Protein Tyrosine Phosphatases, TC-PTP, SHP1, and SHP2, Cooperate in Rapid Dephosphorylation of Stat3 in Keratinocytes Following UVB Irradiation

Stat3 is initially dephosphorylated in murine keratinocytes in response to UVB irradiation. Treatment with Na3VO4 desensitized keratinocytes to UVB-induced apoptosis with the recovery of phosphorylated Stat3 protein levels, implying that a protein tyrosine phosphatase (PTP) is involved in this mechanism. In the current work, we report that three PTPs including TC45 (the nuclear form of TC-PTP), SHP1, and SHP2 are involved in this rapid dephosphorylation of Stat3 in keratinocytes induced by UVB irradiation. Dephosphorylation of Stat3 was increased rapidly after UVB irradiation of cultured keratinocytes. Knockdown of TC-PTP, SHP1, or SHP2 using RNAi showed that these PTPs are likely responsible for most of the rapid Stat3 dephosphorylation observed following UVB irradiation. The level of phosphorylated Stat3 was significantly higher in keratinocytes transfected with TC-PTP, SHP1, or SHP2 siRNA in the presence or absence of UVB compared with keratinocytes transfected with control siRNA. TC45 was mainly localized in the cytoplasm of keratinocytes and translocated from cytoplasm to nucleus upon UVB irradiation. Stat3 dephosphorylation was associated with nuclear translocation of TC45. Further studies revealed that knockdown of all three phosphatases, using RNAi, prevented the rapid dephosphorylation of Stat3 following UVB irradiation. In mouse epidermis, the level of phosphorylated Stat3 was initially decreased, followed by a significant increase at later time points after UVB exposure. The levels of Stat3 target genes, such as cyclin D1 and c-Myc, followed the changes in activated Stat3 in response to UVB irradiation. Collectively, these results suggest that three phosphatases, TC45, SHP1, and SHP2, are primarily responsible for UVB-mediated Stat3 dephosphorylation and may serve as part of an initial protective mechanism against UV skin carcinogenesis

Cyclic Ferroelectric Switching and Quantized Charge Transport in CuInP2_2S6_6

The van der Waals layered ferroelectric CuInP$_2$S$_6$ has been found to exhibit a variety of intriguing properties arising from the fact that the Cu ions are unusually mobile in this system. While the polarization switching mechanism is usually understood to arise from Cu ion motion within the monolayers, a second switching path involving Cu motion across the van der Waals gaps has been suggested. In this work, we perform zero-temperature first-principles calculations on such switching paths, focusing on two types that preserve the periodicity of the primitive unit cell: ``cooperative" paths preserving the system's glide mirror symmetry, and ``sequential" paths in which the two Cu ions in the unit cell move independently of each other. We find that CuInP$_2$S$_6$ features a rich and varied energy landscape, and that sequential paths are clearly favored energetically both for cross-gap and through-layer paths. Importantly, these segments can be assembled to comprise a globally insulating cycle with the out-of-plane polarization evolving by a quantum as the Cu ions shift to neighboring layers. In this sense, we argue that CuInP$_2$S$_6$ embodies the physics of a quantized adiabatic charge pump

Roundabout Maintenance Manual

In recent years, roundabouts have been rapidly growing in popularity. As a result, many communities are installing them in their roadways; however, they are encountering difficulties in maintaining them. Uneducated workers can cause damage to roundabouts and to themselves, costing cities time and money. This project aims to create a guide for communities new to roundabouts in order to reduce damages and unnecessary maintenance costs. Data was gathered by determining the most common maintenance questions and problems along with what information was already available on roundabout maintenance. Next, agencies most experienced with roundabouts were surveyed on the best maintenance practices. The responses from interview subjects gave detailed information on winter maintenance, summer maintenance, pavement maintenance, and vehicle and pedestrian access during maintenance activities. The data was compiled to create the roundabout maintenance manual. The guide created from the data collection will be helpful for communities new to roundabouts and serve as a reference for agencies in Indiana and surrounding states. In future years, the methods established in this guide should be re-evaluated and updated

