Poloxomer 188 Has a Deleterious Effect on Dystrophic Skeletal Muscle Function

Duchenne muscular dystrophy (DMD) is an X-linked, fatal muscle wasting disease for which there is currently no cure and limited palliative treatments. Poloxomer 188 (P188) is a tri-block copolymer that has been proposed as a potential treatment for cardiomyopathy in DMD patients. Despite the reported beneficial effects of P188 on dystrophic cardiac muscle function, the effects of P188 on dystrophic skeletal muscle function are relatively unknown. Mdx mice were injected intraperitoneally with 460 mg/kg or 30 mg/kg P188 dissolved in saline, or saline alone (control). The effect of single-dose and 2-week daily treatment was assessed using a muscle function test on the Tibialis Anterior (TA) muscle in situ in anaesthetised mice. The test comprises a warm up, measurement of the force-frequency relationship and a series of eccentric contractions with a 10% stretch that have previously been shown to cause a drop in maximum force in mdx mice. After 2 weeks of P188 treatment at either 30 or 460 mg/kg/day the drop in maximum force produced following eccentric contractions was significantly greater than that seen in saline treated control mice (P = 0.0001). Two week P188 treatment at either dose did not significantly change the force-frequency relationship or maximum isometric specific force produced by the TA muscle. In conclusion P188 treatment increases susceptibility to contraction-induced injury following eccentric contractions in dystrophic skeletal muscle and hence its suitability as a potential therapeutic for DMD should be reconsidered

Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) in infants is characterized by rearrangements of the mixed lineage leukemia (MLL) gene, drug resistance, and a poor treatment outcome. Therefore, novel therapeutic strategies are needed to improve prognosis. Recently, we showed that FLT3 is highly expressed in MLL rearranged ALL (MLL). Here we demonstrate FLT3 expression in infants with MLL (n = 41) to be significantly higher compared to both infant (n = 8; P < .001) and noninfant patients with ALL (n = 23; P = .001) carrying germline MLL genes. Furthermore, leukemic cells from infants with MLL were significantly more sensitive to the Fms-like tyrosine kinase 3 (FLT3) inhibitor PKC412 (N-benzoyl staurosporine) than noninfant ALL cells, and at least as sensitive as internal tandem duplication-positive (ITD+) AML cells. Surprisingly, activation loop mutations only occurred in about 3% (1 of 36) of the cases and no FLT3/ITDs were observed. However, measuring FLT3 phosphorylation in infants with MLL expressing varying levels of wild-type FLT3 revealed that high-level FLT3 expression is associated with ligand-independent FLT3 activation. This suggests that infant MLL cells displaying activated FLT3 as a result of overexpression can be targeted by FLT3 inhibitors such as PKC412. However, at concentrations of PKC412 minimall

Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory

The Auger Engineering Radio Array (AERA) is part of the Pierre Auger Observatory and is used to detect the radio emission of cosmic-ray air showers. These observations are compared to the data of the surface detector stations of the Observatory, which provide well-calibrated information on the cosmic-ray energies and arrival directions. The response of the radio stations in the 30 to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of the incoming electric field. For the latter, the energy deposit per area is determined from the radio pulses at each observer position and is interpolated using a two-dimensional function that takes into account signal asymmetries due to interference between the geomagnetic and charge-excess emission components. The spatial integral over the signal distribution gives a direct measurement of the energy transferred from the primary cosmic ray into radio emission in the AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air shower arriving perpendicularly to the geomagnetic field. This radiation energy -- corrected for geometrical effects -- is used as a cosmic-ray energy estimator. Performing an absolute energy calibration against the surface-detector information, we observe that this radio-energy estimator scales quadratically with the cosmic-ray energy as expected for coherent emission. We find an energy resolution of the radio reconstruction of 22% for the data set and 17% for a high-quality subset containing only events with at least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Measurement of the Radiation Energy in the Radio Signal of Extensive Air Showers as a Universal Estimator of Cosmic-Ray Energy

We measure the energy emitted by extensive air showers in the form of radio emission in the frequency range from 30 to 80 MHz. Exploiting the accurate energy scale of the Pierre Auger Observatory, we obtain a radiation energy of 15.8 \pm 0.7 (stat) \pm 6.7 (sys) MeV for cosmic rays with an energy of 1 EeV arriving perpendicularly to a geomagnetic field of 0.24 G, scaling quadratically with the cosmic-ray energy. A comparison with predictions from state-of-the-art first-principle calculations shows agreement with our measurement. The radiation energy provides direct access to the calorimetric energy in the electromagnetic cascade of extensive air showers. Comparison with our result thus allows the direct calibration of any cosmic-ray radio detector against the well-established energy scale of the Pierre Auger Observatory.Comment: Replaced with published version. Added journal reference and DOI. Supplemental material in the ancillary file

