Disrupting Roquin-1 interaction with Regnase-1 induces autoimmunity and enhances antitumor responses.

Roquin and Regnase-1 proteins bind and post-transcriptionally regulate proinflammatory target messenger RNAs to maintain immune homeostasis. Either the sanroque mutation in Roquin-1 or loss of Regnase-1 cause systemic lupus erythematosus-like phenotypes. Analyzing mice with T cells that lack expression of Roquin-1, its paralog Roquin-2 and Regnase-1 proteins, we detect overlapping or unique phenotypes by comparing individual and combined inactivation. These comprised spontaneous activation, metabolic reprogramming and persistence of T cells leading to autoimmunity. Here, we define an interaction surface in Roquin-1 for binding to Regnase-1 that included the sanroque residue. Mutations in Roquin-1 impairing this interaction and cooperative regulation of targets induced T follicular helper cells, germinal center B cells and autoantibody formation. These mutations also improved the functionality of tumor-specific T cells by promoting their accumulation in the tumor and reducing expression of exhaustion markers. Our data reveal the physical interaction of Roquin-1 with Regnase-1 as a hub to control self-reactivity and effector functions in immune cell therapies.

Novel Nanoencapsulation Technology and its Potential Role in Bile Acid-Based Targeted Gene Delivery to the Inner Ear.

Hearing loss impacts a large proportion of the global population. Damage to the inner ear, in particular the sensitive hair cells, can impact individuals for the rest of their lives. There are very limited options for interventions after damage to these cells has occurred. Targeted gene delivery may provide an effective means to trigger appropriate differentiation of progenitor cells for effective replacement of these sensitive hair cells. There are several hurdles that need to be overcome to effectively deliver these genes. Nanoencapsulation technology has previously been used for the delivery of pharmaceuticals, proteins and nucleic acids, and may provide an effective means of delivering genes to trigger appropriate differentiation. This review investigates the background of hearing loss, current advancements and pitfalls of gene delivery, and how nanoencapsulation may be useful.

Evaluating the Efficacy and Pharmacoeconomics of Semaglutide and Tirzepatide in the Setting of Obesity.

BACKGROUND: Obesity is a major and growing public health concern. The associated cost for obesity and its related comorbidities is approximately 30% of US health care expenditures annually. As additional pharmacotherapeutic options join the market to combat obesity, it is important to understand the financial impact it may have on overall health care costs. This article explores the efficacy and pharmacoeconomics of incretin mimetics, semaglutide and tirzepatide, in the setting of obesity. AREA OF UNCERTAINTY: The cost of incretin mimetics (semaglutide and tirzepatide) and its overall impact on obesity management within the health care arena is being explored. The cost comparison of these medications is to be determined; however, it may represent an added cost to the total US health care expenditures. DATA SOURCES: A PubMed and Google Scholar search was conducted using various search terms (eg, semaglutide, tirzepatide, pharmacoeconomics, and obesity). THERAPEUTIC ADVANCES: Based on the data reviewed, both semaglutide and tirzepatide are effective medication options for obesity management. Obesity-related management expenditures exceed $173 billion for the US health care system annually. The cost needed to treat for 1% of weight loss with semaglutide and tirzepatide was reported as $1845 and $985, respectively. More than 40% of adults (60 years or older) experience obesity. If 1%, 5%, or 10% of this population is treated with semaglutide, the annual Medicare costs will translate to excess of $2.6 billion, $13.3 billion, and $26.8 billion, respectively. Tirzepatide is not yet approved in the United States for obesity and its financial impact remains to be seen. CONCLUSIONS: Obesity is associated with burdensome health complications and costs. Semaglutide and tirzepatide are effective drug options for the management of obesity. The cost of these medications will no doubt present a challenge to the total health care expenditures, although the cost-benefit ratio may ultimately be favorable.

Tirzepatide: A Dual Glucose-dependent Insulinotropic Polypeptide and Glucagon-Like Peptide-1 Agonist for the Management of Type 2 Diabetes Mellitus.

