Sentence superiority in the reading brain.

When a sequence of written words is briefly presented and participants are asked to identify just one word at a post-cued location, then word identification accuracy is higher when the word is presented in a grammatically correct sequence compared with an ungrammatical sequence. This sentence superiority effect has been reported in several behavioral studies and two EEG investigations. Taken together, the results of these studies support the hypothesis that the sentence superiority effect is primarily driven by rapid access to a sentence-level representation via partial word identification processes that operate in parallel over several words. Here we used MEG to examine the neural structures involved in this early stage of written sentence processing, and to further specify the timing of the different processes involved. Source activities over time showed grammatical vs. ungrammatical differences first in the left inferior frontal gyrus (IFG: 321-406 ms), then the left anterior temporal lobe (ATL: 466-531 ms), and finally in both left IFG (549-602 ms) and left posterior superior temporal gyrus (pSTG: 553-622 ms). We interpret the early IFG activity as reflecting the rapid bottom-up activation of sentence-level representations, including syntax, enabled by partly parallel word processing. Subsequent activity in ATL and pSTG is thought to reflect the constraints imposed by such sentence-level representations on on-going word-based semantic activation (ATL), and the subsequent development of a more detailed sentence-level representation (pSTG). These results provide further support for a cascaded interactive-activation account of sentence reading.

Auditory and motor priming of metric structure improves understanding of degraded speech.

Speech comprehension is enhanced when preceded (or accompanied) by a congruent rhythmic prime reflecting the metrical sentence structure. Although these phenomena have been described for auditory and motor primes separately, their respective and synergistic contribution has not been addressed. In this experiment, participants performed a speech comprehension task on degraded speech signals that were preceded by a rhythmic prime that could be auditory, motor or audiomotor. Both auditory and audiomotor rhythmic primes facilitated speech comprehension speed. While the presence of a purely motor prime (unpaced tapping) did not globally benefit speech comprehension, comprehension accuracy scaled with the regularity of motor tapping. In order to investigate inter-individual variability, participants also performed a Spontaneous Speech Synchronization test. The strength of the estimated perception-production coupling correlated positively with overall speech comprehension scores. These findings are discussed in the framework of the dynamic attending and active sensing theories.

Quantifying cardiac dysfunction and valvular heart disease associated with subretinal drusenoid deposits in age-related macular degeneration.

BACKGROUND/AIMS: Demonstrate through objective multidisciplinary imaging that subretinal drusenoid deposits (SDDs) in age-related macular degeneration (AMD) are linked to both coexistent valvular heart disease (VHD) and reduced systemic perfusion via cardiac index (CI). METHODS: Post-hoc analysis of cross-sectional study. 200 intermediate AMD (iAMD) subjects were assigned by masked readers to two groups: SDD (with or without drusen) and drusen (only) based on multimodal ophthalmic imaging. 65 transthoracic echocardiograms (TTEs) reports were available for cardiologist evaluation of VHD severity of the four cardiac valves and the presences of precursor lesions of aortic sclerosis (ASc) and mitral annular calcification (MAC). Necessary parameters to calculate CI were also obtained. Univariate testing was performed using Fisher's Exact test and t-test. RESULTS: 82.6% (19/23) of the iAMD subjects with at least one moderate/severe VHD had concurrent SDDs (p = 0.0040). All cases of aortic regurgitation (6/6, p = 0.0370) and mitral regurgitation (13/13, p = 0.0004) were found with coexisting SDDs. Stenotic VHD was not significantly associated with SDDs, however 70.7% of subjects with ASc (29/41, p = 0.0108) and 76.0% of subjects with MAC (19/25, 0.0377) had coexisting SDDs. CI was available in 48 subjects and was significantly below normal levels in the SDD cohort (mean CI SDD 1.95 ± 0.60 L/min/m2, non-SDD 2.71 ± 0.73 L/min/m2, p = 0.0004). CONCLUSIONS: Several specific VHDs have been found associated with the SDD form of AMD. Decreased systemic perfusion as measured by CI was also associated with SDDs, which supports a perfusion hypothesis of SDD pathogenesis. Further research is warranted to understand the relationship between cardiovascular disease and SDDs.

