The data-driven future of high-energy-density physics.

High-energy-density physics is the field of physics concerned with studying matter at extremely high temperatures and densities. Such conditions produce highly nonlinear plasmas, in which several phenomena that can normally be treated independently of one another become strongly coupled. The study of these plasmas is important for our understanding of astrophysics, nuclear fusion and fundamental physics-however, the nonlinearities and strong couplings present in these extreme physical systems makes them very difficult to understand theoretically or to optimize experimentally. Here we argue that machine learning models and data-driven methods are in the process of reshaping our exploration of these extreme systems that have hitherto proved far too nonlinear for human researchers. From a fundamental perspective, our understanding can be improved by the way in which machine learning models can rapidly discover complex interactions in large datasets. From a practical point of view, the newest generation of extreme physics facilities can perform experiments multiple times a second (as opposed to approximately daily), thus moving away from human-based control towards automatic control based on real-time interpretation of diagnostic data and updates of the physics model. To make the most of these emerging opportunities, we suggest proposals for the community in terms of research design, training, best practice and support for synthetic diagnostics and data analysis.

Time-resolved turbulent dynamo in a laser plasma.

Understanding magnetic-field generation and amplification in turbulent plasma is essential to account for observations of magnetic fields in the universe. A theoretical framework attributing the origin and sustainment of these fields to the so-called fluctuation dynamo was recently validated by experiments on laser facilities in low-magnetic-Prandtl-number plasmas ([Formula: see text]). However, the same framework proposes that the fluctuation dynamo should operate differently when [Formula: see text], the regime relevant to many astrophysical environments such as the intracluster medium of galaxy clusters. This paper reports an experiment that creates a laboratory [Formula: see text] plasma dynamo. We provide a time-resolved characterization of the plasma's evolution, measuring temperatures, densities, flow velocities, and magnetic fields, which allows us to explore various stages of the fluctuation dynamo's operation on seed magnetic fields generated by the action of the Biermann-battery mechanism during the initial drive-laser target interaction. The magnetic energy in structures with characteristic scales close to the driving scale of the stochastic motions is found to increase by almost three orders of magnitude and saturate dynamically. It is shown that the initial growth of these fields occurs at a much greater rate than the turnover rate of the driving-scale stochastic motions. Our results point to the possibility that plasma turbulence produced by strong shear can generate fields more efficiently at the driving scale than anticipated by idealized magnetohydrodynamics (MHD) simulations of the nonhelical fluctuation dynamo; this finding could help explain the large-scale fields inferred from observations of astrophysical systems.

Amyloid Precursor Protein (APP) Regulates Gliogenesis and Neurogenesis of Human Neural Stem Cells by Several Signaling Pathways.

Numerous studies have focused on the pathophysiological role of amyloid precursor protein (APP) because the proteolytic processing of APP to ß-amyloid (Aß) peptide is a central event in Alzheimer's disease (AD). However, many authors consider that alterations in the physiological functions of APP are likely to play a key role in AD. Previous studies in our laboratory revealed that APP plays an important role in the differentiation of human neural stem cells (hNSCs), favoring glial differentiation (gliogenesis) and preventing their differentiation toward a neuronal phenotype (neurogenesis). In the present study, we have evaluated the effects of APP overexpression in hNSCs at a global gene level by a transcriptomic analysis using the massive RNA sequencing (RNA-seq) technology. Specifically, we have focused on differentially expressed genes that are related to neuronal and glial differentiation processes, as well as on groups of differentially expressed genes associated with different signaling pathways, in order to find a possible interaction between them and APP. Our data indicate a differential expression in genes related to Notch, Wnt, PI3K-AKT, and JAK-STAT signaling, among others. Knowledge of APP biological functions, as well as the possible signaling pathways that could be related to this protein, are essential to advance our understanding of AD.

Neurogenesis Is Increased in Human Neural Stem Cells by Aß40 Peptide.