BACKGROUND: Diabetes is a chronic disease that can lead to many complications, and controlling glucose balance is essential. Incretin hormones are produced in the gut and are essential to maintaining glucose homeostasis. Their effects range from increasing insulin synthesis, insulin secretion, and glucose sensing and decreasing glucagon secretion to promote satiety and suppressing appetite. Tirzepatide is a first in class dual glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GIP) analog approved for the management of adult patients with type 2 diabetes mellitus as an adjunct to diet and exercise. PHARMACODYNAMICS AND PHARMACOKINETICS: Tirzepatide is a synthetic chemical structure based on the GIP sequence and consists of 39 amino acid peptides. Tirzepatide increases insulin secretion, reduces glucagon release in a glucose-dependent manner, decreases fasting and postprandial glucose levels, promotes satiety, decreases body weight, and delays gastric emptying. Pharmacodynamics and pharmacokinetics properties of tirzepatide were similar in patients with kidney and hepatic impairment, and its metabolites are excreting through urine and feces. CLINICAL TRIALS: The SURPASS trials are pivotal phase 3 trials assessing the efficacy and safety of tirzepatide as monotherapy and as an add-on to different antihyperglycemic drugs for the management of T2DM. Tirzepatide consistently showed reductions in HbA1c, as well as benefits with weight loss, with common adverse events reported related to gastrointestinal issues. THERAPEUTIC ADVANCE: Tirzepatide is a novel first in class dual GIP and glucagon-like peptide-1 agonist that improves overall glycemic control as an adjunct to diet and exercise. It has the potential benefits in other therapeutic areas such as obesity.

Dynamic changes in cis-regulatory occupancy by Six1 and its cooperative interactions with distinct cofactors drive lineage-specific gene expression programs during progressive differentiation of the auditory sensory epithelium.

The transcription factor Six1 is essential for induction of sensory cell fate and formation of auditory sensory epithelium, but how it activates gene expression programs to generate distinct cell-types remains unknown. Here, we perform genome-wide characterization of Six1 binding at different stages of auditory sensory epithelium development and find that Six1-binding to cis-regulatory elements changes dramatically at cell-state transitions. Intriguingly, Six1 pre-occupies enhancers of cell-type-specific regulators and effectors before their expression. We demonstrate in-vivo cell-type-specific activity of Six1-bound novel enhancers of Pbx1, Fgf8, Dusp6, Vangl2, the hair-cell master regulator Atoh1 and a cascade of Atoh1's downstream factors, including Pou4f3 and Gfi1. A subset of Six1-bound sites carry consensus-sequences for its downstream factors, including Atoh1, Gfi1, Pou4f3, Gata3 and Pbx1, all of which physically interact with Six1. Motif analysis identifies RFX/X-box as one of the most significantly enriched motifs in Six1-bound sites, and we demonstrate that Six1-RFX proteins cooperatively regulate gene expression through binding to SIX:RFX-motifs. Six1 targets a wide range of hair-bundle regulators and late Six1 deletion disrupts hair-bundle polarity. This study provides a mechanistic understanding of how Six1 cooperates with distinct cofactors in feedforward loops to control lineage-specific gene expression programs during progressive differentiation of the auditory sensory epithelium.

Localization of TMC1 and LHFPL5 in auditory hair cells in neonatal and adult mice.

The channel that governs mechanotransduction (MT) by hair cells in the inner ear has been investigated intensively for 4 decades, but its precise molecular composition remains enigmatic. Transmembrane channel-like protein 1 (TMC1) was recently identified as a component of the MT channel, and lipoma HMGIC fusion partner-like 5 (LHFPL5) is considered to be part of the MT complex and may functionally couple the tip link to the MT channel. As components of the MT complex, TMC1 and LHFPL5 are expected to localize at the lower end of the tip link in hair cells, a notion generally supported by previous studies on neonatal mice. However, the localization of these 2 proteins, particularly in the hair cells of adult mice, remains incompletely elucidated. Because determination of TMC1 and LHFPL5 localization at distinct developmental stages is essential for understanding their function and regulation, we used several approaches to examine the localization of these proteins in neonatal and adult hair cells in the mouse. We report several notable findings: 1) TMC1 and LHFPL5 predominantly localize at the tip of the shorter rows of stereocilia in neonatal hair cells, which largely verifies the previously published findings in neonatal hair cells; 2) LHFPL5 persists in the hair bundle of hair cells after postnatal day (P)7, which clarifies the previously reported unexpected absence of LHFPL5 after P7 and supports the view that LHFPL5 is a permanent component in the MT complex; and 3) TMC1 and LHFPL5 remain at the tip of the shorter rows of stereocilia in adult outer hair cells, but in adult inner hair cells, TMC1 is uniformly distributed in both the tallest row and the shorter rows of stereocilia, whereas LHFPL5 is uniformly distributed in the shorter rows of stereocilia. These findings raise intriguing questions regarding the turnover rate, regulation, additional functions, and functional interaction of TMC1 and LHFPL5. Our study confirms the previous findings in neonatal hair cells and reveals several previously unidentified aspects of TMC1 and LHFPL5 localization in more mature hair cells.-Li, X., Yu, X., Chen, X., Liu, Z., Wang, G., Li, C., Wong, E. Y. M., Sham, M. H., Tang, J., He, J., Xiong, W., Liu, Z., Huang, P. Localization of TMC1 and LHFPL5 in auditory hair cells in neonatal and adult mice.