A deep learning algorithm to detect cutaneous squamous cell carcinoma on frozen sections in Mohs micrographic surgery: A retrospective assessment.

Intraoperative margin analysis is crucial for the successful removal of cutaneous squamous cell carcinomas (cSCC). Artificial intelligence technologies (AI) have previously demonstrated potential for facilitating rapid and complete tumour removal using intraoperative margin assessment for basal cell carcinoma. However, the varied morphologies of cSCC present challenges for AI margin assessment. The aim of this study was to develop and evaluate the accuracy of an AI algorithm for real-time histologic margin analysis of cSCC. To do this, a retrospective cohort study was conducted using frozen cSCC section slides. These slides were scanned and annotated, delineating benign tissue structures, inflammation and tumour to develop an AI algorithm for real-time margin analysis. A convolutional neural network workflow was used to extract histomorphological features predictive of cSCC. This algorithm demonstrated proof of concept for identifying cSCC with high accuracy, highlighting the potential for integration of AI into the surgical workflow. Incorporation of AI algorithms may improve efficiency and completeness of real-time margin assessment for cSCC removal, particularly in cases of moderately and poorly differentiated tumours/neoplasms. Further algorithmic improvement incorporating surrounding tissue context is necessary to remain sensitive to the unique epidermal landscape of well-differentiated tumours, and to map tumours to their original anatomical position/orientation.

Circulating Sphingolipids and Glucose Homeostasis: An Update.

Sphingolipids are a family of lipid molecules produced through different pathways in mammals. Sphingolipids are structural components of membranes, but in response to obesity, they are implicated in the regulation of various cellular processes, including inflammation, apoptosis, cell proliferation, autophagy, and insulin resistance which favors dysregulation of glucose metabolism. Of all sphingolipids, two species, ceramides and sphingosine-1-phosphate (S1P), are also found abundantly secreted into the bloodstream and associated with lipoproteins or extracellular vesicles. Plasma concentrations of these sphingolipids can be altered upon metabolic disorders and could serve as predictive biomarkers of these diseases. Recent important advances suggest that circulating sphingolipids not only serve as biomarkers but could also serve as mediators in the dysregulation of glucose homeostasis. In this review, advances of molecular mechanisms involved in the regulation of ceramides and S1P association to lipoproteins or extracellular vesicles and how they could alter glucose metabolism are discussed.

A deep learning algorithm to detect cutaneous squamous cell carcinoma on frozen sections in Mohs micrographic surgery: a retrospective assessment.

