Merkel Cell Polyomavirus Small T Antigen Promotes Pro-Glycolytic Metabolic Perturbations Required for Transformation

An accurate analytic model describing the microscopic mechanism of high-harmonic generation (HHG) in solids is derived. Extensive first-principles simulations within a time-dependent density-functional framework corroborate the conclusions of the model. Our results reveal that (i) the emitted HHG spectra are highly anisotropic and laser-polarization dependent even for cubic crystals; (ii) the harmonic emission is enhanced by the inhomogeneity of the electron-nuclei potential; the yield is increased for heavier atoms; and (iii) the cutoff photon energy is driver-wavelength independent. Moreover, we show that it is possible to predict the laser polarization for optimal HHG in bulk crystals solely from the knowledge of their electronic band structure. Our results pave the way to better control and optimize HHG in solids by engineering their band structure

Real-time Monitoring for the Next Core-Collapse Supernova in JUNO

Core-collapse supernova (CCSN) is one of the most energetic astrophysical events in the Universe. The early and prompt detection of neutrinos before (pre-SN) and during the SN burst is a unique opportunity to realize the multi-messenger observation of the CCSN events. In this work, we describe the monitoring concept and present the sensitivity of the system to the pre-SN and SN neutrinos at the Jiangmen Underground Neutrino Observatory (JUNO), which is a 20 kton liquid scintillator detector under construction in South China. The real-time monitoring system is designed with both the prompt monitors on the electronic board and online monitors at the data acquisition stage, in order to ensure both the alert speed and alert coverage of progenitor stars. By assuming a false alert rate of 1 per year, this monitoring system can be sensitive to the pre-SN neutrinos up to the distance of about 1.6 (0.9) kpc and SN neutrinos up to about 370 (360) kpc for a progenitor mass of 30$M_{\odot}$ for the case of normal (inverted) mass ordering. The pointing ability of the CCSN is evaluated by using the accumulated event anisotropy of the inverse beta decay interactions from pre-SN or SN neutrinos, which, along with the early alert, can play important roles for the followup multi-messenger observations of the next Galactic or nearby extragalactic CCSN.Comment: 24 pages, 9 figure

What interventions add value in lateral compression type 1 fragility pelvis fractures? A retrospective cohort study

Introduction: Fragility fractures are a large source of morbidity and mortality in the elderly. Orthopaedic surgeons are regularly the main point of contact in patients with lateral compression type 1 pelvis fractures, despite many of these being treated non-operatively. This study aims to identify risk factors for mortality and elucidate which follow-up visits have the potential to improve care for these patients. Methods and materials: In all, 211 patients have been identified with fragility lateral compression type 1 fractures at a level 1 trauma centre over a 5-year period. For all patients, we recorded patient demographics, imaging data, hospital readmissions, medical complications and death dates if applicable. Results: Of the 211 patients identified, 56.4% had at least one orthopaedic follow-up, of which no patient had a clinically meaningful medical intervention initiated. 30-day readmission rate was 19%, and 1-year mortality was 24%. Male sex, need for an assist device, higher Charlson Comorbidity Index and increased age were found to be statistically associated with increased risk of mortality. Patients who followed up with their primary care physician were found to have a statistically lower risk of mortality. Computed tomography scans were obtained in 70% of patients and never limited patient weight-bearing status or found any additional injury not already identified on the radiograph. Discussion/Conclusions: For patients with lateral compression type 1 type fragility fractures, orthopaedic surgeons did not offer additional clinically meaningful intervention after the time of initial diagnosis in this patient cohort. The rate of clinical follow-up with a primary care physician is relatively low despite high rates of medical comorbidity. Computed tomography scans were utilised frequently but did not change recommendations. The high rate of medical complications and lack of orthopaedic intervention suggest that we should re-evaluate the role of the orthopaedic surgeon versus the primary care physician as the primary point of medical contact for patients with these injuries

A case of distal limb arterial tortuosity and dilation: observations and potential clinical significance

Arterial tortuosity describes variation via bending of the arterial wall and has been noted in several arteries throughout the body. Tortuous blood vessels can cause nerve compression, as well as present difficulties to surgeons and radiologists. Here we present an unusual case of multi-vessel arterial tortuosity discovered in 78-year-old Hispanic male cadaver, independent of systemic pathology. The left ulnar and right tibial arteries were dissected, and using calibrated digital calipers, their external and internal diameters were measured both at the origin site and at the site of greatest dilation. Both wall thickness and the number of inflection points were also measured. Six bends were noticed in the ulnar artery and its diameter measured 8.11 mm at its widest, with a wall thickness of 0.88mm. On the lower extremity, the right tibial artery had three bends and its diameter measured 4.86 mm at its widest, with a wall thickness of 1.32 mm. This uncommon tortuosity is not only more prone to laceration during surgery, but the bending and thickening can be mistaken for tumors. Finally, fluid dynamics can be altered, resulting in an impact on blood pressure in the extremities. Thus, raising awareness is crucial to prevent both symptoms and iatrogenic complications

MCC cell lines exhibit variable ECAR and sensitivity to MCT1 inhibition.