Comprehensive characterization and resolution of discrepant spectrophotometric bilirubin results in patients on eltrombopag therapy.

Background Eltrombopag is a thrombopoietin receptor agonist used for the treatment of thrombocytopenic conditions. It can cause pH-dependent discoloration of plasma/serum. Eltrombopag is potentially hepatotoxic. It can affect the assessment of hyperbilirubinemia because of its (i) absorbance at ~450 nm (bilirubin), (ii) absorbance at ~550 nm (diazo-bilirubin) and (iii) it can cause yellowish discoloration of the eyes at normal circulating bilirubin levels. Methods We collected 66 samples from patients on a range of eltrombopag dosages up to 150 mg daily. Bilirubin was measured using multiple routine spectrophotometric analyzers, the Doumas reference method and high-performance liquid chromatography (HPLC). Plasma/serum eltrombopag concentrations were determined using liquid chromatography tandem mass spectrometry (LC-MS/MS). Spike-in and admixture experiments delineated the effects of eltrombopag and its metabolites. Results Forty-nine of 52 samples from patients on ≥50 mg daily eltrombopag therapy showed significantly discrepant inter-analyzer total bilirubin results, a difference up to 64 µmol/L (3.7 mg/dL). In one sample, total bilirubin varied from 8 to 65 µmol/L (0.4-3.8 mg/dL) by different routine analyzers, with direct bilirubin ≤4 µmol/L (0.2 mg/dL). There was a positive correlation between total bilirubin difference and plasma eltrombopag concentration (r = 0.679), and spike-in experiments demonstrated that Beckman AU and Doumas reference methods were susceptible to positive interference. HPLC can quantify bilirubin after separating eltrombopag, and results suggest different analyzers are affected to varying degrees by eltrombopag and its metabolites. Conclusions Eltrombopag and its metabolites can cause positive interference to the spectrophotometric measurements of total bilirubin. Accurate measurements of total bilirubin may improve our understanding of the prevalence of hyperbilirubinemia in patients on eltrombopag therapy.

High-speed indoor optical wireless communication system employing a silicon integrated photonic circuit.

Beam-steering-based optical wireless technologies are being widely investigated due to the capability of providing high-speed wireless connectivity in indoor applications. However, high-speed indoor optical wireless systems are traditionally realized with discrete bulky components, significantly limiting their practical applications. In this Letter, we demonstrate an infrared optical wireless communication system employing a miniaturized silicon integrated photonic circuit for beam steering for the first time. Experimental results show that up to 12.5 Gb/s optical wireless communication can be achieved with error-free performance over a free-space range of 140 cm, and limited mobility of users can be realized. The experimental results of this Letter open the way for realizing integrated high-speed optical wireless communications.

Onsite defluoridation system for drinking water treatment using calcium carbonate.

Fluoride in drinking water has several effects on teeth and bones. At concentrations of 1-1.5 mg/L, fluoride can strengthen enamel, improving dental health, but at concentrations above 1.5 to 4 mg/L can cause dental fluorosis. At concentrations of 4-10 mg/L, skeletal fluorosis can occur. There are many areas of the world that have excessive fluoride in drinking water, such as China, India, Sri Lanka, and the Rift Valley countries in Africa. Treatment solutions are needed, especially in poor areas where drinking water treatment plants are not available. On-site or individual treatment alternatives can be attractive if constructed from common materials and if simple enough to be constructed and maintained by users. Advanced on-site methods, such as under sink reserve osmosis units, can remove fluoride but are too expensive for developing areas. This paper investigates calcium carbonate as a cost effective sorbent for an onsite defluoridation drinking water system. Batch and column experiments were performed to characterize F- removal properties. Fluoride sorption was described by a Freundlich isotherm model, and it was found that the equilibrium time was approximately 3 h. Calcium carbonate was found to have comparable F- removal abilities as the commercial ion exchange resins and possessed higher removal effectiveness compared to calcium containing eggshells and seashells. It was also found that the anion Cl- did not compete with F- at typical drinking water concentrations, having little impact on the effectiveness of the treatment system. A fluoride removal system is proposed that can be used at home and can be maintained by users. Through this work, we can be a step closer to bringing safe drinking water to those that do not have access to it.