Amyloid-ß 40 peptides [Aß1-40 (Aß40)] are present within amyloid plaques in the brains of patients with Alzheimer's disease (AD). Even though Aß peptides are considered neurotoxic, they can mediate many biological processes, both in adult brains and throughout brain development. However, the physiological function of these Aß peptides remains poorly understood, and the existing data are sometimes controversial. Here, we analyze and compare the effects of monomeric Aß40 on the biology of differentiating human neural stem cells (human NSCs). For that purpose, we used a model of human NSCs called hNS1. Our data demonstrated that Aß40 at high concentrations provokes apoptotic cellular death and the damage of DNA in human NSCs while also increasing the proliferation and favors neurogenesis by raising the percentage of proliferating neuronal precursors. These effects can be mediated, at least in part, by ß-catenin. These results provide evidence of how Aß modulate/regulate human NSC proliferation and differentiation, suggesting Aß40 may be a pro-neurogenic factor. Our data could contribute to a better understanding of the molecular mechanisms involved in AD pathology and to the development of human NSC-based therapies for AD treatment, since these results could then be used in diagnosing the disease at early stages and be applied to the development of new treatment options.

High-resolution µCT of a mouse embryo using a compact laser-driven X-ray betatron source.

In the field of X-ray microcomputed tomography (µCT) there is a growing need to reduce acquisition times at high spatial resolution (approximate micrometers) to facilitate in vivo and high-throughput operations. The state of the art represented by synchrotron light sources is not practical for certain applications, and therefore the development of high-brightness laboratory-scale sources is crucial. We present here imaging of a fixed embryonic mouse sample using a compact laser-plasma-based X-ray light source and compare the results to images obtained using a commercial X-ray µCT scanner. The radiation is generated by the betatron motion of electrons inside a dilute and transient plasma, which circumvents the flux limitations imposed by the solid or liquid anodes used in conventional electron-impact X-ray tubes. This X-ray source is pulsed (duration <30 fs), bright (>1010 photons per pulse), small (diameter <1 µm), and has a critical energy >15 keV. Stable X-ray performance enabled tomographic imaging of equivalent quality to that of the µCT scanner, an important confirmation of the suitability of the laser-driven source for applications. The X-ray flux achievable with this approach scales with the laser repetition rate without compromising the source size, which will allow the recording of high-resolution µCT scans in minutes.

Oligomeric and Fibrillar Species of Aß42 Diversely Affect Human Neural Stem Cells.

Amyloid-ß 42 peptide (Aß1-42 (Aß42)) is well-known for its involvement in the development of Alzheimer's disease (AD). Aß42 accumulates and aggregates in fibers that precipitate in the form of plaques in the brain causing toxicity; however, like other forms of Aß peptide, the role of these peptides remains unclear. Here we analyze and compare the effects of oligomeric and fibrillary Aß42 peptide on the biology (cell death, proliferative rate, and cell fate specification) of differentiating human neural stem cells (hNS1 cell line). By using the hNS1 cells we found that, at high concentrations, oligomeric and fibrillary Aß42 peptides provoke apoptotic cellular death and damage of DNA in these cells, but Aß42 fibrils have the strongest effect. The data also show that both oligomeric and fibrillar Aß42 peptides decrease cellular proliferation but Aß42 oligomers have the greatest effect. Finally, both, oligomers and fibrils favor gliogenesis and neurogenesis in hNS1 cells, although, in this case, the effect is more prominent in oligomers. All together the findings of this study may contribute to a better understanding of the molecular mechanisms involved in the pathology of AD and to the development of human neural stem cell-based therapies for AD treatment.

Therapeutic avenues in bone repair: Harnessing an anabolic osteopeptide, PEPITEM, to boost bone growth and prevent bone loss.

The existing suite of therapies for bone diseases largely act to prevent further bone loss but fail to stimulate healthy bone formation and repair. We describe an endogenous osteopeptide (PEPITEM) with anabolic osteogenic activity, regulating bone remodeling in health and disease. PEPITEM acts directly on osteoblasts through NCAM-1 signaling to promote their maturation and formation of new bone, leading to enhanced trabecular bone growth and strength. Simultaneously, PEPITEM stimulates an inhibitory paracrine loop: promoting osteoblast release of the decoy receptor osteoprotegerin, which sequesters RANKL, thereby limiting osteoclast activity and bone resorption. In disease models, PEPITEM therapy halts osteoporosis-induced bone loss and arthritis-induced bone damage in mice and stimulates new bone formation in osteoblasts derived from patient samples. Thus, PEPITEM offers an alternative therapeutic option in the management of diseases with excessive bone loss, promoting an endogenous anabolic pathway to induce bone remodeling and redress the imbalance in bone turnover.

