pH-Induced Folding of the Caspase-Cleaved Par-4 Tumor Suppressor: Evidence of Structure Outside of the Coiled Coil Domain

Prostate apoptosis response-4 (Par-4) is a 38 kDa largely intrinsically disordered tumor suppressor protein that functions in cancer cell apoptosis. Par-4 down-regulation is often observed in cancer while up-regulation is characteristic of neurodegenerative conditions such as Alzheimer’s disease. Cleavage of Par-4 by caspase-3 activates tumor suppression via formation of an approximately 25 kDa fragment (cl-Par-4) that enters the nucleus and inhibits Bcl-2 and NF-ƙB, which function in pro-survival pathways. Here, we have investigated the structure of cl-Par-4 using biophysical techniques including circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), and intrinsic tyrosine fluorescence. The results demonstrate pH-dependent folding of cl-Par-4, with high disorder and aggregation at neutral pH, but a largely folded, non-aggregated conformation at acidic p

Inferred Hα flux as a star formation rate indicator at z ∼ 4–5: implications for dust properties, burstiness, and the z = 4–8 star formation rate functions

We derive Hα fluxes for a large spectroscopic and photometric-redshift-selected sample of sources over GOODSNorth and South in the redshift range z = 3.8–5.0 with deep Hubble Space Telescope (HST), Spitzer/IRAC, and ground-based observations. The Hα flux is inferred based on the offset between the IRAC 3.6 μm flux and that predicted from the best-fit spectral energy distribution (SED). We demonstrate that the Hα flux correlates well with dust-corrected UV star formation rate (SFR) and therefore can serve as an independent SFR indicator. However, we also find a systematic offset in the SFR SFR H UV a +b ratios for z ∼ 4–5 galaxies relative to local relations (assuming the same dust corrections for nebular regions and stellar light). We show that we can resolve the modest tension in the inferred SFRs by assuming bluer intrinsic UV slopes (increasing the dust correction), a rising star formation history, or assuming a low-metallicity stellar population with a hard ionizing spectrum (increasing the LHa SFR ratio). Using Hα as an SFR indicator, we find a normalization of the star formation main sequence in good agreement with recent SED-based determinations and also derive the SFR functions at z ~ 4 8– . In addition, we assess for the first time the burstiness of star formation in z ~ 4 galaxies on <100 Myr timescales by comparing UV and Hα-based sSFRs; their one-to-one relationship argues against significantly bursty star formation histories

Quantifying the UV-continuum slopes of galaxies to z ˜ 10 using deep Hubble+Spitzer/IRAC observations

Measurements of the UV-continuum slopes β provide valuable information on the physical properties of galaxies forming in the early universe, probing the dust reddening, age, metal content, and even the escape fraction. While constraints on these slopes generally become more challenging at higher redshifts as the UV-continuum shifts out of the Hubble Space Telescope bands (particularly at z > 7), such a characterization actually becomes abruptly easier for galaxies in the redshift window z = 9.5-10.5 due to the Spitzer/Infrared Array Camera 3.6 μm-band probing the rest-UV continuum and the long wavelength baseline between this Spitzer band and the Hubble Hf160w band. Higher S/N constraints on β are possible at z ˜ 10 than at z = 8. Here, we take advantage of this opportunity and five recently discovered bright z = 9.5-10.5 galaxies to present the first measurements of the mean β for a multi-object sample of galaxy candidates at z ˜ 10. We find the measured βobs's of these candidates are -2.1 ± 0.3 ± 0.2 (random and systematic), only slightly bluer than the measured β's (βobs ≈ -1.7) at 3.5 < z < 7.5 for galaxies of similar luminosities. Small increases in the stellar ages, metallicities, and dust content of the galaxy population from z ˜ 10 to z ˜ 7 could easily explain the apparent evolution in β

Corrigendum: Inexpensive Aerial Photogrammetry for Studies of Whales and Large Marine Animals

