Search

Abstract Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of compounds transported by OCT1, such as those used for cardiovascular, oncological, and psychological indications. Despite its importance in drug pharmacokinetics, the substrate selectivity and underlying structural mechanisms of OCT1 remain poorly understood. Here, we present cryo-EM structures of full-length human OCT1 in the inward-open conformation, both ligand-free and drug-bound, indicating the basis for its broad substrate recognition. Comparison of our structures with those of outward-open OCTs provides molecular insight into the alternating access mechanism of OCTs. We observe that hydrophobic gates stabilize the inward-facing conformation, whereas charge neutralization in the binding pocket facilitates the release of cationic substrates. These findings provide a framework for understanding the structural basis of the promiscuity of drug binding and substrate translocation in OCT1.

This semi-analytical study is presented examining the quasi-steady creeping flow caused by a soft (composite) spherical particle, which is a hard (impermeable) sphere core covered by a porous (permeable) layer, translating in an incompressible Newtonian fluid within a non-concentric spherical cavity along the line joining their centers. To solve the Brinkman and Stokes equations for the flow fields inside and outside the porous layer, respectively, general solutions are constructed in two spherical coordinate systems attached to the particle and cavity individually. The boundary conditions at the cavity wall and particle surface are fulfilled through a collocation method. Numerical results of the normalized drag force exerted by the fluid on the particle are obtained for numerous values of the ratios of core-to-particle radii, particle-to-cavity radii, the distance between the centers to the radius difference of the particle and cavity, and the particle radius to porous layer permeation length. For the translation of a soft sphere within a concentric cavity or near a small-curvature cavity wall, our drag results agree with solutions available in the literature. The cavity effect on the drag force of a translating soft sphere is monotonically increasing functions of the ratios of core-to-particle radii and the particle radius to porous layer permeation length. While the drag force generally rises with an increase in the ratio of particle-to-cavity radii, a weak minimum (surprisingly, smaller than that for an unconfined soft sphere) may occur for the case of low ratios of core-to-particle radii and of the particle radius to permeation length. This drag force generally increases with an increase in the eccentricity of the particle position, but in the case of low ratios of core-to-particle radii and particle radius to permeation length, the drag force may decrease slightly with increasing eccentricity.

Cryo-EM structures of E. coli F1Fo ATP synthase highlight the role of the inhibitory ε subunit in regulating the torsional movement of the central stalk within the Fo motor and central stalk flexibility in coupling the F1 and Fo motors.

F1Fo ATP synthase consists of two coupled rotary molecular motors: the soluble ATPase F1 and the transmembrane Fo. Here, the authors present cryo-EM structures of E. coli ATP synthase in four discrete rotational sub-states at 3.1-3.4 Å resolution and observe a rotary sub-step of the Fo motor cring that reveals the mechanism of elastic coupling between the two rotary motors, which is essential for effective ATP synthesis.

Background: Primary cardiac angiosarcomas, especially those originating in the pericardium, are extremely rare and aggressive tumors with poor prognosis. These types of malignant tumors have diverse clinical presentations and are often masked by other comorbidities.Case Summary: Our hospital reported a 59-year-old woman who initially presented with pulmonary thromboembolism (PTE) and was subsequently treated with low-molecular-weight heparin. However, she experienced acute pericardial tamponade after anticoagulation therapy, where no obvious mass was primarily identified upon imaging, both in the pericardium or within the heart. Emergency pericardiocentesis and drainage were performed, where a total of 210 mL of bloody effusion was drained. Four months later, she was hospitalized with progressive hemoptysis and dyspnea. A large mixed mass occupying the right pericardium was later identified by coronary computed tomography angiography (CCTA). The mass was consistent with the right atrium, with heterogeneous thickened pericardium and localized moderate pericardial effusion. CCTA and positron emission tomography scans later showed metastases in both lungs and bilateral pleura. Nodules in hilar and mediastinal lymph nodes were also significant. Ultrasound-guided biopsy was performed, and the patient was ultimately diagnosed with an angiosarcoma based on final positive results for both CD31 and CD34 markers. The patient refused chemotherapy and passed away while waiting for her pathology results. The patient survived for 6 months since the first reported episode of PTE.Conclusions: Our case indicates that patients presenting with both embolism and hemorrhage should urgently be channeled to a clinical specialist to confirm any malignant etiology. This would be beneficial to confirm an early diagnosis and lengthen the duration of patient survival. However, the diagnosis of primary cardiac angiosarcoma is still challenging and requires multiple imaging modalities and biopsies in order to assist the accurate diagnosis of disease and achieve effective patient management.

We describe an easy-to-assemble and robust design of a ConFlat (CF) iris diaphragm device installed in a vacuum environment with its aperture size directly adjustable by users outside the vacuum. This design involves commercially available vacuum equipment, 3D-printed but vacuum-compatible components and a minimal need of professional machining to be straightforwardly taken advantage by a wide range of research groups. The iris diaphragm is centered in a 4.5 in. o.d. double-sided CF flange with user-customizable mounting orientation to allow a maximum range of aperture opening from 0.5 mm to 15 mm in diameter. Installation of this device does not require an additional pump for differential pumping across the iris diaphragm. The functionality of this device is examined at a pressure of ∼7 ×10−9 Torr to provide continuous control on the cross section of a light beam passed through the aperture.