Importance: Intraoperative margin analysis is crucial for the successful removal of cutaneous squamous cell carcinomas (cSCC). Artificial intelligence technologies (AI) have previously demonstrated potential for facilitating rapid and complete tumor removal using intraoperative margin assessment for basal cell carcinoma. However, the varied morphologies of cSCC present challenges for AI margin assessment. Objective: To develop and evaluate the accuracy of an AI algorithm for real-time histologic margin analysis of cSCC. Design: A retrospective cohort study was conducted using frozen cSCC section slides and adjacent tissues. Setting: This study was conducted in a tertiary care academic center. Participants: Patients undergoing Mohs micrographic surgery for cSCC between January and March 2020. Exposures: Frozen section slides were scanned and annotated, delineating benign tissue structures, inflammation, and tumor to develop an AI algorithm for real-time margin analysis. Patients were stratified by tumor differentiation status. Epithelial tissues including epidermis and hair follicles were annotated for moderate-well to well differentiated cSCC tumors. A convolutional neural network workflow was used to extract histomorphological features predictive of cSCC at 50-micron resolution. Main Outcomes and Measures: The performance of the AI algorithm in identifying cSCC at 50-micron resolution was reported using the area under the receiver operating characteristic curve. Accuracy was also reported by tumor differentiation status and by delineation of cSCC from epidermis. Model performance using histomorphological features alone was compared to architectural features (i.e., tissue context) for well-differentiated tumors. Results: The AI algorithm demonstrated proof of concept for identifying cSCC with high accuracy. Accuracy differed by differentiation status, driven by challenges in separating cSCC from epidermis using histomorphological features alone for well-differentiated tumors. Consideration of broader tissue context through architectural features improved the ability to delineate tumor from epidermis. Conclusions and Relevance: Incorporating AI into the surgical workflow may improve efficiency and completeness of real-time margin assessment for cSCC removal, particularly in cases of moderately and poorly differentiated tumors/neoplasms. Further algorithmic improvement is necessary to remain sensitive to the unique epidermal landscape of well-differentiated tumors, and to map tumors to their original anatomical position/orientation. Future studies should assess the efficiency improvements and cost benefits and address other confounding pathologies such as inflammation and nuclei. Funding sources: JL is supported by NIH grants R24GM141194, P20GM104416 and P20GM130454. Support for this work was also provided by the Prouty Dartmouth Cancer Center development funds. Key Points: Question: How can the efficiency and accuracy of real-time intraoperative margin analysis for the removal of cutaneous squamous cell carcinoma (cSCC) be improved, and how can tumor differentiation be incorporated into this approach?Findings: A proof-of-concept deep learning algorithm was trained, validated, and tested on frozen section whole slide images (WSI) for a retrospective cohort of cSCC cases, demonstrating high accuracy in identifying cSCC and related pathologies. Histomorphology alone was found to be insufficient to delineate tumor from epidermis in histologic identification of well-differentiated cSCC. Incorporation of surrounding tissue architecture and shape improved the ability to delineate tumor from normal tissue.Meaning: Integrating artificial intelligence into surgical procedures has the potential to enhance the thoroughness and efficiency of intraoperative margin analysis for cSCC removal. However, accurately accounting for the epidermal tissue based on the tumor's differentiation status requires specialized algorithms that consider the surrounding tissue context. To meaningfully integrate AI algorithms into clinical practice, further algorithmic refinement is needed, as well as the mapping of tumors to their original surgical site, and evaluation of the cost and efficacy of these approaches to address existing bottlenecks.

Conditional deletion of LRRC8A in the brain reduces stroke damage independently of swelling-activated glutamate release.

The ubiquitous volume-regulated anion channels (VRACs) facilitate cell volume control and contribute to many other physiological processes. Treatment with non-specific VRAC blockers or brain-specific deletion of the essential VRAC subunit LRRC8A is highly protective in rodent models of stroke. Here, we tested the widely accepted idea that the harmful effects of VRACs are mediated by release of the excitatory neurotransmitter glutamate. We produced conditional LRRC8A knockout either exclusively in astrocytes or in the majority of brain cells. Genetically modified mice were subjected to an experimental stroke (middle cerebral artery occlusion). The astrocytic LRRC8A knockout yielded no protection. Conversely, the brain-wide LRRC8A deletion strongly reduced cerebral infarction in both heterozygous (Het) and full KO mice. Yet, despite identical protection, Het mice had full swelling-activated glutamate release, whereas KO animals showed its virtual absence. These findings suggest that LRRC8A contributes to ischemic brain injury via a mechanism other than VRAC-mediated glutamate release.

Ceramide analog C2-cer induces a loss in insulin sensitivity in muscle cells through the salvage/recycling pathway.

