Zimmermanandreassen5665

SLC45A2 encodes a putative transporter expressed primarily in pigment cells. SLC45A2 mutations cause oculocutaneous albinism type 4 (OCA4) and polymorphisms are associated with pigmentation variation, but the localization, function, and regulation of SLC45A2 and its variants remain unknown. We show that SLC45A2 localizes to a cohort of mature melanosomes that only partially overlaps with the cohort expressing the chloride channel OCA2. SLC45A2 expressed ectopically in HeLa cells localizes to lysosomes and raises lysosomal pH, suggesting that in melanocytes SLC45A2 expression, like OCA2 expression, results in the deacidification of maturing melanosomes to support melanin synthesis. Interestingly, OCA2 overexpression compensates for loss of SLC45A2 expression in pigmentation. Analyses of SLC45A2- and OCA2-deficient mouse melanocytes show that SLC45A2 likely functions later during melanosome maturation than OCA2. Moreover, the light skin-associated SLC45A2 allelic F374 variant restores only moderate pigmentation to SLC45A2-deficient melanocytes due to rapid proteasome-dependent degradation resulting in lower protein expression levels in melanosomes than the dark skin-associated allelic L374 variant. Our data suggest that SLC45A2 maintains melanosome neutralization that is initially orchestrated by transient OCA2 activity to support melanization at late stages of melanosome maturation, and that a common allelic variant imparts reduced activity due to protein instability.Chaperones can mediate both protein folding and degradation. This process is referred to as protein triage, which demands study to reveal mechanisms of quality control for both basic scientific and translational purposes. In yeast, many misfolded proteins undergo chaperone-dependent ubiquitination by the action of the E3 ligases Ubr1 and San1, allowing detailed study of protein triage. In cells, both HSP70 and HSP90 mediated substrate ubiquitination, and the canonical ATP cycle was required for HSP70's role we have found that ATP hydrolysis by HSP70, the nucleotide exchange activity of Sse1, and the action of J-proteins are all needed for Ubr1-mediated quality control. To discern whether chaperones were directly involved in Ubr1-mediated ubiquitination, we developed a bead-based assay with covalently immobilized but releasable misfolded protein to obviate possible chaperone effects on substrate physical state or transport. In this in vitro assay, only HSP70 was required, along with its ATPase cycle and relevant cochaperones, for Ubr1-mediated ubiquitination. The requirement for the HSP70 ATP cycle in ubiquitination suggests a possible model of triage in which efficiently folded proteins are spared, while slow-folding or nonfolding proteins are iteratively tagged with ubiquitin for subsequent degradation.Significance Since the last Food and Drug Administration (FDA) approval of a wound healing therapeutic in 1997, no new therapeutic candidate (excluding physical therapies, devices, dressings, and antimicrobial agents) has advanced to clinical applications. During this period, the FDA drug approvals for tumors, which have been referred to as "wounds that do not heal," have reached a total of 284 (by end of 2018). Both political and scientific factors may explain this large discrepancy in drug approvals for the two seemingly related and equally complex pathophysiological conditions. Recent Advances Using the current research funding ratio of 1150 for wound healing to cancer and the 5% FDA drug approval rate for oncology, we reach a crude estimate of a 0.03% success rate for wound healing therapeutics. Unless a drastic improvement of the current situation, we express a pessimistic outlook toward new and effective wound healing drugs. Critical Issues We argue that successful development of wound healing therapeutics will rely on identification of wound healing driver genes (WDGs), and the focus should be on WDGs for the wound closure phase of wound healing. Therefore, WDGs must be both necessary and sufficient for wound closure; the absence of a WDG disrupts wound closure, while its supplementation alone is sufficient to restore full wound closure. Successful translation of a WDG into therapeutics requires availability of well-defined animal models with a high degree of relevance to humans. This review discusses the main hurdles faced by the wound healing research community behind the development of so-called "rescuing drugs" for wound healing. Future Directions Given the lack of new wound healing drugs for the past 23 years, there is a need for a wide range of fresh, innovative, and thorough debates on wound healing drug development, including an organized movement to raise public support for wound healing research.

Opioid prescribing patterns play an important role in the opioid epidemic in the United States. this website The purpose of this study is to examine the trends and geographic variation in opioid prescribing patterns after anterior cruciate ligament (ACL) reconstruction.

Regional differences in opioid prescribing patterns after ACL reconstruction are present.

Descriptive epidemiology study.

Level 4.

The Truven Health MarketScan Commercial Claims database was used to analyze all patients with perioperative private insurance coverage who underwent ACL reconstruction from January 1, 2010, to November 31, 2017. Total number and morphine milligram equivalents per day (MMED) of opioid prescriptions were examined, and regional and statewide variation was assessed.

A total of 90,068 ACL reconstruction patients who underwent surgery between 2010 and 2017 were included in the study. Overall, 67% received an opioid prescription within 30 days of surgery and 17% received an opioid prescription ≥90 MMED. The West (20%) had atterns after specific procedures may help provide more direct insight and guidance to surgeons and patients regarding postoperative pain management.

Knowledge of prescribing patterns after specific procedures may help provide more direct insight and guidance to surgeons and patients regarding postoperative pain management.We read with interest the article "Role of Ultra-widefield Imaging in Eales' Disease A Case Series" by Agarwal et al. We would like to congratulate the authors for their nice work and make few observations. We noted few discrepancies between the results and conclusions. Results revealed disease activity in 10/57 (17.5%), 20/57 (35%), and 29/57 (50.9%) patient visits with clinical examination, UWF Optos imaging, and wide-field FFA respectively. However, authors conclude that "ultra-widefield imaging is a very helpful tool in the management of a patient with Eales'disease." This is in spite of the fact that widefield FA resulted in better documentation in 56% of the patient visits in their series. Widefield FA detected significantly more number of active vasculitis as compared to Optos, and alteration in the treatment plan was done in 18/57 (31.6%) patient visits based on FA.