Mineral Detection of Neutrinos and Dark Matter 2024. Proceedings

The second "Mineral Detection of Neutrinos and Dark Matter" (MDvDM'24) meeting was held January 8-11, 2024 in Arlington, VA, USA, hosted by Virginia Tech's Center for Neutrino Physics. This document collects contributions from this workshop, providing an overview of activities in the field. MDvDM'24 was the second topical workshop dedicated to the emerging field of mineral detection of neutrinos and dark matter, following a meeting hosted by IFPU in Trieste, Italy in October 2022. Mineral detectors have been proposed for a wide variety of applications, including searching for dark matter, measuring various fluxes of astrophysical neutrinos over gigayear timescales, monitoring nuclear reactors, and nuclear disarmament protocols; both as paleo-detectors using natural minerals that could have recorded the traces of nuclear recoils for timescales as long as a billion years and as detectors recording nuclear recoil events on laboratory timescales using natural or artificial minerals. Contributions to this proceedings discuss the vast physics potential, the progress in experimental studies, and the numerous challenges lying ahead on the path towards mineral detection. These include a better understanding of the formation and annealing of recoil defects in crystals; identifying the best classes of minerals and, for paleo-detectors, understanding their geology; modeling and control of the relevant backgrounds; developing, combining, and scaling up imaging and data analysis techniques; and many others. During the last years, MDvDM has grown rapidly and gained attention. Small-scale experimental efforts focused on establishing various microscopic readout techniques are underway at institutions in North America, Europe and Asia. We are looking ahead to an exciting future full of challenges to overcome, surprises to be encountered, and discoveries lying ahead of us.Comment: Summary and proceedings of the MDvDM'24 conference, Jan 8-11 202

Pathways to cellular supremacy in biocomputing

Synthetic biology uses living cells as the substrate for performing human-defined computations. Many current implementations of cellular computing are based on the “genetic circuit” metaphor, an approximation of the operation of silicon-based computers. Although this conceptual mapping has been relatively successful, we argue that it fundamentally limits the types of computation that may be engineered inside the cell, and fails to exploit the rich and diverse functionality available in natural living systems. We propose the notion of “cellular supremacy” to focus attention on domains in which biocomputing might offer superior performance over traditional computers. We consider potential pathways toward cellular supremacy, and suggest application areas in which it may be found.A.G.-M. was supported by the SynBio3D project of the UK Engineering and Physical Sciences Research Council (EP/R019002/1) and the European CSA on biological standardization BIOROBOOST (EU grant number 820699). T.E.G. was supported by a Royal Society University Research Fellowship (grant UF160357) and BrisSynBio, a BBSRC/ EPSRC Synthetic Biology Research Centre (grant BB/L01386X/1). P.Z. was supported by the EPSRC Portabolomics project (grant EP/N031962/1). P.C. was supported by SynBioChem, a BBSRC/EPSRC Centre for Synthetic Biology of Fine and Specialty Chemicals (grant BB/M017702/1) and the ShikiFactory100 project of the European Union’s Horizon 2020 research and innovation programme under grant agreement 814408

The WSES/SICG/ACOI/SICUT/AcEMC/SIFIPAC guidelines for diagnosis and treatment of acute left colonic diverticulitis in the elderly

Acute left colonic diverticulitis (ALCD) in the elderly presents with unique epidemiological features when compared with younger patients. The clinical presentation is more nuanced in the elderly population, having higher in-hospital and postoperative mortality. Furthermore, geriatric comorbidities are a risk factor for complicated diverticulitis. Finally, elderly patients have a lower risk of recurrent episodes and, in case of recurrence, a lower probability of requiring urgent surgery than younger patients. The aim of the present work is to study age-related factors that may support a unique approach to the diagnosis and treatment of this problem in the elderly when compared with the WSES guidelines for the management of acute left-sided colonic diverticulitis. During the 1 degrees Pisa Workshop of Acute Care & Trauma Surgery held in Pisa (Italy) in September 2019, with the collaboration of the World Society of Emergency Surgery (WSES), the Italian Society of Geriatric Surgery (SICG), the Italian Hospital Surgeons Association (ACOI), the Italian Emergency Surgery and Trauma Association (SICUT), the Academy of Emergency Medicine and Care (AcEMC) and the Italian Society of Surgical Pathophysiology (SIFIPAC), three panel members presented a number of statements developed for each of the four themes regarding the diagnosis and management of ALCD in older patients, formulated according to the GRADE approach, at a Consensus Conference where a panel of experts participated. The statements were subsequently debated, revised, and finally approved by the Consensus Conference attendees. The current paper is a summary report of the definitive guidelines statements on each of the following topics: diagnosis, management, surgical technique and antibiotic therapy.Peer reviewe