<p><b>A)</b> ECAR (mpH/min) of MKL-1, MKL-2 and WaGa lines (minutes). Cells were treated with oligomycin (1 μM) at the indicated time point (arrow). <b>B-D)</b> XTT proliferation assay of MKL-1, MKL-2 and WaGa cells treated with either DMSO, CHC (5 mM), SR13800 (100 nM), or SR13801 (100 nM) (days).</p

MYC isoforms differentially regulate glycolysis gene expression and ECAR of MCC cells.

<p><b>A)</b> MKL-1 and WaGa cells containing inducible vectors for MYC, MYCN or MYCL were treated with (+) or without (-) dox for 72 hours and lysates were immunoblotted with the indicated antibodies. <b>B)</b> ECAR (mpH/min) of MKL-1 cells inducibly expressing GFP, MYC, MYCN or MYCL after 72 hours of dox addition (minutes). Cells were treated with oligomycin (1 μM) at the indicated time point. *P < 0.05 calculated using unpaired student’s T test between MYC and MYCL samples.</p

MCPyV-transformed cells exhibit elevated ECAR and sensitivity to MCT1 inhibitors.

<p><b>A)</b> Anchorage-independent growth of IMR90 PH, PHL, PHE and PHEL cells. ****P < 0.0001 calculated using ordinary one-way ANOVA with multiple comparisons. <b>B)</b> Basal ECAR (mpH/min) measurement of p53DD, PH, PHE and PHE + MYCL (PHEL) cells. **P < 0.005 and ****P < 0.0001 calculated using ordinary one-way ANOVA with multiple comparisons. <b>C)</b> Proliferation of PHEL cells treated with DMSO, CHC (5 mM), SR13800 (100 nM), or SR13801 (100 nM) was assessed by crystal violet staining. *P < 0.05 calculated using student’s T test between DMSO-SR13800 and DMSO-SR13801 samples. <b>D)</b> Anchorage-independent growth of IMR90 PHE and PHEL cells treated with DMSO, CHC, SR13800 (SR800) or SR13801 (SR801). ****P < 0.0001 calculated using ordinary one-way ANOVA with multiple comparisons.</p

Temporal transcriptome of IMR90 fibroblasts inducibly expressing MCPyV ST.

<p><b>A)</b> IMR90 fibroblasts containing dox-inducible MCPyV ST or GFP vectors were treated with dox and harvested every 8 hours for RNA extraction. Each time point represents three biological replicas. <b>B)</b> Mean ST transcript levels and <b>C)</b> immunoblotting for ST, GFP and vinculin from cells collected every 8 hours for 96 hours following dox treatment. <b>D)</b> Hierarchical clustering and fold change between MCPyV ST and GFP following dox induction for 96 hours. Each bar represents an average of three experiments for each time point. The enrichment of “Cancer Hallmark” gene sets are represented relative to the ST-differentially expressed clusters, including epithelial to mesenchymal transition (EMT), tumor necrosis factor-α (TNFA signaling via NF-κB), hypoxia, mTORC1, oxidative phosphorylation, glycolysis, MYC, and several cell cycle clusters including E2F targets, G2M checkpoint and mitotic spindle. The color bar indicates statistical significance, yellow p < 0.05 and gray p > 0.05.</p

MCPyV ST increases aerobic glycolysis and MCT1 sensitivity.

<p><b>A)</b> Media glucose (Glc) and lactate (Lac) levels (mM) from cultures of IMR90 cells expressing ST or GFP were measured at the indicated day following dox addition. **P < 0.005 calculated using unpaired student’s T test between the marked GFP and ST points. <b>B)</b> ECAR (mpH/min) of IMR90 cells inducibly expressing ST with and without dox addition for 48 hours. ***P < 0.0005 calculated using unpaired student’s T test. <b>C)</b> ECAR of IMR90 cells expressing ST or GFP with CHC (5 mM) or DMSO (minutes) following 48 hours of dox treatment. Cells were treated with oligomycin (1 μM) at the indicated time point. ***P < 0.0005 calculated using unpaired student’s T test between GFP-DMSO and ST-DMSO samples. <b>D)</b> OCR (pmoles/min) of cells (minutes) as in C. <b>E)</b> Growth of IMR90 cells expressing ST or GFP treated with dox and CHC or DMSO was assessed by crystal violet every day for 5 days. ***P < 0.0005 calculated using unpaired, two-tailed student’s T test between ST-DMSO and ST-CHC treatments. Key same as in C.</p