Are diabetes self-management interventions delivered in the psychiatric inpatient setting effective? A protocol for a systematic review.

INTRODUCTION: Diabetes is a major risk factor for cardiovascular disease, which is the most significant contributor to increased mortality due to natural causes in those with severe mental illness (SMI). Self-management interventions for diabetes have been shown to be effective in the general population, however, effects of these interventions in those with SMI is still unclear. Psychiatric admission could be used opportunistically to deliver interventions of this kind and help improve diabetes self-management. This review aims to assess whether interventions of this kind improve diabetes outcomes and have an effect on reducing cardiovascular risk. METHODS AND ANALYSIS: This review will include studies assessing diabetes self-management interventions designed to be delivered to those aged 18 and over with comorbid type 2 diabetes and SMI during admission to psychiatric inpatient settings. Databases including the Cochrane Library, Medline, Psychinfo, CINAHL, Embase, WHO's International Clinical Trials Registry Platform, International Health Technology Assessment Database, UK Clinical Research Network and ClinicalTrials.gov will be searched from inception to September 2022. Where possible, meta-analysis of included studies will be conducted. If heterogeneity is high and meta-analysis is not possible, we will use other means of data synthesis and will include a narrative description of included studies. ETHICS AND DISSEMINATION: Ethical approval is not required as the systematic review will only include data from existing studies. The results will be disseminated via peer-reviewed publication and presentation at relevant national and international conferences. PROSPERO REGISTRATION NUMBER: CRD42022357672.

Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma.

Multiple myeloma (MM) is a plasma cell malignancy characterised by aberrant production of immunoglobulins requiring survival mechanisms to adapt to proteotoxic stress. We here show that glutamyl-prolyl-tRNA synthetase (GluProRS) inhibition constitutes a novel therapeutic target. Genomic data suggest that GluProRS promotes disease progression and is associated with poor prognosis, while downregulation in MM cells triggers apoptosis. We developed NCP26, a novel ATP-competitive ProRS inhibitor that demonstrates significant anti-tumour activity in multiple in vitro and in vivo systems and overcomes metabolic adaptation observed with other inhibitor chemotypes. We demonstrate a complex phenotypic response involving protein quality control mechanisms that centers around the ribosome as an integrating hub. Using systems approaches, we identified multiple downregulated proline-rich motif-containing proteins as downstream effectors. These include CD138, transcription factors such as MYC, and transcription factor 3 (TCF3), which we establish as a novel determinant in MM pathobiology through functional and genomic validation. Our preclinical data therefore provide evidence that blockade of prolyl-aminoacylation evokes a complex pro-apoptotic response beyond the canonical integrated stress response and establish a framework for its evaluation in a clinical setting.

Improving physical health monitoring and interventions in a learning disabilities forensic psychiatric secure service.

BACKGROUND: Patients in psychiatric inpatient settings are at increased risk of developing physical health complications due to the structure of inpatient wards, the metabolic side-effects of antipsychotic medications and socioeconomic factors. Robust physical health monitoring and interventions are paramount in reducing this health inequality. OBJECTIVE: To improve the quality of physical health interventions in the ward environment and empower patients to follow healthy lifestyle guidance to reduce their risk of metabolic syndrome. METHODS: Patient weight and waist circumference data were collected at baseline and weekly throughout the 8-week intervention period. A questionnaire was recorded from baseline to week-5 to assess patient understanding. Two Plan-Do-Study-Act (PDSA) cycles were completed: (1) Series of weekly psychoeducation sessions and group exercise and (2) Implementation of healthy living diaries. RESULTS: Our data did not demonstrate any definitive impact upon the waist circumference and weight of participants. However, analysis of the questionnaires showed a consistent trend in knowledge improvement. CONCLUSION: Whilst our aim of reducing patient weight and waist circumference was not realised, there was a significant impact on participant's knowledge, demonstrating a subjective benefit of our interventions. Our project also highlighted inconsistencies in physical health measurements and data collection, providing vital information for further quality improvement measures.

Metabolic profiling of prostate cancer in skeletal microenvironments identifies G6PD as a key mediator of growth and survival.

The spread of cancer to bone is invariably fatal, with complex cross-talk between tumor cells and the bone microenvironment responsible for driving disease progression. By combining in silico analysis of patient datasets with metabolomic profiling of prostate cancer cells cultured with bone cells, we demonstrate the changing energy requirements of prostate cancer cells in the bone microenvironment, identifying the pentose phosphate pathway (PPP) as elevated in prostate cancer bone metastasis, with increased expression of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD) associated with a reduction in progression-free survival. Genetic and pharmacologic manipulation demonstrates that G6PD inhibition reduces prostate cancer growth and migration, associated with changes in cellular redox state and increased chemosensitivity. Genetic blockade of G6PD in vivo results in reduction of tumor growth within bone. In summary, we demonstrate the metabolic plasticity of prostate cancer cells in the bone microenvironment, identifying the PPP and G6PD as metabolic targets for the treatment of prostate cancer bone metastasis.

Prospective Assessment of Tumour Burden and Bone Disease in Plasma Cell Dyscrasias Using DW-MRI and Exploratory Bone Biomarkers.

Novel biomarkers for tumour burden and bone disease are required to guide clinical management of plasma cell dyscrasias. Recently, bone turnover markers (BTMs) and Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) have been explored, although their role in the prospective assessment of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) is unclear. Here, we conducted a pilot observational cohort feasibility study combining serum BTMs and DW-MRI in addition to standard clinical assessment. Fifty-five patients were recruited (14 MGUS, 15 smouldering MM, 14 new MM and 12 relapsed MM) and had DW-MRI and serum biomarkers (P1NP, CTX-1, ALP, DKK1, sclerostin, RANKL:OPG and BCMA) measured at baseline and 6-month follow-up. Serum sclerostin positively correlated with bone mineral density (r = 0.40-0.54). At baseline, serum BCMA correlated with serum paraprotein (r = 0.42) and serum DKK1 correlated with serum free light chains (r = 0.67); the longitudinal change in both biomarkers differed between International Myeloma Working Group (IMWG)-defined responders and non-responders. Myeloma Response Assessment and Diagnosis System (MY-RADS) scoring of serial DW-MRI correlated with conventional IMWG response criteria for measuring longitudinal changes in tumour burden. Overall, our pilot study suggests candidate radiological and serum biomarkers of tumour burden and bone loss in MM/MGUS, which warrant further exploration in larger cohorts to validate the findings and to better understand their clinical utility.

Strong suppression of heat conduction in a laboratory replica of galaxy-cluster turbulent plasmas.

In conventional gases and plasmas, it is known that heat fluxes are proportional to temperature gradients, with collisions between particles mediating energy flow from hotter to colder regions and the coefficient of thermal conduction given by Spitzer's theory. However, this theory breaks down in magnetized, turbulent, weakly collisional plasmas, although modifications are difficult to predict from first principles due to the complex, multiscale nature of the problem. Understanding heat transport is important in astrophysical plasmas such as those in galaxy clusters, where observed temperature profiles are explicable only in the presence of a strong suppression of heat conduction compared to Spitzer's theory. To address this problem, we have created a replica of such a system in a laser laboratory experiment. Our data show a reduction of heat transport by two orders of magnitude or more, leading to large temperature variations on small spatial scales (as is seen in cluster plasmas).

Phenotypic and functional characterization of a CD4(+) CD25(high) FOXP3(high) regulatory T-cell population in the dog.

Relatively little is known about regulatory T (Treg) cells and their functional responses in dogs. We have used the cross-reactive anti-mouse/rat Foxp3 antibody clone FJK-16s to identify a population of canine CD4(+) FOXP3(high) T cells in both the peripheral blood (PB) and popliteal lymph node (LN). FOXP3(+) cells in both PB and LN yielded positive staining with the newly developed anti-murine/human Helios antibody clone 22F6, consistent with the notion that they were naturally occurring Treg cells. Stimulation of mononuclear cells of LN origin with concanavalin A (Con A) in vitro yielded increased proportions and median fluorescence intensity of FOXP3 expression by both CD4(+) and CD8(+) T cells. Removal of the Con A and continued culture disclosed a CD4(+) FOXP3(high) population, distinct from the CD4(+) FOXP3(intermediate) T cells; very few CD8(+) FOXP3(high) T cells were observed, though CD8(+) FOXP3(intermediate) cells were present in equal abundance to CD4(+) FOXP3(intermediate) cells. The CD4(+) FOXP3(high) T cells were thought to represent activated Treg cells, in contrast to the FOXP3(intermediate) cells, which were thought to be a more heterogeneous population comprising predominantly activated conventional T cells. Co-staining with interferon-γ (IFN-γ) supported this notion, because the FOXP3(high) T cells were almost exclusively IFN-γ(-) , whereas the FOXP3(intermediate) cells expressed a more heterogeneous IFN-γ phenotype. Following activation of mononuclear cells with Con A and interleukin-2, the 5% of CD4(+) T cells showing the highest CD25 expression (CD4(+) CD25(high) ) were enriched in cells expressing FOXP3. These cells were anergic in vitro, in contrast to the 20% of CD4(+) T cells with the lowest CD25 expression (CD4(+) CD25(-) ), which proliferated readily. The CD4(+) CD25(high) FOXP3(high) T cells were able to suppress the proliferation of responder CD4(+) T cells in vitro, in contrast to the CD4(+) CD25(-) cells, which showed no regulatory properties.

Monoenergetic proton beams accelerated by a radiation pressure driven shock.

We report on the acceleration of impurity-free quasimononenergetic proton beams from an initially gaseous hydrogen target driven by an intense infrared (λ=10 µm) laser. The front surface of the target was observed by optical probing to be driven forward by the radiation pressure of the laser. A proton beam of ∼MeV energy was simultaneously recorded with narrow energy spread (σ∼4%), low normalized emittance (∼8 nm), and negligible background. The scaling of proton energy with the ratio of intensity over density (I/n) confirms that the acceleration is due to the radiation pressure driven shock.

Modeling Primary Bone Tumors and Bone Metastasis with Solid Tumor Graft Implantation into Bone.

Primary bone tumors or bone metastasis from solid tumors result in painful osteolytic, osteoblastic, or mixed osteolytic/osteoblastic lesions. These lesions compromise bone structure, increase the risk of pathologic fracture, and leave patients with limited treatment options. Primary bone tumors metastasize to distant organs, with some types capable of spreading to other skeletal sites. However, recent evidence suggests that with many solid tumors, cancer cells that have spread to bone may be the primary source of cells that ultimately metastasize to other organ systems. Most syngeneic or xenograft mouse models of primary bone tumors involve intra-osseous (orthotopic) injection of tumor cell suspensions. Some animal models of skeletal metastasis from solid tumors also depend on direct bone injection, while others attempt to recapitulate additional steps of the bone metastatic cascade by injecting cells intravascularly or into the organ of the primary tumor. However, none of these models develop bone metastasis reliably or with an incidence of 100%. In addition, direct intra-osseous injection of tumor cells has been shown to be associated with potential tumor embolization of the lung. These embolic tumor cells engraft but do not recapitulate the metastatic cascade. We reported a mouse model of osteosarcoma in which fresh or cryopreserved tumor fragments (consisting of tumor cells plus stroma) are implanted directly into the proximal tibia using a minimally invasive surgical technique. These animals developed reproducible engraftment, growth, and, over time, osteolysis and lung metastasis. This technique has the versatility to be used to model solid tumor bone metastasis and can readily employ grafts consisting of one or multiple cell types, genetically-modified cells, patient-derived xenografts, and/or labeled cells that can be tracked by optical or advanced imaging. Here, we demonstrate this technique, modeling primary bone tumors and bone metastasis using solid tumor graft implantation into bone.

Physiological and pathological effects of amyloid-ß species in neural stem cell biology.

Although amyloid-ß peptide is considered neurotoxic, it may mediate several physiological processes during embryonic development and in the adult brain. The pathological function of amyloid-ß peptide has been extensively studied due to its implication in Alzheimer's disease, but its physiological function remains poorly understood. Amyloid-ß peptide can be detected in non-aggregated (monomeric) and aggregated (oligomeric and fibrillary) forms. Each form has different cytotoxic and/or physiological properties, so amyloid-ß peptide and its role in Alzheimer's disease need to be studied further. Neural stem cells and neural precursor cells are good tools for the study on neurodegenerative diseases and can provide future therapeutic applications in diseases such as Alzheimer's disease. In this review, we provide an outline of the effects of amyloid-ß peptide, in monomeric and aggregated forms, on the biology of neural stem cells/neural precursor cells, and discuss the controversies. We also describe the possible molecular targets that could be implicated in these effects, especially GSK3ß. A better understanding of amyloid-ß peptide (both physiological and pathological), and the signaling pathways involved are essential to advance the field of Alzheimer's disease.

Physiological effects of amyloid precursor protein and its derivatives on neural stem cell biology and signaling pathways involved.

The pathological implication of amyloid precursor protein (APP) in Alzheimer's disease has been widely documented due to its involvement in the generation of amyloid-ß peptide. However, the physiological functions of APP are still poorly understood. APP is considered a multimodal protein due to its role in a wide variety of processes, both in the embryo and in the adult brain. Specifically, APP seems to play a key role in the proliferation, differentiation and maturation of neural stem cells. In addition, APP can be processed through two canonical processing pathways, generating different functionally active fragments: soluble APP-α, soluble APP-ß, amyloid-ß peptide and the APP intracellular C-terminal domain. These fragments also appear to modulate various functions in neural stem cells, including the processes of proliferation, neurogenesis, gliogenesis or cell death. However, the molecular mechanisms involved in these effects are still unclear. In this review, we summarize the physiological functions of APP and its main proteolytic derivatives in neural stem cells, as well as the possible signaling pathways that could be implicated in these effects. The knowledge of these functions and signaling pathways involved in the onset or during the development of Alzheimer's disease is essential to advance the understanding of the pathogenesis of Alzheimer's disease, and in the search for potential therapeutic targets.

Neuronal and Glial Differentiation of Human Neural Stem Cells Is Regulated by Amyloid Precursor Protein (APP) Levels.

Amyloid precursor protein (APP) is implicated in neural development as well as in the pathology of Alzheimer's disease (AD); however, its biological function still remains unclear. It has been reported that APP stimulates the proliferation and neuronal differentiation of neural stem cells (NSCs), while other studies suggest an important effect enhancing gliogenesis in NSCs. As expected, APP protein/mRNA is detected in hNS1 cells, a model cell line of human NSCs, both under proliferation and throughout the differentiation period. To investigate the potential function that APP plays in cell fate specification and differentiation of hNS1 cells, we transiently increased human APP levels in these cells and analyzed its cell intrinsic effects. Our data indicate that increased levels of APP induce early cell cycle exit and instructively direct hNS1 cell fate towards a glial phenotype, while decreasing neuronal differentiation. Since elevated APP levels also enhanced APP intracellular domain (AICD)-immunoreactivity, these effects could be, in part, mediated by the APP/AICD system. The AICD domain can play a potential role in signal transduction by its molecular interaction with different target genes such as GSK3B, whose expression was also increased in APP-overexpressing cells that, in turn, may contribute to promoting gliogenesis and inhibiting neurogenesis in NSCs. These data suggest an important action of APP in modulating hNSCs differentiation (probably in an AICD-GSK-3ß-dependent manner) and may thus be important for the future development of stem cell therapy strategies for the diseased mammalian brain.