We describe a simple system enabling accurate measurement of swimming marine mammals and other large vertebrates from low-altitude single-frame photogrammetry via inexpensive modifications to a “prosumer” unmanned aerial vehicle (UAV) equipped with gimballed micro4/3 camera and 25 mm lens. Image scale is established via an independently powered LIDAR/GPS data-logging system recording altitude and GPS location at 1 Hz. Photogrammetric calibration of the camera and lens allowed distortion parameters to be rigorously accounted for during image analysis, via a custom-programmed Graphical User Interface (GUI) running in MATLAB. The datalogger, camera calibration methods and measurement software are adaptable to a wide range of UAV platforms. Mean LIDAR accuracy, measured from 10 bridges 9–39 m above water, was 99.9%. We conducted 136 flights in New Zealand's subantarctic Auckland Islands to measure southern right whales. Mean lengths of 10 individual whales, each photographed between 7 and 15 times, had CVs (SD/mean) ranging from 0.5 to 1.8% (mean = 1.2%). Repeated measurements of a floating reference target showed a mean error of c.1%. Our system is relatively inexpensive, easily put together, produces accurate, repeatable measurements from single vertical images, and hence is applicable to a wide range of ecological questions in marine and terrestrial habitats

End-tidal to arterial carbon dioxide gradient is associated with increased mortality in patients with traumatic brain injury: a retrospective observational study

Early definitive airway protection and normoventilation are key principles in the treatment of severe traumatic brain injury. These are currently guided by end tidal CO2 as a proxy for PaCO2. We assessed whether the difference between end tidal CO2 and PaCO2 at hospital admission is associated with in-hospital mortality. We conducted a retrospective observational cohort study of consecutive patients with traumatic brain injury who were intubated and transported by Helicopter Emergency Medical Services to a Level 1 trauma center between January 2014 and December 2019. We assessed the association between the CO2 gap-defined as the difference between end tidal CO2 and PaCO2-and in-hospital mortality using multivariate logistic regression models. 105 patients were included in this study. The mean ± SD CO2 gap at admission was 1.64 ± 1.09 kPa and significantly greater in non-survivors than survivors (2.26 ± 1.30 kPa vs. 1.42 ± 0.92 kPa, p < .001). The correlation between EtCO2 and PaCO2 at admission was low (Pearson's r = .287). The mean CO2 gap after 24 h was only 0.64 ± 0.82 kPa, and no longer significantly different between non-survivors and survivors. The multivariate logistic regression model showed that the CO2 gap was independently associated with increased mortality in this cohort and associated with a 2.7-fold increased mortality for every 1 kPa increase in the CO2 gap (OR 2.692, 95% CI 1.293 to 5.646, p = .009). This study demonstrates that the difference between EtCO2 and PaCO2 is significantly associated with in-hospital mortality in patients with traumatic brain injury. EtCO2 was significantly lower than PaCO2, making it an unreliable proxy for PaCO2 when aiming for normocapnic ventilation. The CO2 gap can lead to iatrogenic hypoventilation when normocapnic ventilation is aimed and might thereby increase in-hospital mortality

Leishmaniavirus-dependent metastatic leishmaniasis is prevented by blocking IL-17A

Cutaneous leishmaniasis has various outcomes, ranging from self-healing reddened papules to extensive open ulcerations that metastasise to secondary sites and are often resistant to standard therapies. In the case of L. guyanensis (L.g), about 5-10% of all infections result in metastatic complications. We recently showed that a cytoplasmic virus within L.g parasites (LRV1) is able to act as a potent innate immunogen, worsening disease outcome in a murine model. In this study, we investigated the immunophenotype of human patients infected by L.g and found a significant association between the inflammatory cytokine IL-17A, the presence of LRV1 and disease chronicity. Further, IL-17A was inversely correlated to the protective cytokine IFN-γ. These findings were experimentally corroborated in our murine model, where IL-17A produced in LRV1+ L.g infection contributed to parasite virulence and dissemination in the absence of IFN-γ. Additionally, IL-17A inhibition in mice using digoxin or SR1001, showed therapeutic promise in limiting parasite virulence. Thus, this murine model of LRV1-dependent infectious metastasis validated markers of disease chronicity in humans and elucidated the immunologic mechanism for the dissemination of Leishmania parasites to secondary sites. Moreover, it confirms the prognostic value of LRV1 and IL-17A detection to prevent metastatic leishmaniasis in human patients