Ceramides have been shown to play a major role in the onset of skeletal muscle insulin resistance and therefore in the prevalence of type 2 diabetes. However, many of the studies involved in the discovery of deleterious ceramide actions used a nonphysiological, cell-permeable, short-chain ceramide analog, the C2-ceramide (C2-cer). In the present study, we determined how C2-cer promotes insulin resistance in muscle cells. We demonstrate that C2-cer enters the salvage/recycling pathway and becomes deacylated, yielding sphingosine, re-acylation of which depends on the availability of long chain fatty acids provided by the lipogenesis pathway in muscle cells. Importantly, we show these salvaged ceramides are actually responsible for the inhibition of insulin signaling induced by C2-cer. Interestingly, we also show that the exogenous and endogenous monounsaturated fatty acid oleate prevents C2-cer to be recycled into endogenous ceramide species in a diacylglycerol O-acyltransferase 1-dependent mechanism, which forces free fatty acid metabolism towards triacylglyceride production. Altogether, the study highlights for the first time that C2-cer induces a loss in insulin sensitivity through the salvage/recycling pathway in muscle cells. This study also validates C2-cer as a convenient tool to decipher mechanisms by which long-chain ceramides mediate insulin resistance in muscle cells and suggests that in addition to the de novo ceramide synthesis, recycling of ceramide could contribute to muscle insulin resistance observed in obesity and type 2 diabetes.

Development of a predictive model for recurrence-free survival in pTa low-grade bladder cancer.

BACKGROUND: Data on Ta low-grade (LG) non-muscle invasive bladder cancer (NMIBC) have shown that follow-up cystoscopies are normal in 82% and 67% of patients with single and multiple tumors, respectively. OBJECTIVE: To develop a predictive model associated with recurrence-free survival (RFS) at 6, 12, 18 and 24 months in TaLG cases that consider the patients' risk aversion. MATERIALS AND METHODS: Data from a prospectively maintained database of 202 newly diagnosed TaLG NMIBC patients treated at Scandinavian institutions were used for the analysis. To identify risk groups associated with recurrence, we performed a classification tree analysis. Association between risk groups and RFS was evaluated by Kaplan Meier analysis. A Cox proportional hazard model selected significant risk factors associated with RFS using the variables defining the risk groups. The reported C index for the Cox model was 0.7. The model was internally validated and calibrated using 1000 bootstrapped samples. A nomogram to estimate RFS at 6, 12, 18, and 24 months was generated. The performance of our model was compared to EUA/AUA stratification using a decision curve analysis (DCA). RESULTS: The tree classification found that tumor number, tumor size and age were the most relevant variables associated with recurrence. The patients with the worst RFS were those with multifocal or single, ≥ 4cm tumors. All the relevant variables identified by the classification tree were significantly associated with RFS in the Cox proportional hazard model. DCA analysis showed that our model outperformed EUA/AUA stratification and the treat all/none approaches. CONCLUSION: We developed a predictive model to identify TaLG patients that benefit from less frequent follow-up cystoscopy schedule based on the estimated RFS and personal recurrence risk aversion.

Is beta band desynchronization related to skin conductance biofeedback effectiveness in drug resistant focal epilepsy?

Skin Conductance Biofeedback (SCB) is a non-invasive behavioral treatment for epilepsy based on modulation of Galvanic Skin Response (GSR). We evaluated changes in functional connectivity occurring after SCB. Six patients with drug-resistant temporal lobe epilepsy underwent monthly SCB sessions. For each patient, 10 min of resting-state magnetoencephalographic (MEG) recording were acquired before and after the first and the last SCB session. For each recording we computed the mean weighted phase lag index (WPLI) across all pair of MEG sensors. After SCB, two patients had consistent reduction of seizure frequency (>50 %). Connectivity analysis revealed a decrease of WPLI-beta band in the two responders and an increase of WPLI-alpha connectivity in all patients regardless of the clinical effect. Results suggest that reduction of WPLI-beta-low connectivity is related to the clinical response after SCB.

Development and testing of a self-report measure of preparing to parent in the context of a fetal anomaly diagnosis.

