equilibrium point is found locally stable irrespective of the delay effect under certain parametric conditions. Further, we have analyzed the model system for different scenarios of both delays (i.e., no delay, only one delay, and both delay present). Due to these delays, oscillatory nature of the population is obtained with the help of Hopf bifurcation analysis in each scenario. Moreover, at two different time delays (delay in information's propagation), the emergence of multiple stability switches is investigated for the model system which is termed as Hopf-Hopf (double) bifurcation. Also, the global stability of the endemic equilibrium point is established under some parametric conditions by constructing a suitable Lyapunov function irrespective of time lags. In order to support and explore qualitative results, exhaustive numerical experimentations are carried out which lead to important biological insights and also, these results are compared with existing results.

In this article, we have presented a mathematical model to study the dynamics of hepatitis C virus (HCV) disease considering three populations namely the uninfected liver cells, infected liver cells, and HCV with the aim to control the disease. The model possesses two equilibria namely the disease-free steady state and the endemically infected state. There exists a threshold condition (basic reproduction number) that determines the stability of the disease-free equilibrium and the number of the endemic states. We have further introduced impulsive periodic therapy using DAA into the system and studied the efficacy of the DAA therapy for hepatitis C infected patients in terms of a threshold condition. Finally, impulse periodic dosing with varied rate and time interval is adopted for cost effective disease control for finding the proper dose and dosing interval for the control of HCV disease.

Clinically nonfunctioning pituitary adenomas (NFAs) may be hormonally inactive tumors of differentiated cells, mainly not only gonadotroph adenomas (GAs) but also silent corticotroph adenomas (SCAs) and other differentiated silent adenomas. Recently, the use of transcription factors has been recommended to confirm cytodiffererentiation of these neoplasms. Our objective was to assess the clinical significance of the new classification system using transcription factors. Five hundred sixteen consecutive NFAs were studied retrospectively. They were initially classified based on hormone immunohistochemistry as follows: 119 hormone-negative adenomas (23.1 %), 300 GAs (58.1 %), 51 SCAs (9.9 %), and 46 other silent adenomas. The 119 hormone-negative adenomas were further evaluated for expression of transcription factors including steroidogenic factor-1 (SF-1), estrogen receptor-α (ERα), pituitary-specific transcription factor 1 (Pit-1), and t-box transcription factor (Tpit). One hundred thirteen of 119 (95 %) hormone-negative adenomas showed mutually exclusive lineage-specific differentiation as gonadotrophs (SF-1 positive), corticotrophs (Tpit positive), or somatotrophs/mammosomatotrophs/lactotrophs/thyrotrophs (Pit-1 positive) in 79 cases (66.4 %), 32 cases (26.9 %), and 2 cases, respectively. The 32 ACTH-negative and Tpit-positive adenomas had higher pro-opiomelanocortin mRNA expression levels compared with GAs ( P  = 0.0001) on quantitative real-time PCR. They showed a female preponderance ( P  < 0.0001) and were more frequently giant adenomas ( P  = 0.0028) associated with marked cavernous sinus invasion ( P  < 0.0001) compared with GAs. These clinical features were identical to those of the 51 ACTH-positive SCAs. Our results justify the complementary role of transcription factors in the precise classification of NFAs that can more accurately characterize biological behavior. Our data suggest that more than one quarter of hormone-negative adenomas are SCAs that share distinct clinicopathological features with ACTH-expressing SCAs.

Purpose Several osteoanabolic agents have been developed to build new bone more efficiently than anti-resorptive drugs. Among them, romosozumab, an anti-sclerostin antibody, is a potent pharmacological tool to prevent fractures in osteoporosis patients. The efficacy of romosozumab in preventing osteoporotic fractures is robust. However, there remains a concern about increased cardiovascular (CV) adverse events related to romosozumab. Available data have been reviewed to address this concern. Methods Published articles on romosozumab of which pivotal randomized controlled trials (RCTs), meta-analyses of RCTs, pharmacovigilance investigations, and retrospective observational clinical studies using real-world data were collected through PubMed and other available tools. Results Meta-analyses of RCTs of romosozumab compared to placebo and other anti-osteoporosis drugs have left room for controversy in the CV safety of romosozumab. Investigations of the real-world data also provide no conclusive evidence in this issue. Conclusion We need more robust evidence to establish an appropriate and reasonable guide to prescribe romosozumab in our clinical practice.

IntroductionPrimary hyperparathyroidism (PHPT) is caused by parathyroid adenoma, primary parathyroid hyperplasia, or parathyroid carcinoma. For some patients with PHPT controlling serum calcium levels is critical.Materials and methodsWe conducted an open-label, single-arm, 52-week, phase III study in Japanese patients with hypercalcemia due to PHPT to demonstrate efficacy and safety of evocalcet, a new calcimimetic. Patients with intractable PHPT (n = 13), postsurgical recurrence (n = 2), and parathyroid carcinoma (n = 3) were enrolled. Evocalcet administration started at a dose of 2 mg once or twice daily and was titrated to achieve the target serum corrected calcium (cCa) concentration (≤ 10.3 mg/dL) for two consecutive weeks (maximal dose 24 mg/day).ResultsFourteen patients achieved the target (77.8%; 95% confidence interval [CI] 52.4–93.6). The lower limit of 95% CI exceeded the predetermined reference limit (11%), and thus, efficacy was confirmed. Of 18 patients, 12 (66.7%; 95% CI 41.0–86.7) showed decreased serum cCa of ≥ 1.0 mg/dL from the baseline for two consecutive weeks during the titration phase. Sixteen patients entered the maintenance phase, and 15 patients completed the study. Treatment-emergent adverse events (TEAEs) were recorded in 18/18 patients (100%) and drug-related TEAEs in 8/18 (44.4%). The most commonly observed drug-related TEAE was nausea (2/18 patients). No unexpected drug-related TEAEs were observed. All drug-related TEAEs were mild in severity. No patient discontinued the study because of drug-related TEAEs.ConclusionEvocalcet demonstrated long-term effectiveness in reducing serum cCa concentrations and safety without any unexpected drug-related TEAEs in PHPT patients.