The nasal mucosa provides first line defense against inhaled pathogens while creating a unique microenvironment for bacterial communities. Studying the impact of microbiota in the nasal cavity has been difficult due to limitations with current models including explant cultures, primary cells, or neoplastic cell lines. Most notably, none have been shown to support reproducible colonization by bacterial communities from human donors. Therefore, to conduct controlled studies of the human nasal ecosystem, we have developed a novel ex vivo mucosal model that supports bacterial colonization of a cultured host mucosa created by immortalized human nasal epithelial cells (NEC). For this model, immortalized NEC established from 5 male and 5 female donors were cultured with an air-interfaced, apical surface on a porous transwell membrane. NEC were grown from nasal turbinate tissues harvested from willed bodies or from discarded tissue collected during sinonasal procedures. Immortalized cells were evaluated through molecular verification of cell type, histological confirmation of tissue differentiation including formation of tight junctions, NEC multilayer viability, metabolism, physiology and imaging of the luminal surface by scanning electron microscopy. Results showed proper differentiation and multilayer formation at seven to 10 days after air interface that was maintained for up to 3 weeks. The optimized mucosal cultures created an environment necessary to sustain colonization by nasal microbiomes (NMBs) that were collected from healthy volunteers, cryogenically preserved and characterized with customized quantitative polymerase chain reaction (qPCR) arrays. Polymicrobial communities of nasal bacteria associated with healthy and inflamed states were consistently reproduced in matured NEC co-cultures by transplant of NMBs from multiple community types. The cultured NMBs were stable after an initial period of bacterial replication and equilibration. This novel ex vivo culture system is the first model that supports controlled cultivation of NMBs, allowing for lab-based causation studies and further experimentation to explore the complexities of host-microbe and microbe-microbe interactions.

Background: Patient satisfaction is one of the essential indicators for assessing the quality of healthcare services being delivered, including pharmacy ambulatory care service, as it determines the practicability and sustainability of the service provided. As such, pharmaceutical care services provided during medication therapy adherence clinic (MTAC) sessions need to be assessed to maximise its effectiveness and benefits to the patients. Objective: This study aimed to assess the association between patient satisfaction and socio-demographic characteristics, as well as the predictors for patient satisfaction. Methods: This was a cross-sectional study conducted at the medical outpatient department in Hospital Port Dickson from January until October 2019. Convenience sampling method was used to recruit potential study participants. Patient satisfaction was measured using Validated Patient Satisfaction with Pharmacist Services Questionnaire (PSPSQ2.0), consisted of quality of care and interpersonal relationship between pharmacist and patient domains. Descriptive data were presented as mean and standard deviation or numbers and percentages, while Independent Sample t-test, ANOVA and post-hoc analysis, and multiple linear regression were used for inferential data analysis. Results: There were 37 (25%) diabetes MTAC, 36 (24.3%) respiratory MTAC, and 75 (50.7%) warfarin MTAC patients recruited. On average, the mean overall satisfaction score was 3.30(SD=0.43). The mean satisfaction score in the interpersonal relationship domain [3.35(SD=0.44)] was higher than the quality of care domain [3.26(SD=0.45)]. There was a significant association between gender, education level, and patient satisfaction towards pharmaceutical care service (p

Human induced pluripotent stem cells (iPSCs) can be differentiated in vitro into bona fide cardiomyocytes for disease modelling and personalized medicine. Mitochondrial morphology and metabolism change dramatically as iPSCs differentiate into mesodermal cardiac lineages. Inhibiting mitochondrial fission has been shown to promote cardiac differentiation of iPSCs. However, the effect of hydrazone M1, a small molecule that promotes mitochondrial fusion, on cardiac mesodermal commitment of human iPSCs is unknown. Here, we demonstrate that treatment with M1 promoted mitochondrial fusion in human iPSCs. Treatment of iPSCs with M1 during embryoid body formation significantly increased the percentage of beating embryoid bodies and expression of cardiac-specific genes. The pro-fusion and pro-cardiogenic effects of M1 were not associated with changes in expression of the α and β subunits of adenosine triphosphate (ATP) synthase. Our findings demonstrate for the first time that hydrazone M1 is capable of promoting cardiac differentiation of human iPSCs, highlighting the important role of mitochondrial dynamics in cardiac mesoderm lineage specification and cardiac development. M1 and other mitochondrial fusion promoters emerge as promising molecular targets to generate lineages of the heart from human iPSCs for patient-specific regenerative medicine.