OBJECTIVE: To generate a self-report instrument to capture clinically relevant variations in expectant parents' caregiving development, specified by how they are preparing to parent an infant with a major congenital anomaly. METHODS: Recent literature structured domains to guide item generation. Evaluations by experts and expectant parents led to a refined instrument for field testing. Psychometric testing included exploratory factor analysis, internal consistency, and test-retest reliability. RESULTS: Samples included expert evaluators (n = 9), and expectant parent evaluators (n = 20) and expectant mother field testers (n = 67) with fetal anomaly diagnoses. Preparing to Parent-Act, Relate, Engage (PreP-ARE) resulted from a three factor solution that explained 71.8 % of the total variance, with global Cronbach's α = 0.72, and sub-scales 0.81, 0.65, 0.72 respectively. Cohen's weighted kappa indicated all items were acceptably reliable, with 14 of 19 items showing moderate (≥ 0.41) or good (≥ 0.61) reliability. Convergent validity was found between the maternal antenatal attachment and Act scales (r = 0.39, p = 0.001). CONCLUSION: This empirically-based instrument was demonstrated to be valid and reliable, and has potential for studying this transitional time. PRACTICE IMPLICATIONS: PreP-ARE could be used to understand patient responses to the diagnosis, level of engagement, readiness to make decisions, and ability to form collaborative partnerships to manage healthcare.

Sphingolipid Metabolism and Signaling in Skeletal Muscle: From Physiology to Physiopathology.

Sphingolipids represent one of the major classes of eukaryotic lipids. They play an essential structural role, especially in cell membranes where they also possess signaling properties and are capable of modulating multiple cell functions, such as apoptosis, cell proliferation, differentiation, and inflammation. Many sphingolipid derivatives, such as ceramide, sphingosine-1-phosphate, and ganglioside, have been shown to play many crucial roles in muscle under physiological and pathological conditions. This review will summarize our knowledge of sphingolipids and their effects on muscle fate, highlighting the role of this class of lipids in modulating muscle cell differentiation, regeneration, aging, response to insulin, and contraction. We show that modulating sphingolipid metabolism may be a novel and interesting way for preventing and/or treating several muscle-related diseases.

Sphingosine-1-Phosphate Metabolism in the Regulation of Obesity/Type 2 Diabetes.

Obesity is a pathophysiological condition where excess free fatty acids (FFA) target and promote the dysfunctioning of insulin sensitive tissues and of pancreatic ß cells. This leads to the dysregulation of glucose homeostasis, which culminates in the onset of type 2 diabetes (T2D). FFA, which accumulate in these tissues, are metabolized as lipid derivatives such as ceramide, and the ectopic accumulation of the latter has been shown to lead to lipotoxicity. Ceramide is an active lipid that inhibits the insulin signaling pathway as well as inducing pancreatic ß cell death. In mammals, ceramide is a key lipid intermediate for sphingolipid metabolism as is sphingosine-1-phosphate (S1P). S1P levels have also been associated with the development of obesity and T2D. In this review, the current knowledge on S1P metabolism in regulating insulin signaling in pancreatic ß cell fate and in the regulation of feeding by the hypothalamus in the context of obesity and T2D is summarized. It demonstrates that S1P can display opposite effects on insulin sensitive tissues and pancreatic ß cells, which depends on its origin or its degradation pathway.

[Ceramides, crucial actors in the development of insulin resistance and type 2 diabetes]. / Céramides, acteurs cruciaux dans le développement de l'insulino-résistance et du diabète de type 2.

In healthy subjects, the balance between glucose production and its usage is precisely controlled. When circulating glucose reaches a critical threshold, pancreatic ß-cells secrete insulin, which has two major actions: lowering circulating glucose concentrations by facilitating its uptake mainly in skeletal muscles and the liver, and inhibiting glucose production. Triglycerides are the main source of fatty acids to meet the energy needs of oxidative tissues and any excess is stored in adipocytes. Thus, adipose tissue acts as a trap for excess fatty acids released from plasma triglycerides. When the buffering action of adipose tissue to store fatty acids is impaired, they accumulate in other tissues where they are metabolized in several lipid species, including sphingolipid derivatives such as ceramides. Numerous studies have shown that ceramides are among the most active lipid second messengers to inhibit insulin signalling. This review describes the major role played by ceramides in the development of insulin resistance in peripheral tissues.

