In adult ventricular myocytes, the slow delayed rectifier (I Ks ) channels are distributed on the surface sarcolemma, not t-tubules.r In adult ventricular myocytes, KCNQ1 and KCNE1 have distinct cell surface and cytoplasmic pools.r KCNQ1 and KCNE1 traffic from the endoplasmic reticulum to the plasma membrane by separate routes, and assemble into I Ks channels on the cell surface.r Liquid chromatography/tandem mass spectrometry applied to affinity-purified KCNQ1 and KCNE1 interacting proteins reveals novel interactors involved in protein trafficking and assembly.r Microtubule plus-end binding protein 1 (EB1) binds KCNQ1 preferentially in its dimer form, and promotes KCNQ1 to reach the cell surface.r An LQT1-associated mutation, Y111C, reduces KCNQ1 binding to EB1 dimer.

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Left maxillary permanent first molar showed minimum mean difference of measurements on study cast and introrally than right, thus better predictor for gender dimorphism in forensics.

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Background: Polycystic ovarian syndrome (PCOS) is one of the most frequently encountered endocrine disorders that occurs in as many as 4 to 10% of women of reproductive age group. It presents with a series of skin changes including acne, hirsutism, seborrhea, androgenetic alopecia (AGA) and acanthosis nigricans. Aim of the study was to determine the prevalence and frequency of different cutaneous manifestations in PCOS patients and to correlate them with the degree of hormonal abnormalities. Methods: A total 100 patients with features of PCOS who presented to department of dermatology, gynecology (January 2018-December 2019) with cutaneous manifestations were recorded and diagnosis of PCOS was made using Rotterdam's criteria. Pregnant women and diagnosed cases of any other endocrine disorder were excluded. Hirsutism was assessed using Ferriman-Gallwey score and AGA according to Ludwig's classification. Serum hormonal profile including FSH, LH, prolactin, testosterone (free), DHEAS, TSH, FBS, fasting insulin were done. Insulin resistance was determined by calculating HOMA-IR score. Results: Among cutaneous manifestations of PCOS, hirsutism (85%) was the most common finding followed by acne (73%), seborrhea (50%), AGA (36%), acanthosis nigricans (29%) and acrochordons (9%). The most common hormonal abnormality was insulin resistance in 53% patients, followed by raised free testosterone in 19% and serum prolactin in 18% patients. A statistically significant association was present between AGA and insulin resistance, hirsutism and raised prolactin levels, seborrhea and raised body mass index (p < 0.05). Conclusions: Dermatological manifestations of PCOS play a significant role in making the diagnosis and constitute a substantial portion of the symptoms experienced by women with this syndrome.

I Ks plays a key role in ventricular-repolarization during high b-adrenergic tone, and is composed of KCNQ1 (channel component) and KCNE1 (regulatory subunit). Although KCNQ1 and KCNE1 are obligate partners, we showed that they are largely segregated in AVMs: KCNQ1 mostly in cytosolic compartment while KCNE1 on lateral cell surface (LCS). Only a small portion of KCNQ1 appears to overlap with KCNE1 on LCS. To address the above question, we conduct proof-of-principle experiments by expressing fluorescent protein (FP)-tagged KCNQ1 and KCNE1 in COS-7 cells, and track their movements using confocal, TIRF and structured-illumination microscopies. We use a strategy called 'retention-using-selective-hooks' to differentiate how KCNQ1 and KCNE1 traffic after they exit the endoplasmic reticulum (ER). We use proximity-ligation-amplification (PLA) to locate KCNQ1/KCNE1 assemblies in cells. We conduct physiological experiments by in vitro or in vivo expression of FP-tagged KCNQ1 and KCNE1 in AVMs, using adenovirus or AAV9 respectively. We observe bright spots of KCNQ1-GFP moves within the ER network. When reaching cell edge, KCNQ1-GFP appears to bud off ER in vesicles and disappears presumably by fusing with the plasma membrane (PM). Vesicles of KCNE1-dsRed move in the cytoplasm, and often appear to drag KCNQ1-GFP/ER along tracks or carry bright spot of KCNQ1-GFP transiently. When expressed in AVMs, KCNQ1-GFP clusters to the nuclear envelope and along the z-lines and KCNE1-dsRed is detected in vesicles and LCS. KCNQ1-GFP/KCNE1-dsRed assemblies are present on the LCS and in the sub-sarcolemma compartment beneath LCS. We conclude that KCNQ1 and KCNE1 traffic by different routes to PM and assemble once there: KCNQ1 via an ER/SR route while KCNE1 via a vesicular route. KCNE1 appears capable of guiding KCNQ1 to exit ER/SR, facilitating the formation of I Ks channels on cell surface.

Sickle cell disease (SCD) is accompanied by several complications, which emanate from the sickling of erythrocytes due to a point mutation in the β-globin chain of hemoglobin. Sickled erythrocytes are unable to move smoothly through small blood capillaries and therefore, cause vaso occlusion and severe pain. Apart from pain, continuous lysis of fragile sickled erythrocytes leads to the release of heme, which is a strong activator of the NLRP3 inflammasome, thus producing chronic inflammation in sickle cell disease. In this study, we identified flurbiprofen among other COX-2 inhibitors to be a potent inhibitor of heme-induced NLRP3 inflammasome. We found that apart from being a nociceptive agent, flurbiprofen exerts a strong anti-inflammatory effect by suppressing NF-κB signaling, which was evidenced by reduced levels of TNF-α and IL-6 in wild-type and sickle cell disease Berkeley mice models. Our data further demonstrated the protective effect of flurbiprofen on liver, lungs, and spleen in Berkeley mice. The current sickle cell disease pain management regime relies mainly on opiate drugs, which is accompanied by several side effects without modifying the sickle cell disease-related pathology. Considering the potent role of flurbiprofen in inhibiting NLRP3 inflammasome and other inflammatory cytokines in sickle cell disease, our data suggests that it can be explored further for better sickle cell disease pain management along with the possibility of disease modification.