BAFF, an activator of the noncanonical NFκB pathway, provides critical survival signals during B cell maturation and contributes to B cell proliferation. We found that the NFκB family member RelB is required ex vivo for B cell maturation, but cRel is required for proliferation. Combined molecular network modeling and experimentation revealed Nfkb2 p100 as a pathway switch; at moderate p100 synthesis rates in maturing B cells, BAFF fully utilizes p100 to generate the RelB:p52 dimer, whereas at high synthesis rates, p100 assembles into multimeric IκBsome complexes, which BAFF neutralizes in order to potentiate cRel activity and B cell expansion. Indeed, moderation of p100 expression or disruption of IκBsome assembly circumvented the BAFF requirement for full B cell expansion. Our studies emphasize the importance of p100 in determining distinct NFκB network states during B cell biology, which causes BAFF to have context-dependent functional consequences.

In this paper, we present a simple direct proof of an integration lemma due to Barsegian, Sergeev and Montes-Rodrigues, and extend to rational functions their upper estimates on the total length of Gamma-lines in complex plane. [ABSTRACT FROM AUTHOR]

Limited experimental research has been conducted on organic Rankine cycle (ORC) systems that use wet working fluids. Therefore, the present study examined how the performance of an ORC system that uses a wet working fluid (R134a) was affected by the superheat degree ratio (SDR) under various scroll rotation speeds. The SDR is the dimensionless ratio between superheat degree and evaporation temperature at a given heat source temperature. Experimental results indicated that at scroll rotation speeds of 900, 1350, and 1800 rpm, the maximum output power of the aforementioned system was 1103, 1464, and 1537 W, respectively, with SDRs of 0.49, 0.49, and 0.54, respectively. The maximum net efficiencies at these speeds were 5.87%, 5.91%, and 5.32%, respectively, which occurred at SDRs of 0.61, 0.49, and 0.48, respectively. This level of system performance was attributable to the high enthalpy at the expander inlet and the high mass flow rate at the high evaporation pressure under an SDR of approximately 0.5. Although increasing the SDR did not enhance the scroll expander's isentropic efficiency, this efficiency decreased considerably when the SDR fell below 0.2. These findings emphasize the importance of optimizing the SDR of ORC systems to improve their performance. [ABSTRACT FROM AUTHOR]

This semi-analytical study is presented examining the quasi-steady creeping flow caused by a soft (composite) spherical particle, which is a hard (impermeable) sphere core covered by a porous (permeable) layer, translating in an incompressible Newtonian fluid within a non-concentric spherical cavity along the line joining their centers. To solve the Brinkman and Stokes equations for the flow fields inside and outside the porous layer, respectively, general solutions are constructed in two spherical coordinate systems attached to the particle and cavity individually. The boundary conditions at the cavity wall and particle surface are fulfilled through a collocation method. Numerical results of the normalized drag force exerted by the fluid on the particle are obtained for numerous values of the ratios of core-to-particle radii, particle-to-cavity radii, the distance between the centers to the radius difference of the particle and cavity, and the particle radius to porous layer permeation length. For the translation of a soft sphere within a concentric cavity or near a small-curvature cavity wall, our drag results agree with solutions available in the literature. The cavity effect on the drag force of a translating soft sphere is monotonically increasing functions of the ratios of core-to-particle radii and the particle radius to porous layer permeation length. While the drag force generally rises with an increase in the ratio of particle-to-cavity radii, a weak minimum (surprisingly, smaller than that for an unconfined soft sphere) may occur for the case of low ratios of core-to-particle radii and of the particle radius to permeation length. This drag force generally increases with an increase in the eccentricity of the particle position, but in the case of low ratios of core-to-particle radii and particle radius to permeation length, the drag force may decrease slightly with increasing eccentricity. [ABSTRACT FROM AUTHOR]

This study presents an integrated approach combining surface‐enhanced Raman spectroscopy (SERS) with a specialized deep learning algorithm, SFNet, to offer a rapid, accurate, and label‐free alternative for COVID‐19 diagnosis and viral load quantification. The SiO2‐coated silver nanorod arrays are employed as the SERS substrates, fabricated using a reliable and effective glancing angle deposition technique. A dataset of 4800 SERS spectra from 120 positive and 120 negative inactivated clinical human nasopharyngeal swabs are collected directly on the SERS substrates without any labels. A SFNet algorithm is tailored to adapt to the unique spectral features inherent to SERS data, achieving a test accuracy of 98.5% and a blind test accuracy of 99.04%. Moreover, an optimized SFNet algorithm unveils the capability of estimating SARS‐CoV‐2 viral loads, accurately predicting the cycle threshold values (Ct values) of the three vital gene fragments with a root mean square error (RMSE) of 1.627 (1.3 for blind test). The methodology is substantiated using actual clinical specimens and completed in <15 min, thereby strengthening its real‐world point‐of‐care applicability. This rapid and precise yet label‐free modality competes favorably with classical reverse‐transcription real‐time polymerase chain reaction (RT‐PCR) and marks an advancement in SERS‐based sensor algorithms. [ABSTRACT FROM AUTHOR]