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Wearable and skin electronics benefit from mechanically soft and stretchable materials to conform to curved and dynamic surfaces, thereby enabling seamless integration with the human body. However, such materials are challenging to process using traditional microelectronics techniques. Here, stretchable transistor arrays are patterned exclusively from solution by inkjet printing of polymers and carbon nanotubes. The additive, non-contact and maskless nature of inkjet printing provides a simple, inexpensive and scalable route for stacking and patterning these chemically-sensitive materials over large areas. The transistors, which are stable at ambient conditions, display mobilities as high as 30 cm 2  V −1 s −1 and currents per channel width of 0.2 mA cm −1 at operation voltages as low as 1 V, owing to the ionic character of their printed gate dielectric. Furthermore, these transistors with double-layer capacitive dielectric can mimic the synaptic behavior of neurons, making them interesting for conformal brain-machine interfaces and other wearable bioelectronics. The development of novel low-cost fabrication schemes for realizing stretchable transistor arrays with applicability in wearable electronics remains a challenge. Here, the authors report skin-like electronics with stretchable active materials and devices processed exclusively from ink-jet printing.

T cells expressing chimeric antigen receptors (CAR T cells) targeting human CD19 (hCD19) have shown clinical efficacy against B cell malignancies 1 , 2 . CAR T cells have been less effective against solid tumours 3 – 5 , in part because they enter a hyporesponsive (‘exhausted’ or ‘dysfunctional’) state 6 – 9 triggered by chronic antigen stimulation and characterized by upregulation of inhibitory receptors and loss of effector function. To investigate the function of CAR T cells in solid tumours, we transferred hCD19-reactive CAR T cells into hCD19 + tumour-bearing mice. CD8 + CAR + tumour-infiltrating lymphocytes and CD8 + endogenous tumour-infiltrating lymphocytes expressing the inhibitory receptors PD-1 and TIM3 exhibited similar profiles of gene expression and chromatin accessibility, associated with secondary activation of nuclear receptor transcription factors NR4A1 (also known as NUR77), NR4A2 (NURR1) and NR4A3 (NOR1) by the initiating transcription factor NFAT (nuclear factor of activated T cells) 10 – 12 . CD8 + T cells from humans with cancer or chronic viral infections 13 – 15 expressed high levels of NR4A transcription factors and displayed enrichment of NR4A-binding motifs in accessible chromatin regions. CAR T cells lacking all three NR4A transcription factors ( Nr4a triple knockout) promoted tumour regression and prolonged the survival of tumour-bearing mice. Nr4a triple knockout CAR tumour-infiltrating lymphocytes displayed phenotypes and gene expression profiles characteristic of CD8 + effector T cells, and chromatin regions uniquely accessible in Nr4a triple knockout CAR tumour-infiltrating lymphocytes compared to wild type were enriched for binding motifs for NF-κB and AP-1, transcription factors involved in activation of T cells. We identify NR4A transcription factors as having an important role in the cell-intrinsic program of T cell hyporesponsiveness and point to NR4A inhibition as a promising strategy for cancer immunotherapy. Transfer of NR4A-deficient T cells expressing chimeric antigen receptors is shown to reduce tumour burden and increase survival by shifting T cell transcriptional programs away from exhaustion and towards increased effector function.

A comprehensive review of the single and sequential extraction schemes for metal fractionation in environmental samples such as soil and industrially contaminated soils, sewage sludge and sludge amended soils, road dust and run off, waste and miscellaneous materials along with other approaches of sequential extraction methods are being presented. A discussion on the application of chemometric methods in sequential extraction analysis is also being given. The study of single and sequential extraction methods for various reference materials are also being looked into. The review covers several aspects of the single and sequential extraction methodologies. The use of each reagents involved in these schemes are also discussed briefly. Finally the present upto date information by different workers in various fields of environmental geochemistry along with the possible future developments are also being outlined.

OBJECTIVE To examine the utility of commonly used insulin sensitivity indices in nondiabetic European Americans (EAs) and African Americans (AAs). RESEARCH DESIGN AND METHODS Two-hundred forty nondiabetic participants were studied. Euglycemic-hyperinsulinemic clamp was the gold standard approach to assess glucose disposal rates (GDR) normalized by lean body mass. The homeostatic model assessment for insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI) were calculated from fasting plasma glucose and insulin (FIL). Oral glucose tolerance test (OGTT) was performed to determine Matsuda index, the simple index assessing insulin sensitivity (SI(is)OGTT), Avignon index, and Stomvoll index. Relationships among these indices with GDR were analyzed by multiple regression. RESULTS GDR values were similar in EA and AA subgroups; even so, AA exhibited higher FIL and were insulin-resistant compared with EA, as assessed by HOMA-IR, QUICKI, Matsuda index, SI(is)OGTT, Avignon index, and Stumvoll index. In the overall study population, GDR was significantly correlated with all studied insulin sensitivity indices (/r/ = 0.381-0.513); however, these indices were not superior to FIL in predicting GDR. Race and gender affected the strength of this relationship. In AA males, FIL and HOMA-IR were not correlated with GDR. In contrast, Matsuda index and SI(is)OGTT were significantly correlated with GDR in AA males, and Matsuda index was superior to HOMA-IR and QUICKI in AAs overall. CONCLUSIONS Insulin sensitivity indices based on glucose and insulin levels should be used cautiously as measures of peripheral insulin sensitivity when comparing mixed gender and mixed race populations. Matsuda index and SI(is)OGTT are reliable in studies that include AA males.

As the volume of composite parts continues to rise, quality and performance specifications are becoming more and more demanding. In this context, robust and reliable nondestructive testing (NDT) techniques are necessary. Thanks to numerous recent technological breakthroughs in the THz field, the THz technology has proven to be a highly promising technology for composite NDT inspection. In this introductory review, the most relevant aspects of the THz technology as a tool for NDT inspection of composite materials are synthesized and analyzed based on a comprehensive review of the current literature. To this end, available THz experimental setups are described. Furthermore, THz imaging techniques suitable for composite inspection are analyzed and the THz spectroscopic approach is briefly presented. Finally, a review of the state of the art of THz based composite inspection systems is presented describing and analyzing recent most relevant milestones achieved in the field.

We propose procedures for draws in sports tournaments that will achieve balanced groups of size 3. We start by developing an efficient algorithm that finds all possible balanced groupings; that is, allocations of teams to groups such that the strength of all groups lies between two bounds. The algorithm uses comparison results to discard large sets of unfeasible allocations and backtracking. We then define pot-and-ball draws that randomly pick one of the balanced groupings. Our draw procedures ensure that all groups are of (virtually) identical competitive levels, thereby enhancing the overall fairness and interest of the tournament.

Drug combination discovery depends on reliable synergy metrics but no consensus exists on the correct synergy criterion to characterize combined interactions. The fragmented state of the field confounds analysis, impedes reproducibility, and delays clinical translation of potential combination treatments. Here we present a mass-action based formalism to quantify synergy. With this formalism, we clarify the relationship between the dominant drug synergy principles, and present a mapping of commonly used frameworks onto a unified synergy landscape. From this, we show how biases emerge due to intrinsic assumptions which hinder their broad applicability and impact the interpretation of synergy in discovery efforts. Specifically, we describe how traditional metrics mask consequential synergistic interactions, and contain biases dependent on the Hill-slope and maximal effect of single-drugs. We show how these biases systematically impact synergy classification in large combination screens, potentially misleading discovery efforts. Thus the proposed formalism can provide a consistent, unbiased interpretation of drug synergy, and accelerate the translatability of synergy studies. The lack of a unifying metric characterizing combinatorial drug interactions has impeded the development of combinatorial therapies. Here, the authors present MuSyC, a consensus synergy metric that overcomes several caveats associated with other, popular metrics.

Treatment options for alcohol use disorders (AUDs) have minimally advanced since 2004, while the annual deaths and economic toll have increased alarmingly. Phosphodiesterase type 4 (PDE4) is associated with alcohol and nicotine dependence. PDE4 inhibitors were identified as a potential AUD treatment using a bioinformatics approach. We prioritized a newer PDE4 inhibitor, apremilast, as ideal for repurposing (i.e., FDA approved for psoriasis, low incidence of adverse events, excellent safety profile) and tested it using multiple animal strains and models, as well as in a human phase IIa study. We found that apremilast reduced binge-like alcohol intake and behavioral measures of alcohol motivation in mouse models of genetic risk for drinking to intoxication. Apremilast also reduced excessive alcohol drinking in models of stress-facilitated drinking and alcohol dependence. Using site-directed drug infusions and electrophysiology, we uncovered that apremilast may act to lessen drinking in mice by increasing neural activity in the nucleus accumbens, a key brain region in the regulation of alcohol intake. Importantly, apremilast (90 mg/d) reduced excessive drinking in non-treatment-seeking individuals with AUD in a double-blind, placebo-controlled study. These results demonstrate that apremilast suppresses excessive alcohol drinking across the spectrum of AUD severity.

Localization of single fluorescent emitters is key for physicochemical and biophysical measurements at the nanoscale and beyond ensemble averaging. Examples include single-molecule tracking and super-resolution imaging by single-molecule localization microscopy. Among the numerous localization methods available, MINFLUX outstands for achieving a ~10-fold improvement in resolution over wide-field camera-based approaches, reaching the molecular scale at moderate photon counts. Widespread application of MINFLUX and related methods has been hindered by the technical complexity of the setups. Here, we present RASTMIN, a single-molecule localization method based on raster scanning a light pattern comprising a minimum of intensity. RASTMIN delivers ~1–2 nm localization precision with usual fluorophores and is easily implementable on a standard confocal microscope with few modifications. We demonstrate the performance of RASTMIN in localization of single molecules and super-resolution imaging of DNA origami structures.Localization of single fluorescent emitters is key for physicochemical and biophysical measurements at the nanoscale. Recently, the method called MINFLUX has achieved a ~10-fold improvement in spatial resolution over previously developed techniques, reaching molecular resolution with moderate photon counts. However, the technical complexity of this technique has hindered its widespread application. The new technique called RASTMIN provides equivalent resolution to MINFLUX while it can be implemented in standard scanning (confocal) microscopes.

Background: Body composition changes with aging lead to increased adiposity and decreased muscle mass, making the diagnosis of obesity challenging. Conventional anthropometry, including body mass index (BMI), while easy to use clinically may misrepresent adiposity. We determined the diagnostic accuracy of BMI using dual-energy X-ray absorptiometry (DEXA) in assessing the degree of obesity in older adults. Methods: The National Health and Nutrition Examination Surveys 1999–2004 were used to identify adults aged ⩾60 years with DEXA measures. They were categorized (yes/no) as having elevated body fat by gender (men: ⩾25%; women ⩾35%) and by BMI ⩾25 and ⩾30 kg m − 2 . The diagnostic performance of BMI was assessed. Metabolic characteristics were compared in discordant cases of BMI/body fat. Weighting and analyses were performed per NHANES (National Health and Nutrition Examination Survey) guidelines. Results: We identified 4984 subjects (men: 2453; women: 2531). Mean BMI and % body fat was 28.0 kg m −2 and 30.8% in men, and 28.5 kg m − 2 and 42.1% in women. A BMI ⩾30 kg m − 2 had a low sensitivity and moderately high specificity (men: 32.9 and 80.8%, concordance index 0.66; women: 38.5 and 78.5%, concordance 0.69) correctly classifying 41.0 and 45.1% of obese subjects. A BMI ⩾25 kg m −2 had a moderately high sensitivity and specificity (men: 80.7 and 99.6%, concordance 0.81; women: 76.9 and 98.8%, concordance 0.84) correctly classifying 80.8 and 78.5% of obese subjects. In subjects with BMI <30 kg m − 2 , body fat was considered elevated in 67.1% and 61.5% of men and women, respectively. For a BMI ⩾30 kg m − 2 , sensitivity drops from 40.3% to 14.5% and 44.5% to 23.4%, whereas specificity remains elevated (>98%), in men and women, respectively, in those 60–69.9 years to subjects aged ⩾80 years. Correct classification of obesity using a cutoff of 30 kg m − 2 drops from 48.1 to 23.9% and 49.0 to 19.6%, in men and women in these two age groups. Conclusions: Traditional measures poorly identify obesity in the elderly. In older adults, BMI may be a suboptimal marker for adiposity.