A systematic investigation of the protein kinases involved in NMDA receptor-dependent LTD: evidence for a role of GSK-3 but not other serine/threonine kinases

Background: The signalling mechanisms involved in the induction of N-methyl-D-aspartate (NMDA) receptor-dependent long-term depression (LTD) in the hippocampus are poorly understood. Numerous studies have presented evidence both for and against a variety of second messengers systems being involved in LTD induction. Here we provide the first systematic investigation of the involvement of serine/threonine (ser/thr) protein kinases in NMDAR-LTD, using whole-cell recordings from CA1 pyramidal neurons. Results: Using a panel of 23 inhibitors individually loaded into the recorded neurons, we can discount the involvement of at least 57 kinases, including PKA, PKC, CaMKII, p38 MAPK and DYRK1A. However, we have been able to confirm a role for the ser/thr protein kinase, glycogen synthase kinase 3 (GSK-3). Conclusion: The present study is the first to investigate the role of 58 ser/thr protein kinases in LTD in the same study. Of these 58 protein kinases, we have found evidence for the involvement of only one, GSK-3, in LTD

TWEAK-FN14 signaling induces lysosomal degradation of a cIAP1–TRAF2 complex to sensitize tumor cells to TNFα

Synthetic inhibitor of apoptosis (IAP) antagonists induce degradation of IAP proteins such as cellular IAP1 (cIAP1), activate nuclear factor κB (NF-κB) signaling, and sensitize cells to tumor necrosis factor α (TNFα). The physiological relevance of these discoveries to cIAP1 function remains undetermined. We show that upon ligand binding, the TNF superfamily receptor FN14 recruits a cIAP1–Tnf receptor-associated factor 2 (TRAF2) complex. Unlike IAP antagonists that cause rapid proteasomal degradation of cIAP1, signaling by FN14 promotes the lysosomal degradation of cIAP1–TRAF2 in a cIAP1-dependent manner. TNF-like weak inducer of apoptosis (TWEAK)/FN14 signaling nevertheless promotes the same noncanonical NF-κB signaling elicited by IAP antagonists and, in sensitive cells, the same autocrine TNFα-induced death occurs. TWEAK-induced loss of the cIAP1–TRAF2 complex sensitizes immortalized and minimally passaged tumor cells to TNFα-induced death, whereas primary cells remain resistant. Conversely, cIAP1–TRAF2 complex overexpression limits FN14 signaling and protects tumor cells from TWEAK-induced TNFα sensitization. Lysosomal degradation of cIAP1–TRAF2 by TWEAK/FN14 therefore critically alters the balance of life/death signals emanating from TNF-R1 in immortalized cells

Evidence of significant energy input in the late phase of a solar flare from NuSTAR x-ray observations

We present observations of the occulted active region AR 12222 during the third Nuclear Spectroscopic Telescope ARray (NuSTAR) solar campaign on 2014 December 11, with concurrent Solar Dynamics Observatory (SDO)/AIA and FOXSI-2 sounding rocket observations. The active region produced a medium-size solar flare 1 day before the observations, at ∼18 UT on 2014 December 10, with the post-flare loops still visible at the time of NuSTAR observations. The time evolution of the source emission in the SDO/AIA 335 Å channel reveals the characteristics of an extreme-ultraviolet late-phase event, caused by the continuous formation of new post-flare loops that arch higher and higher in the solar corona. The spectral fitting of NuSTAR observations yields an isothermal source, with temperature 3.8\ndash4.6 MK, emission measure (0.3\ndash1.8) × 10⁴⁶ cm‑3, and density estimated at (2.5\ndash6.0) × 10⁸ cm‑3. The observed AIA fluxes are consistent with the derived NuSTAR temperature range, favoring temperature values in the range of 4.0\ndash4.3 MK. By examining the post-flare loops\rsquo cooling times and energy content, we estimate that at least 12 sets of post-flare loops were formed and subsequently cooled between the onset of the flare and NuSTAR observations, with their total thermal energy content an order of magnitude larger than the energy content at flare peak time. This indicates that the standard approach of using only the flare peak time to derive the total thermal energy content of a flare can lead to a large underestimation of its value

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis