What does the mean mean? A simple test for neuroscience.

Trial-averaged metrics, e.g. tuning curves or population response vectors, are a ubiquitous way of characterizing neuronal activity. But how relevant are such trial-averaged responses to neuronal computation itself? Here we present a simple test to estimate whether average responses reflect aspects of neuronal activity that contribute to neuronal processing. The test probes two assumptions implicitly made whenever average metrics are treated as meaningful representations of neuronal activity: Reliability: Neuronal responses repeat consistently enough across trials that they convey a recognizable reflection of the average response to downstream regions.Behavioural relevance: If a single-trial response is more similar to the average template, it is more likely to evoke correct behavioural responses. We apply this test to two data sets: (1) Two-photon recordings in primary somatosensory cortices (S1 and S2) of mice trained to detect optogenetic stimulation in S1; and (2) Electrophysiological recordings from 71 brain areas in mice performing a contrast discrimination task. Under the highly controlled settings of Data set 1, both assumptions were largely fulfilled. In contrast, the less restrictive paradigm of Data set 2 met neither assumption. Simulations predict that the larger diversity of neuronal response preferences, rather than higher cross-trial reliability, drives the better performance of Data set 1. We conclude that when behaviour is less tightly restricted, average responses do not seem particularly relevant to neuronal computation, potentially because information is encoded more dynamically. Most importantly, we encourage researchers to apply this simple test of computational relevance whenever using trial-averaged neuronal metrics, in order to gauge how representative cross-trial averages are in a given context.

Propagation of activity through the cortical hierarchy and perception are determined by neural variability.

Brains are composed of anatomically and functionally distinct regions performing specialized tasks, but regions do not operate in isolation. Orchestration of complex behaviors requires communication between brain regions, but how neural dynamics are organized to facilitate reliable transmission is not well understood. Here we studied this process directly by generating neural activity that propagates between brain regions and drives behavior, assessing how neural populations in sensory cortex cooperate to transmit information. We achieved this by imaging two densely interconnected regions-the primary and secondary somatosensory cortex (S1 and S2)-in mice while performing two-photon photostimulation of S1 neurons and assigning behavioral salience to the photostimulation. We found that the probability of perception is determined not only by the strength of the photostimulation but also by the variability of S1 neural activity. Therefore, maximizing the signal-to-noise ratio of the stimulus representation in cortex relative to the noise or variability is critical to facilitate activity propagation and perception.

An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinases.

Key molecular regulators of acquired radiation resistance in recurrent glioblastoma (GBM) are largely unknown, with a dearth of accurate preclinical models. To address this, we generated 8 GBM patient-derived xenograft (PDX) models of acquired radiation therapy-selected (RTS) resistance compared with same-patient, treatment-naive (radiation-sensitive, unselected; RTU) PDXs. These likely unique models mimic the longitudinal evolution of patient recurrent tumors following serial radiation therapy. Indeed, while whole-exome sequencing showed retention of major genomic alterations in the RTS lines, we did detect a chromosome 12q14 amplification that was associated with clinical GBM recurrence in 2 RTS models. A potentially novel bioinformatics pipeline was applied to analyze phenotypic, transcriptomic, and kinomic alterations, which identified long noncoding RNAs (lncRNAs) and targetable, PDX-specific kinases. We observed differential transcriptional enrichment of DNA damage repair pathways in our RTS models, which correlated with several lncRNAs. Global kinomic profiling separated RTU and RTS models, but pairwise analyses indicated that there are multiple molecular routes to acquired radiation resistance. RTS model-specific kinases were identified and targeted with clinically relevant small molecule inhibitors. This cohort of in vivo RTS patient-derived models will enable future preclinical therapeutic testing to help overcome the treatment resistance seen in patients with GBM.

Open-source, Python-based, hardware and software for controlling behavioural neuroscience experiments.

Laboratory behavioural tasks are an essential research tool. As questions asked of behaviour and brain activity become more sophisticated, the ability to specify and run richly structured tasks becomes more important. An increasing focus on reproducibility also necessitates accurate communication of task logic to other researchers. To these ends, we developed pyControl, a system of open-source hardware and software for controlling behavioural experiments comprising a simple yet flexible Python-based syntax for specifying tasks as extended state machines, hardware modules for building behavioural setups, and a graphical user interface designed for efficiently running high-throughput experiments on many setups in parallel, all with extensive online documentation. These tools make it quicker, easier, and cheaper to implement rich behavioural tasks at scale. As important, pyControl facilitates communication and reproducibility of behavioural experiments through a highly readable task definition syntax and self-documenting features. Here, we outline the system's design and rationale, present validation experiments characterising system performance, and demonstrate example applications in freely moving and head-fixed mouse behaviour.

Clinical impact of NPM1-mutant molecular persistence after chemotherapy for acute myeloid leukemia.

Monitoring of NPM1 mutant (NPM1mut) measurable residual disease (MRD) in acute myeloid leukemia (AML) has an established role in patients who are treated with intensive chemotherapy. The European LeukemiaNet has defined molecular persistence at low copy number (MP-LCN) as an MRD transcript level <1% to 2% with a <1-log change between any 2 positive samples collected after the end of treatment (EOT). Because the clinical impact of MP-LCN is unknown, we sought to characterize outcomes in patients with persistent NPM1mut MRD after EOT and identify factors associated with disease progression. Consecutive patients with newly diagnosed NPM1mut AML who received ≥2 cycles of intensive chemotherapy were included if bone marrow was NPM1mut MRD positive at the EOT, and they were not transplanted in first complete remission. One hundred patients were followed for a median of 23.5 months; 42% remained free of progression at 1 year, either spontaneously achieving complete molecular remission (CRMRD-; 30%) or retaining a low-level NPM1mut transcript (12% for ≥12 months and 9% at last follow-up). Forty percent met the criteria for MP-LCN. Preemptive salvage therapy significantly prolonged relapse-free survival. Risk factors associated with disease progression were concurrent FLT3-internal tandem duplication at diagnosis and suboptimal MRD response (NPM1mut reduction <4.4-log) at EOT.

Distinct roles of parvalbumin and somatostatin interneurons in gating the synchronization of spike times in the neocortex.

Synchronization of precise spike times across multiple neurons carries information about sensory stimuli. Inhibitory interneurons are suggested to promote this synchronization, but it is unclear whether distinct interneuron subtypes provide different contributions. To test this, we examined single-unit recordings from barrel cortex in vivo and used optogenetics to determine the contribution of parvalbumin (PV)- and somatostatin (SST)-positive interneurons to the synchronization of spike times across cortical layers. We found that PV interneurons preferentially promote the synchronization of spike times when instantaneous firing rates are low (<12 Hz), whereas SST interneurons preferentially promote the synchronization of spike times when instantaneous firing rates are high (>12 Hz). Furthermore, using a computational model, we demonstrate that these effects can be explained by PV and SST interneurons having preferential contributions to feedforward and feedback inhibition, respectively. Our findings demonstrate that distinct subtypes of inhibitory interneurons have frequency-selective roles in the spatiotemporal synchronization of precise spike times.

Systematic review of interventions to improve safety and quality of anticoagulant prescribing for therapeutic indications for hospital inpatients.

PURPOSE: Anticoagulation-associated adverse drug events are common in hospitalised patients and result in morbidity, mortality, increased length of hospital stay and higher costs of care. Many are preventable. We reviewed the literature to identify and assess interventions intended to improve safety or quality anticoagulant prescribing. METHODS: A systematic search of EMBASE, MEDLINE, the Cochrane Library, Pretty Darn Quick-Evidence and Health Systems Evidence was undertaken to identify controlled studies assessing system-level interventions to improve prescribing of oral or parenteral therapeutic anticoagulation for any indication in hospitalised adults. Data were extracted for safety and quality outcomes, with studies grouped by intervention type for meta-analysis and narrative review. RESULTS: Of 10,640 records screened, 19 trials evaluating 12,742 participants were included for analysis. No study specifically evaluated prescribing of low molecular weight heparins (LMWHs) or direct acting oral anticoagulants (DOACs). Our findings suggest that physician-led anticoagulation consultation services may reduce bleeding rates in high-risk patients. On meta-analysis, decision supported warfarin dosing resulted in higher proportion of time with international normalised ratio in therapeutic range (p = 0.0007). Studies of other clinical decision support systems and heparin monitoring systems did not demonstrate improved safety, and quality findings were inconsistent. Systematic education and feedback programs were not efficacious. CONCLUSIONS: There is currently insufficient high-quality evidence to recommend any reviewed intervention, though several warrant closer evaluation. Adequately powered controlled trials assessing safety outcomes and evidence-based quality markers in high-risk patient groups and studies of interventions to improve safety of LMWH and DOAC prescribing are needed.

A Novel Assay for Profiling GBM Cancer Model Heterogeneity and Drug Screening.

Accurate patient-derived models of cancer are needed for profiling the disease and for testing therapeutics. These models must not only be accurate, but also suitable for high-throughput screening and analysis. Here we compare two derivative cancer models, microtumors and spheroids, to the gold standard model of patient-derived orthotopic xenografts (PDX) in glioblastoma multiforme (GBM). To compare these models, we constructed a custom NanoString panel of 350 genes relevant to GBM biology. This custom assay includes 16 GBM-specific gene signatures including a novel GBM subtyping signature. We profiled 11 GBM-PDX with matched orthotopic cells, derived microtumors, and derived spheroids using the custom NanoString assay. In parallel, these derivative models underwent drug sensitivity screening. We found that expression of certain genes were dependent on the cancer model while others were model-independent. These model-independent genes can be used in profiling tumor-specific biology and in gauging therapeutic response. It remains to be seen whether or not cancer model-specific genes may be directly or indirectly, through changes to tumor microenvironment, manipulated to improve the concordance of in vitro derivative models with in vivo models yielding better prediction of therapeutic response.

Spin-Hall Topological Hall Effect in Highly Tunable Pt/Ferrimagnetic-Insulator Bilayers.

Electrical detection of topological magnetic textures such as skyrmions is currently limited to conducting materials. Although magnetic insulators offer key advantages for skyrmion technologies with high speed and low loss, they have not yet been explored electrically. Here, we report a prominent topological Hall effect in Pt/Tm3Fe5O12 bilayers, where the pristine Tm3Fe5O12 epitaxial films down to 1.25 unit cell thickness allow for tuning of topological Hall stability over a broad range from 200 to 465 K through atomic-scale thickness control. Although Tm3Fe5O12 is insulating, we demonstrate the detection of topological magnetic textures through a novel phenomenon: "spin-Hall topological Hall effect" (SH-THE), where the interfacial spin-orbit torques allow spin-Hall-effect generated spins in Pt to experience the unique topology of the underlying skyrmions in Tm3Fe5O12. This novel electrical detection phenomenon paves a new path for utilizing a large family of magnetic insulators in future skyrmion technologies.

Evaluation of Different Carbon Monoxide Sensors for Battery Charging Stations.

Hydrogen (H2) gas released during battery charging can result in cross-interference for carbon monoxide (CO) sensors used for early fire detection and compromise the integrity of the mine atmospheric monitoring system (AMS). In this study, a series of laboratory-scale and full-scale experiments were conducted to evaluate the responses of different CO sensors to H2 gas. In the laboratory-scale experiments, constant H2 concentrations in the airflow, from 100 to 500 ppm, pass through sensors. While in the full-scale experiments, increasing H2 concentrations generated as a byproduct from charging the batteries at the battery charging station rise to the sensors under different ventilation scenarios. The H2 concentrations at the CO sensor location were measured using H2 sensors and were correlated with the CO sensor response. The effects of ventilation and sensor location on the CO sensors responses were also analyzed. The results of this study can help mining companies to select appropriate CO sensors and improve the deployment of these sensors to ensure the safeguard of underground miners.

Numerical and experimental investigation of carbon monoxide spread in underground mine fires.

The primary danger with underground mine fires is carbon monoxide poisoning. A good knowledge of smoke and carbon monoxide movement in an underground mine during a fire is of importance for the design of ventilation systems, emergency response, and miners' escape and rescue. Mine fire simulation software packages have been widely used to predict carbon monoxide concentration and its spread in a mine for effective mine fire emergency planning. However, they are not highly recommended to be used to forecast the actual carbon monoxide concentration due to lack of validation studies. In this article, MFIRE, a mine fire simulation software based on ventilation networks, was evaluated for its carbon monoxide spread prediction capabilities using experimental results from large-scale diesel fuel and conveyor belt fire tests conducted in the Safety Research Coal Mine at The National Institute for Occupational Safety and Health. The comparison between the simulation and test results of carbon monoxide concentration shows good agreement and indicates that MFIRE is able to predict the carbon monoxide spread in underground mine fires with confidence.

Early fire detection for underground diesel fuel storage areas.

With the increased use of mobile diesel-powered equipment in underground mines, the fire risk posed by underground diesel fuel storage areas is a concern. To reduce the risk associated with the storage and transfer of large quantities of diesel fuel in permanent underground mine storage areas, an experimental study was conducted to investigate the responses of different sensors for early detection of diesel fuel fires in a storage area. Fire sensors tested in this study were four carbon monoxide (CO) sensors, two smoke sensors, and one flame sensor. A series of fire tests were conducted in the NIOSH Safety Research Coal Mine, Bruceton, PA, using various fire sizes at different ventilation airflow velocities and fire locations. Response times for different sensors were analyzed, and the results suggest that the flame sensor and smoke sensors resulted in shorter response times in most tests compared to the CO sensors. Based on the test results, the appropriate sensor locations for early fire detection in a diesel fuel storage area were identified. The results of this study can help mining companies to select appropriate fire sensors for underground diesel fuel storage areas and improve the deployment of these sensors to ensure the safety of underground miners.

The climate hazards infrared precipitation with stations--a new environmental record for monitoring extremes.

The Climate Hazards group Infrared Precipitation with Stations (CHIRPS) dataset builds on previous approaches to 'smart' interpolation techniques and high resolution, long period of record precipitation estimates based on infrared Cold Cloud Duration (CCD) observations. The algorithm i) is built around a 0.05° climatology that incorporates satellite information to represent sparsely gauged locations, ii) incorporates daily, pentadal, and monthly 1981-present 0.05° CCD-based precipitation estimates, iii) blends station data to produce a preliminary information product with a latency of about 2 days and a final product with an average latency of about 3 weeks, and iv) uses a novel blending procedure incorporating the spatial correlation structure of CCD-estimates to assign interpolation weights. We present the CHIRPS algorithm, global and regional validation results, and show how CHIRPS can be used to quantify the hydrologic impacts of decreasing precipitation and rising air temperatures in the Greater Horn of Africa. Using the Variable Infiltration Capacity model, we show that CHIRPS can support effective hydrologic forecasts and trend analyses in southeastern Ethiopia.

A vectorial capacity product to monitor changing malaria transmission potential in epidemic regions of Africa.

Rainfall and temperature are two of the major factors triggering malaria epidemics in warm semi-arid (desert-fringe) and high altitude (highland-fringe) epidemic risk areas. The ability of the mosquitoes to transmit Plasmodium spp. is dependent upon a series of biological features generally referred to as vectorial capacity. In this study, the vectorial capacity model (VCAP) was expanded to include the influence of rainfall and temperature variables on malaria transmission potential. Data from two remote sensing products were used to monitor rainfall and temperature and were integrated into the VCAP model. The expanded model was tested in Eritrea and Madagascar to check the viability of the approach. The analysis of VCAP in relation to rainfall, temperature and malaria incidence data in these regions shows that the expanded VCAP correctly tracks the risk of malaria both in regions where rainfall is the limiting factor and in regions where temperature is the limiting factor. The VCAP maps are currently offered as an experimental resource for testing within Malaria Early Warning applications in epidemic prone regions of sub-Saharan Africa. User feedback is currently being collected in preparation for further evaluation and refinement of the VCAP model.

Generation of neural stem cells from embryonic stem cells using the default mechanism: in vitro and in vivo characterization.

Neural stem cell-based approaches to repair damaged white matter in the central nervous system have shown great promise; however, the optimal cell population to employ in these therapies remains undetermined. A default mechanism of neural induction may function during development, and in embryonic stem cells (ESCs) neural differentiation is elicited in the absence of any extrinsic signaling in minimal, serum-free culture conditions. The default mechanism can be used to derive clonal neurosphere-forming populations of neural stem cells that have been termed leukemia inhibitory factor-dependent primitive neural stem cells (pNSCs), which subsequently give rise to fibroblast growth factor 2-dependent definitive NSCs (dNSCs). Here we characterized the neural differentiation pattern of these two cell types in vitro and in vivo when transplanted into the dysmyelinated spinal cords of shiverer mice. We compared the differentiation pattern to that observed for neural stem/progenitor cells derived from the adult forebrain subependymal zone [adult neural precursor cells (aNPCs)]. dNSCs produced a differentiation pattern similar to that of aNPCs in vitro and in the shiverer model in vivo, where both cell types produced terminally differentiated oligodendrocytes that associated with host axons and expressed myelin basic protein. This is the first demonstration of the in vivo differentiation of NSCs, derived from ESCs through the default mechanism, into the oligodendrocyte lineage. We conclude that dNSCs derived through the default pathway of neural induction are a similar cell population to aNPCs and that the default mechanism is a promising approach to generate NSCs from pluripotent cell populations for use in cell therapy or other research applications.

Auscultation of the fetal heart in early pregnancy.

INTRODUCTION: Auscultation of the fetal heart is a common event in antenatal care, in early pregnancy it may be associated with false negative results, which require ultrasound scan to confirm fetal viability. METHODS: We studied 197 women in early pregnancy to determine the gestational age at which the fetal heart can be reliably identified and the factors which determined the accuracy of the test. RESULTS: The proportion of successful auscultations increased with advancing gestation (p < 0.001). There was no effect of maternal body mass index or the level of midwifery experience. CONCLUSION: For a sensitivity of 90%, the fetal heart should be auscultated after 13 week gestation. If a sensitivity of 80% is acceptable the fetal heart can be auscultated after 12 + 1 week gestation.

Protection and repair of the injured spinal cord: a review of completed, ongoing, and planned clinical trials for acute spinal cord injury.

Over the past 2 decades, advances in understanding the pathophysiology of spinal cord injury (SCI) have stimulated the recent emergence of several therapeutic strategies that are being examined in Phase I/II clinical trials. Ten randomized controlled trials examining methylprednisolone sodium succinate, tirilizad mesylate, monosialotetrahexosylganglioside, thyrotropin releasing hormone, gacyclidine, naloxone, and nimodipine have been completed. Although the primary outcomes in these trials were laregely negative, a secondary analysis of the North American Spinal Cord Injury Study II demonstrated that when administered within 8 hours of injury, methylprednisolone sodium succinate was associated with modest clinical benefits, which need to be weighed against potential complications. Thyrotropin releasing hormone (Phase II trial) and monosialotetrahexosylganglioside (Phase II and III trials) also showed some promise, but we are unaware of plans for future trials with these agents. These studies have, however, yielded many insights into the conduct of clinical trials for SCI. Several current or planned clinical trials are exploring interventions such as early surgical decompression (Surgical Treatment of Acute Spinal Cord Injury Study) and electrical field stimulation, neuroprotective strategies such as riluzole and minocycline, the inactivation of myelin inhibition by blocking Nogo and Rho, and the transplantation of various cellular substrates into the injured cord. Unfortunately, some experimental and poorly characterized SCI therapies are being offered outside a formal investigational structure, which will yield findings of limited scientific value and risk harm to patients with SCI who are understandably desperate for any intervention that might improve their function. Taken together, recent advances suggest that optimism for patients and clinicians alike is justified, as there is real hope that several safe and effective therapies for SCI may become available over the next decade.

Current status of acute spinal cord injury pathophysiology and emerging therapies: promise on the horizon.

This review summarizes the current understanding of spinal cord injury pathophysiology and discusses important emerging regenerative approaches that have been translated into clinical trials or have a strong potential to do so. The pathophysiology of spinal cord injury involves a primary mechanical injury that directly disrupts axons, blood vessels, and cell membranes. This primary mechanical injury is followed by a secondary injury phase involving vascular dysfunction, edema, ischemia, excitotoxicity, electrolyte shifts, free radical production, inflammation, and delayed apoptotic cell death. Following injury, the mammalian central nervous system fails to adequately regenerate due to intrinsic inhibitory factors expressed on central myelin and the extracellular matrix of the posttraumatic gliotic scar. Regenerative approaches to block inhibitory signals including Nogo and the Rho-Rho-associated kinase pathways have shown promise and are in early stages of clinical evaluation. Cell-based strategies including using neural stem cells to remyelinate spared axons are an attractive emerging approach.

Olfactory ensheathing cells express smooth muscle alpha-actin in vitro and in vivo.

One strategy for spinal cord repair after injury that has moved quickly from the research laboratory to the clinic is the implantation of olfactory ensheathing cells (OECs). These unique glial cells of the olfactory system have been associated with axonal remyelination and regeneration after grafting into spinalized animals. Despite these promising observations, there remains a lack of direct empirical evidence of the exact fate of OECs after intraspinal implantation, in large part because of a surprising paucity of defined biomarkers that unequivocally distinguish these cells from phenotypically similar Schwann cells. Here we provide direct neurochemical proof that OECs, both in vitro and in vivo, express smooth muscle alpha-actin. That OECs synthesize this contractile protein (and a variety of actin-binding proteins including caldesmon) provides compelling evidence that these cells are, in fact, quite different from Schwann cells. The identification of several smooth muscle-related proteins in OECs points to a new appreciation of the structural and functional features of this population of olfactory glia. These biomarkers can now be used to elucidate the fate of OECs after intraspinal implantation, in particular assessing whether smooth muscle alpha-actin-expressing OECs are capable of facilitating axon remyelination and regeneration.