Secure multiple access for indoor optical wireless communications with time-slot coding and chaotic phase.

In this paper, we report a novel mechanism to simultaneously provide secure connections for multiple users in indoor optical wireless communication systems by employing the time-slot coding scheme together with chaotic phase sequence. The chaotic phase sequence is generated according to the logistic map and applied to each symbol to secure the transmission. Proof-of-concept experiments are carried out for multiple system capacities based on both 4-QAM and 16-QAM modulation formats, i.e. 1.25 Gb/s, 2 Gb/s and 2.5 Gb/s for 4-QAM, and 2.5 Gb/s, 3.33 Gb/s and 4 Gb/s for 16-QAM. Experimental results show that in all cases the added chaotic phase does not degrade the legitimate user's signal quality while the illegal user cannot detect the signal without the key.

An Exploratory Study on Exemplary Practice of Nurse Consultants.

PURPOSE: To examine the exemplary practice of nurse consultants (NCs) and derive a model to illustrate the highest level of advanced nursing practice. DESIGN: A descriptive study was conducted to examine the practice and outcomes of seven NC roles in varied clinical specialties in Hong Kong. Exemplary practice was examined in relation to competencies for advanced practice nursing in Hong Kong and the United Kingdom. METHODS: Data about NC characteristics and their practices were collected using a structured questionnaire and analyzed using descriptive statistics. Health service documents and clinical notes were analyzed using the framework approach. FINDINGS: All NCs demonstrated the competence expected of an advanced practice nurse with impacts on patients, nursing profession, and the organization as identified in the advanced nursing practice framework in Hong Kong. NCs also performed at the highest level of practice delineated by Skills for Health in the United Kingdom. They were involved in diagnostic and therapeutic practice, and identified patient satisfaction and symptom management as key outcomes. CONCLUSIONS: This study provides new insight into levels of advanced practice and illustrates the exemplary work of NCs to demonstrate how they have developed and shaped services to bring about positive patient and organizational outcomes. Career laddering that places NCs at the highest level of advanced practice is important for making the best use of nursing expertise to achieve optimal patient and organizational outcomes. CLINICAL RELEVANCE: This study addresses a knowledge gap to enrich our current understanding of the impact of advanced practice nursing roles by linking NC role practices and competencies to key outcomes.

Time-slot coding scheme for multiple access in indoor optical wireless communications.

This letter proposes what we believe is a novel time-slot coding (TSC) scheme to provide optical wireless communications to multiple users simultaneously with limited multiuser interference. We studied the proposed TSC experimentally and our results show that the code alignment tolerance, due to imperfect timing during the code generation process in practice, is 90.2%, 91.8%, and 93.1% with 4-QAM modulation at the received optical power of -22 dBm, -20 dBm, and -18 dBm, respectively. Furthermore, we also demonstrated a proof-of-concept experiment for simultaneous wireless connectivity for up to five users at multiple gross data rates (0.5 Gbps, 1 Gb/s, 1.6 Gb/s, 2 Gb/s, and 2.5 Gb/s).

Treatment registry for outcomes in patients with castration-resistant prostate cancer (TRUMPET): a methodology for real-world evidence and research.

AIM: This study seeks to improve the understanding of treatment patterns and associated health-related quality of life (HRQoL), clinical outcomes and healthcare utilization in US patients with castration-resistant prostate cancer (CRPC). PATIENTS & METHODS: Treatment Registry for Outcomes in CRPC Patients (TRUMPET) is a US-based, prospective, observational multicenter registry (NCT02380274) involving patients with CRPC and their caregivers. Patients initiating their first active treatment course will be enrolled from urology and medical oncology practices, with data captured up to 4 years. RESULTS: Information on prescribing patterns, HRQoL, clinical outcomes and healthcare utilization will be collected. CONCLUSION: TRUMPET will enable scientific understanding of disease management in terms of HRQoL, clinical outcomes and healthcare utilization in clinical practice for patients with CRPC.

