The Status of Clinical Faculty in the Legal Academy: Report of the Task Force on the Status of Clinicians and the Legal Academy

In the midst of ongoing debates within the legal academy and the American Bar Association on the need for \u27practice-ready law school graduates through enhanced attention to law clinics and externships and on the status of faculty teaching in those courses, this report identifies and evaluates the most appropriate modes for clinical faculty appointments. Drawing on data collected through a survey of clinical program directors and faculty, the report analyzes the five most identifiable clinical faculty models: unitary tenure track; clinical tenure track; long-term contract; short-term contract; and clinical fellowships. It determines that, despite great strides in the growth of clinical legal education in the last 30 years, equality between clinical and non-clinical faculty remains elusive. Clinical faculty still lag behind non-clinical faculty in security of position and governance rights at most law schools. The report then identifies four core principles that should guide decisions about clinical faculty appointments: 1) clinical education is a foundational and essential component of legal education; 2) the legal academy and profession benefit from full inclusion of clinical faculty on all matters affecting the mission, function, and direction of law schools; 3) there is no justification for creating hierarchies between clinical and non-clinical faculty; and 4) the standards for hiring, retention, and promotion of clinical faculty must recognize and value the responsibilities and methodologies of clinical teaching. The report concludes that these core principles are best realized when full-time clinical faculty are appointed to a unitary tenure track. This conclusion does not ignore the imperfections of a tenure system. However, to the extent that tenure remains the strongest measure of the legal academy\u27s investment in its faculty and is the surest guarantee of academic freedom, inclusion in faculty governance and job security, the report recommends that law schools predominantly place their clinical faculty on dedicated tenure lines. In addition, it recommends that schools implement standards for hiring, promotion, and retention that reflect the teaching responsibilities and methodologies, as well as practice and service obligations, unique to their clinical faculty. To facilitate the development of such standards, the report suggests good practices for the appointment of clinical faculty on a unitary tenure track

Fibroblast Growth Factor Signaling Mediates Pulmonary Endothelial Glycocalyx Reconstitution

The endothelial glycocalyx is a heparan sulfate (HS)-rich endovascular structure critical to endothelial function. Accordingly, endothelial glycocalyx degradation during sepsis contributes to tissue edema and organ injury. We determined the endogenous mechanisms governing pulmonary endothelial glycocalyx reconstitution, and if these reparative mechanisms are impaired during sepsis. We performed intravital microscopy of wild-type and transgenic mice to determine the rapidity of pulmonary endothelial glycocalyx reconstitution after nonseptic (heparinase-III mediated) or septic (cecal ligation and puncture mediated) endothelial glycocalyx degradation. We used mass spectrometry, surface plasmon resonance, and in vitro studies of human and mouse samples to determine the structure of HS fragments released during glycocalyx degradation and their impact on fibroblast growth factor receptor (FGFR) 1 signaling, a mediator of endothelial repair. Homeostatic pulmonary endothelial glycocalyx reconstitution occurred rapidly after nonseptic degradation and was associated with induction of the HS biosynthetic enzyme, exostosin (EXT)-1. In contrast, sepsis was characterized by loss of pulmonary EXT1 expression and delayed glycocalyx reconstitution. Rapid glycocalyx recovery after nonseptic degradation was dependent upon induction of FGFR1 expression and was augmented by FGF-promoting effects of circulating HS fragments released during glycocalyx degradation. Although sepsis-released HS fragments maintained this ability to activate FGFR1, sepsis was associated with the downstream absence of reparative pulmonary endothelial FGFR1 induction. Sepsis may cause vascular injury not only via glycocalyx degradation, but also by impairing FGFR1/EXT1-mediated glycocalyx reconstitution

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

To date severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected nearly 100 million individuals resulting in over two million deaths. Many vaccines are being deployed to prevent coronavirus disease-2019 (COVID-19) including two novel mRNA-based vaccines. These vaccines elicit neutralizing antibodies and appear to be safe and effective, but the precise nature of the elicited antibodies is not known. Here we report on the antibody and memory B cell responses in a cohort of 20 volunteers who received either the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines. Consistent with prior reports, 8 weeks after the second vaccine injection volunteers showed high levels of IgM, and IgG anti-SARS-CoV-2 spike protein (S), receptor binding domain (RBD) binding titers. Moreover, the plasma neutralizing activity, and the relative numbers of RBD-specific memory B cells were equivalent to individuals who recovered from natural infection. However, activity against SARS-CoV-2 variants encoding E484K or N501Y or the K417N:E484K:N501Y combination was reduced by a small but significant margin. Consistent with these findings, vaccine-elicited monoclonal antibodies (mAbs) potently neutralize SARS-CoV-2, targeting a number of different RBD epitopes epitopes in common with mAbs isolated from infected donors. Structural analyses of mAbs complexed with S trimer suggest that vaccine- and virus-encoded S adopts similar conformations to induce equivalent anti-RBD antibodies. However, neutralization by 14 of the 17 most potent mAbs tested was reduced or abolished by either K417N, or E484K, or N501Y mutations. Notably, the same mutations were selected when recombinant vesicular stomatitis virus (rVSV)/SARS-CoV-2 S was cultured in the presence of the vaccine elicited mAbs. Taken together the results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy

A spatially resolved analysis of star-formation burstiness by comparing UV and Hα\alpha in galaxies at z∼\sim1 with UVCANDELS

The UltraViolet imaging of the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey Fields (UVCANDELS) program provides HST/UVIS F275W imaging for four CANDELS fields. We combine this UV imaging with existing HST/near-IR grism spectroscopy from 3D-HST+AGHAST to directly compare the resolved rest-frame UV and H$\alpha$ emission for a sample of 979 galaxies at $0.7<z<1.5$ spanning a range in stellar mass of $10^{8-11.5}~M_\odot$. Since both rest-UV and H$\alpha$ are sensitive to on-going star-formation but over different timescales, their resolved comparison allows us to infer the burstiness in star-formation as a function of galaxy structural parameters. We generate homogenized maps of rest-UV and H$\alpha$ emission for all galaxies in our sample and stack them to compute the average UV-to-H$\alpha$ luminosity ratio as a function of galactocentric radius. We find that galaxies below stellar mass of $\sim10^{9.5}~M_\odot$, at all radii, have a UV-to-H$\alpha$ ratio higher than the equilibrium value expected from constant star-formation, indicating a significant contribution from bursty star-formation. Even for galaxies with stellar mass $\gtrsim10^{9.5} M_\odot$, the UV-to-H$\alpha$ ratio is elevated towards in their outskirts ($R/R_{eff}>1.5$), suggesting that bursty star-formation is likely prevalent in the outskirts of even the most massive galaxies but is likely over-shadowed by their brighter cores. Furthermore, we present the UV-to-H$\alpha$ ratio as a function of galaxy surface brightness, a proxy for stellar mass surface density, and find that regions below $\sim10^8~M_\odot~kpc^{-2}$ are consistent with bursty star-formation, regardless of their galaxy stellar mass, potentially suggesting that local star-formation is independent of global galaxy properties at the smallest scales.Comment: 19 pages, 8 figures; submitted to Ap

JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies

BACKGROUND. Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment

Zebrafish as a model for kidney function and disease

Kidney disease is a global problem with around three million people diagnosed in the UK alone and the incidence is rising. Research is critical to develop better treatments. Animal models can help to better understand the pathophysiology behind the various kidney diseases and to screen for therapeutic compounds, but the use especially of mammalian models should be minimised in the interest of animal welfare. Zebrafish are increasingly used, as they are genetically tractable and have a basic renal anatomy comparable to mammalian kidneys with glomerular filtration and tubular filtration processing. Here, we discuss how zebrafish have advanced the study of nephrology and the mechanisms underlying kidney disease