An International Survey on Grading, Diagnosis, and Management of Immune Effector Cell-Associated Hematotoxicity (ICAHT) Following CAR T-cell Therapy on Behalf of the EBMT and EHA

Hematological toxicity represents the most common grade =3 toxicity after chimeric antigen receptor (CAR) T-cell therapy. However, its underlying pathophysiology is incompletely understood and its grading and management remains ill-defined. To inform the forthcoming European Hematology Association/European Society for Blood and Marrow Transplantation (EHA/EBMT) guidelines on the management of immune effector cell-associated hematotoxicity (ICAHT), we undertook a survey of experienced clinicians using an online survey focusing on (1) grading, (2) risk-stratification and diagnostic work-up, (3) short-term, and (4) long-term management of ICAHT. There were 81 survey respondents across 18 countries. A high degree of variability was noted for cytopenia grading in regards to depth, duration, and time from CAR-T infusion. The majority of experts favored pre-CAR-T bone marrow studies, especially in case of a high-risk profile. Most respondents felt that the work-up for patients with severe hematotoxicity should rule-out viral infections (96%), substrate deficiency (80%), or coincident sHLH/MAS (serum ferritin, 92%), and should include bone marrow aspiration (86%) and/or biopsy (61%). Clinicians were divided as to whether the occurrence of coincident immunotoxicity should influence the decision to apply G-CSF, and when to initiate G-CSF support. In case of prolonged thrombocytopenia, most survey participants favored thrombopoietin agonists (86%). Conversely, autologous hematopoietic cell boosts represented the preferred choice for neutropenia (63%), although they were frequently not available and no consensus was reached regarding the optimal trigger point. These findings underline the current heterogeneity of practice patterns regarding ICAHT and invite the development of consensus guidelines, which may harmonize grading, establish standard operating procedures for diagnosis, and set management guidelines

Radiatively-Induced First-Order Phase Transitions: The Necessity of the Renormalization Group

We advocate a (Wilson) renormalization-group (RG) treatment of finite-temperature first-order phase transitions, in particular those driven by radiative corrections such as occur in the standard model, and other spontaneously-broken gauge theories. We introduce the scale-dependent coarse-grained free energy S_\La[\phi] which we explicitly calculate, using the Wilson RG and a (4-\ep)-expansion, for a scalar toy model that shares many features of the gauged case. As argued by Langer and others, the dynamics of the phase transition are described by S_\La[\phi] with \La of order the bubble wall thickness, and {\it not} by the usual (RG-improved) finite-temperature effective action which is reproduced by S_\La[\phi] for \La\to 0. We argue that for weakly first-order transitions (such as that in the standard model) the (4-\ep)-expansion is necessary to control an inevitable growth of the effective scale-dependent coupling towards the strong-coupling regime, and that diagrammatic resummation techniques are unlikely to be appropriate.Comment: 26 pages, two figures, LaTex macropackage. References added and appendix A revised. LBL preprint LBL-3457

Neurotrophic Corneal Ulcer Development Following Cataract Surgery with a Limbal Relaxing Incision

A 60-year-old man with bilateral corneal opacity underwent cataract extraction surgery involving the use of a limbal relaxing incision in his left eye. He had lower lid ectropion and lagophthalmos in both eyes. Eleven days after the surgery, a slit-lamp examination revealed a neurotrophic corneal ulcer with a punch-out epithelial defect and rolled edges at the center of the pre-existing corneal opacity. The patient was treated with sodium hyaluronate, autologous serum, and oral doxycycline. Six weeks after the surgery an improvement in corneal sensation was observed and the neurotrophic corneal ulcer subsequently healed over the course of one year. In this report, we present a case of neurotrophic keratitis that occurred after performing cataract surgery concurrent with a limbal relaxing incision. As such, we suggest that limbal relaxing incisions should be performed cautiously in patients with causative risk factors for corneal hypesthesia

Key Components of Musical Discourse Analysis

Musical discourse analysis is an interdisciplinary study which is incomplete without consideration of relevant social, linguistic, psychological, visual, gestural, ritual, technical, historical and musicological aspects. In the framework of Critical Discourse Analysis, musical discourse can be interpreted as social practice: it refers to specific means of representing specific aspects of the social (musical) sphere. The article introduces a general view of contemporary musical discourse, and analyses genres from the point of ‘semiosis’, ‘social agents’, ‘social relations’, ‘social context’, and ‘text’. These components of musical discourse analysis, in their various aspects and combinations, should help thoroughly examine the context of contemporary musical art, and determine linguistic features specific to different genres of musical discourse

Phase I trial of recombinant human nerve growth factor for neurotrophic keratitis

Neurotrophic keratitis/keratopathy (NK), a rare degenerative corneal disease, lacks effective pharmacologic therapies.1 Because NK pathology involves trigeminal nerve damage and loss of corneal innervation, nerve growth factor (NGF) is surmised to promote healing of NK.2 Preliminary studies with murine NGF demonstrated efficacy for treating corneal neurotrophic ulcers;3 however, the complex tertiary structure of NGF has complicated the production of recombinant human NGF (rhNGF) suitable for clinical development. To this end, we developed an Escherichia coli–derived rhNGF formulation that demonstrated to be well tolerated and safe for topical ophthalmic use in a phase I study in healthy volunteers.4 We report phase I results of topical rhNGF for patients with moderate-to-severe NK

Phase 2 randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor for neurotrophic keratitis

Purpose: To evaluate the safety and efficacy of topical recombinant human nerve growth factor (rhNGF) for treating moderate-to-severe neurotrophic keratitis (NK), a rare degenerative corneal disease resulting from impaired corneal innervation. Design: Phase 2 multicenter, randomized, double-masked, vehicle-controlled trial. Participants: Patients with stage 2 (moderate) or stage 3 (severe) NK in 1 eye. Methods: The REPARO phase 2 study assessed safety and efficacy in 156 patients randomized 1:1:1 to rhNGF 10 μg/ml, 20 μg/ml, or vehicle. Treatment was administered 6 drops per day for 8 weeks. Patients then entered a 48- or 56-week follow-up period. Safety was assessed in all patients who received study treatment, whereas efficacy was by intention to treat. Main Outcome Measures: Corneal healing (defined as <0.5-mm maximum diameter of fluorescein staining in the lesion area) was assessed by masked central readers at week 4 (primary efficacy end point) and week 8 (key secondary end point) of controlled treatment. Corneal healing was reassessed post hoc by masked central readers using a more conservative measure (0-mm staining in the lesion area and no other persistent staining). Results: At week 4 (primary end point), 19.6% of vehicle-treated patients achieved corneal healing (<0.5-mm lesion staining) versus 54.9% receiving rhNGF 10 μg/ml (+35.3%; 97.06% confidence interval [CI], 15.88–54.71; P < 0.001) and 58.0% receiving rhNGF 20 μg/ml (+38.4%; 97.06% CI, 18.96–57.83; P < 0.001). At week 8 (key secondary end point), 43.1% of vehicle-treated patients achieved less than 0.5-mm lesion staining versus 74.5% receiving rhNGF 10 μg/ml (+31.4%; 97.06% CI, 11.25–51.49; P = 0.001) and 74.0% receiving rhNGF 20 μg/ml (+30.9%; 97.06% CI, 10.60–51.13; P = 0.002). Post hoc analysis of corneal healing by the more conservative measure (0-mm lesion staining and no other persistent staining) maintained statistically significant differences between rhNGF and vehicle at weeks 4 and 8. More than 96% of patients who healed after controlled rhNGF treatment remained recurrence free during follow-up. Treatment with rhNGF was well tolerated; adverse effects were mostly local, mild, and transient. Conclusions: Topical rhNGF is safe and more effective than vehicle in promoting healing of moderate-to-severe NK