HIV pharmacotherapy: A review of integrase inhibitors.

Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral agents used to treat HIV. These drugs--raltegravir, elvitegravir, and dolutegravir--are preferred options for treatment-naïve patients when used in combination with two nucleoside reverse transcriptase inhibitors. Based on clinical trials, INSTIs have been proven to be effective with minimal safety concerns. This article reviews the pharmacologic profile, role in therapy, and safety and efficacy of each agent.

Energy-saving framework for passive optical networks with ONU sleep/doze mode.

This paper proposes an energy-saving passive optical network framework (ESPON) that aims to incorporate optical network unit (ONU) sleep/doze mode into dynamic bandwidth allocation (DBA) algorithms to reduce ONU energy consumption. In the ESPON, the optical line terminal (OLT) schedules both downstream (DS) and upstream (US) transmissions in the same slot in an online and dynamic fashion whereas the ONU enters sleep mode outside the slot. The ONU sleep time is maximized based on both DS and US traffic. Moreover, during the slot, the ONU might enter doze mode when only its transmitter is idle to further improve energy efficiency. The scheduling order of data transmission, control message exchange, sleep period, and doze period defines an energy-efficient scheme under the ESPON. Three schemes are designed and evaluated in an extensive FPGA-based evaluation. Results show that whilst all the schemes significantly save ONU energy for different evaluation scenarios, the scheduling order has great impact on their performance. In addition, the ESPON allows for a scheduling order that saves ONU energy independently of the network reach.

Afrezza (Insulin Human) Inhalation Powder: A New Inhaled Insulin for the Management Of Type-1 or Type-2 Diabetes Mellitus.

Afrezza (insulin human) inhalation powder: a new inhaled insulin for the management of type-1 or type-2 diabetes mellitus.

Mipomersen (kynamro): a novel antisense oligonucleotide inhibitor for the management of homozygous familial hypercholesterolemia.

Mipomersen (Kynamro) for homozygous familial hypercholesterolemia.

Tedizolid phosphate (sivextro): a second-generation oxazolidinone to treat acute bacterial skin and skin structure infections.

Tedizolid phosphate: a second-generation oxazolidinone for acute bacterial skin and skin structure infections.

Crosstalk between Regnase-1 and -3 shapes mast cell survival and cytokine expression.

Post-transcriptional regulation of immune-related transcripts by RNA-binding proteins (RBPs) impacts immune cell responses, including mast cell functionality. Despite their importance in immune regulation, the functional role of most RBPs remains to be understood. By manipulating the expression of specific RBPs in murine mast cells, coupled with mass spectrometry and transcriptomic analyses, we found that the Regnase family of proteins acts as a potent regulator of mast cell physiology. Specifically, Regnase-1 is required to maintain basic cell proliferation and survival, whereas both Regnase-1 and -3 cooperatively regulate the expression of inflammatory transcripts upon activation, with Tnf being a primary target in both human and mouse cells. Furthermore, Regnase-3 directly interacts with Regnase-1 in mast cells and is necessary to restrain Regnase-1 expression through the destabilization of its transcript. Overall, our study identifies protein interactors of endogenously expressed Regnase factors, characterizes the regulatory interplay between Regnase family members in mast cells, and establishes their role in the control of mast cell homeostasis and inflammatory responses.

Polymer-Based Nanoparticles for Inner Ear Targeted Trans Differentiation Gene Therapy.

Hearing loss is a significant disability that often goes under recognised, largely due to poor identification, prevention, and treatment. Steps are being made to amend these pitfalls in the investigation of hearing loss, however, the development of a cure to reverse advanced forms remains distant. This review details some current advances in the treatment of hearing loss, with a particular focus on genetic-based nanotechnology and how it may provide a useful avenue for further research. This review presents a broad background on the pathophysiology of hearing loss and some current interventions. We also highlight some potential genes that may be useful in the amelioration of hearing loss. Pathways of cellular differentiation from stem or supporting cell to functional hair cell are covered in detail, as this mechanism represents a key means of regenerating these cell types. Overall, we believe that polymer-based nanotechnology coupled with novel excipients represents a useful area of further research in the treatment of hearing loss, although further studies in this area are required.