TITLE: Céramides, acteurs cruciaux dans le développement de l'insulino-résistance et du diabète de type 2. ABSTRACT: L'insulino-résistance, qui caractérise le diabète de type 2 et l'obésité, est due à une diminution de l'action de l'insuline sur ses tissus cibles (foie, tissu adipeux, muscles squelettiques). Il est maintenant bien documenté qu'au niveau de ces tissus, l'accumulation ectopique d'acides gras, et en particulier de métabolites dérivés de ces acides gras, comme les céramides, joue un rôle crucial dans l'altération du message insulinique. Cette revue décrit le rôle majeur joué par les céramides dans le développement de l'insulino-résistance des tissus périphériques.

Urban Nature Experiences Reduce Stress in the Context of Daily Life Based on Salivary Biomarkers.

Stress reduction through contact with nature is well established, but far less is known about the contribution of contact parameters - duration, frequency, and nature quality. This study describes the relationship between duration of a nature experience (NE), and changes in two physiological biomarkers of stress - salivary cortisol and alpha-amylase. It is the first study to employ long-term, repeated-measure assessment and the first evaluation wherein study participants are free to choose the time of day, duration, and the place of a NE in response to personal preference and changing daily schedules. During an 8-week study period, 36 urban dwellers were asked to have a NE, defined as spending time in an outdoor place that brings a sense of contact with nature, at least three times a week for a duration of 10 min or more. Their goal was compliance within the context of unpredictable opportunity for taking a nature pill. Participants provided saliva samples before and after a NE at four points over the study period. Before-NE samples established the diurnal trajectory of each stress indicator and these were in line with published outcomes of more closely controlled experiments. For salivary cortisol, an NE produced a 21.3%/hour drop beyond that of the hormone's 11.7% diurnal drop. The efficiency of a nature pill per time expended was greatest between 20 and 30 min, after which benefits continued to accrue, but at a reduced rate. For salivary alpha-amylase, there was a 28.1%/h drop after adjusting for its diurnal rise of 3.5%/h, but only for participants that were least active sitting or sitting with some walking. Activity type did not influence cortisol response. The methods for this adaptive management study of nature-based restoration break new ground in addressing some complexities of measuring an effective nature dose in the context of normal daily life, while bypassing the limitations of a clinical pharmacology dose-response study. The results provide a validated starting point for healthcare practitioners prescribing a nature pill to those in their care. This line of inquiry is timely in light of expanding urbanization and rising healthcare costs.

Sphingolipid Metabolism: New Insight into Ceramide-Induced Lipotoxicity in Muscle Cells.

Insulin-resistance is a characteristic feature of type 2 diabetes (T2D) and plays a major role in the pathogenesis of this disease. Skeletal muscles are quantitatively the biggest glucose users in response to insulin and are considered as main targets in development of insulin-resistance. It is now clear that circulating fatty acids (FA), which are highly increased in T2D, play a major role in the development of muscle insulin-resistance. In healthy individuals, excess FA are stored as lipid droplets in adipocytes. In situations like obesity and T2D, FA from lipolysis and food are in excess and eventually accumulate in peripheral tissues. High plasma concentrations of FA are generally associated with increased risk of developing diabetes. Indeed, ectopic fat accumulation is associated with insulin-resistance; this is called lipotoxicity. However, FA themselves are not involved in insulin-resistance, but rather some of their metabolic derivatives, such as ceramides. Ceramides, which are synthetized de novo from saturated FA like palmitate, have been demonstrated to play a critical role in the deterioration of insulin sensitivity in muscle cells. This review describes the latest progress involving ceramides as major players in the development of muscle insulin-resistance through the targeting of selective actors of the insulin signaling pathway.

Estimation of delay time in survival data with delayed treatment effect.

In randomized controlled trials with delayed treatment effect, there is a delay period before the experimental therapy starts to exhibit a beneficial effect. The phenomenon of delayed treatment effect is often observed in the emerging and important field of immuno-oncology. It is important to estimate the duration of delay as this information helps in characterizing the pattern of comparative treatment effect, understanding the mechanism of action of the experimental therapy, and forming optimal treatment strategies. For a fixed delay time, we propose a maximum likelihood estimator and evaluate its asymptotic properties via simulation. We further evaluate two functions that link the pre- and postdelay hazard ratios to the average hazard ratio given a fixed delay time. For the case of random delay time, where the delay time may vary from patient to patient, we propose a semiparametric joint survival model for delay time and event time to estimate the mean delay time and the postdelay hazard ratio, assuming a Beta distribution for the delay time. We describe an extension of the model to estimate subgroup-specific mean delay times. Simulation study and application to data from a clinical trial in colon cancer patients demonstrate the robustness of the proposed model.

Diabetes-Specific Regulation of Adipocyte Metabolism by the Adipose Tissue Extracellular Matrix.

Context: The role of the extracellular matrix (ECM) in regulating adipocyte metabolism in the context of metabolic disease is poorly defined. Objective: The objective of this study was to define the metabolic phenotype of adipocytes associated with human diabetes (DM) and the role of the ECM in regulating adipocyte metabolism. Design: Adipose tissues from obese patients were studied in standard 2-dimensional (2D) cell culture and an in vitro model of decellularized adipose tissue ECM repopulated with human adipocytes, and results were correlated with DM status. Setting: This study was conducted at the Academic University Medical Center and Veteran's Administration Hospital. Patients: Seventy patients with morbid obesity undergoing bariatric surgery were included in the study. Interventions: Visceral and subcutaneous adipose tissues were collected at the time of bariatric surgery. Outcome measures: This study used metabolic assays for glucose uptake, lipolysis, and lipogenesis in adipocytes in 2D cell culture and 3-dimensional ECM culture. Results: Adipocytes from subjects with DM manifest decreased glucose uptake and decreased lipolysis in 2D culture. ECM supports differentiation of mature adipocytes and recapitulates DM-specific differences in adipocyte metabolism observed in 2D culture. ECM from subjects without DM partially rescues glucose uptake and lipolytic defects in adipocytes from subjects with DM, whereas ECM from subjects with DM impairs glucose uptake in adipocytes from subjects without DM. Conclusions: DM is associated with adipocyte metabolic dysfunction. The ECM regulates adipocyte metabolism. Nondiabetic ECM rescues metabolic dysfunction in DM adipocytes, whereas DM ECM imparts features of metabolic dysfunction to nondiabetic adipocytes. These findings suggest the ECM as a target for manipulating adipose tissue metabolism.

Resting state brain dynamics and its transients: a combined TMS-EEG study.

The brain at rest exhibits a spatio-temporally rich dynamics which adheres to systematic behaviours that persist in task paradigms but appear altered in disease. Despite this hypothesis, many rest state paradigms do not act directly upon the rest state and therefore cannot confirm hypotheses about its mechanisms. To address this challenge, we combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to study brain's relaxation toward rest following a transient perturbation. Specifically, TMS targeted either the medial prefrontal cortex (MPFC), i.e. part of the Default Mode Network (DMN) or the superior parietal lobule (SPL), involved in the Dorsal Attention Network. TMS was triggered by a given brain state, namely an increase in occipital alpha rhythm power. Following the initial TMS-Evoked Potential, TMS at MPFC enhances the induced occipital alpha rhythm, called Event Related Synchronisation, with a longer transient lifetime than TMS at SPL, and a higher amplitude. Our findings show a strong coupling between MPFC and the occipital alpha power. Although the rest state is organized around a core of resting state networks, the DMN functionally takes a special role among these resting state networks.

Designing a broad-spectrum integrative approach for cancer prevention and treatment.

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered.