Somatic Responses Research Articles

Improved decision-making and psychophysiological responses in mesial temporal lobe epilepsy after anterior temporal lobectomy.

The somatic marker hypothesis is an influential model of human decision-making postulating that somatic feedback to the brain enhances decision-making in ambiguous circumstances, i.e. when the probabilities of various outcomes are unknown. The somatic feedback can be measured as autonomic responses, which are regulated by the amygdala. The failure to evoke this somatic feedback, which occurs in patients with amygdala lesions, impairs decision-making. The purpose of this study was to investigate the decision-making behaviour of mesial temporal lobe epilepsy patients with pre- and post-epilepsy surgery to ascertain whether the decision-making abilities of groups can be explained by means of the generation of somatic feedback responses. The preoperative group comprised 32 patients with mesial temporal lobe epilepsy due to hippocampal sclerosis, while the postoperative group comprised 23 patients who had undergone anterior temporal lobectomy. The age and gender-matched control group consisted of 30 healthy participants. Decision-making performances were assessed and skin resistance responses were measured simultaneously. The findings of this study reveal that the decision-making performance of preoperative patients with unilateral mesial temporal lobe epilepsy was impaired under conditions of ambiguity, i.e. they did not generate somatic feedback responses before making decisions around ambiguous outcomes, and produced significantly poor scores overall based on a decision-making task. In addition, the resection of epileptogenic limbic structures positively affected the generation of somatic feedback responses, as demonstrated by the significant difference between the magnitudes of autonomic responses of the pre- and post-operative groups. The findings of the study validate the contribution of mesial temporal lobe structures to decision-making behaviour, and also point to the importance of examining the connectivity patterns between the neural structures involved in the decision-making network.

Response to Venetoclax and Hypomethylating Agents Among Prognostic Risk Groups and Genetic Subtypes of Acute Myeloid Leukemia

▪The combination of venetoclax and hypomethylating agents (HMA) has demonstrated potent activity in acute myeloid leukemia (AML), both in newly diagnosed patients (pts) and those with relapsed/refractory (r/r) disease. We analyzed the association between response to therapy and leukemic somatic mutations, cytogenetics, and other pertinent patient- and leukemia-related features in a large series of newly diagnosed and r/r AML in adults treated with venetoclax in combination with HMA at City of Hope between October 2016 and May 2018.We identified 107 evaluable adults with AML treated with the combination of venetoclax and HMA. Sixty-one (57%) pts had r/r AML at the time of initiating treatment (median prior lines of therapy: 2; range: 1-10), while 46 (43%) were treated in the frontline setting. The median age of pts was 68 years (range: 19-86). AML was de novo in 57 (53%), therapy-related in 23 (21%) and secondary in 27 (25%) pts. Thirty-six (34%) pts had prior exposure to HMA, and 21 (20%) pts had relapsed following prior allogeneic hematopoietic cell transplantation (HCT). The majority of treated pts had unfavorable (52%) or intermediate-risk (39%) AML based on combined cytogenetics and molecular profiles. The most common detected somatic mutations (majority by next generation sequencing) were FLT3 (17%), followed by DNMT3A (15%), RAS and TET2 (each 14%), RUNX1 (13%), TP53 (12%), and IDH1/2 (11%). Most pts received decitabine in combination with venetoclax (N=97, 91%); only 10 (9%) pts received 5-azacitidine together with venetoclax.Complete remission (CR)/CR with incomplete hematologic recovery (CRi) was achieved in 57 (53%) pts after a median of 2 (range 1-4) cycles. For 36 pts who achieved CR/CRi and had available minimal residual disease (MRD) assessment by multicolor flow cytometry (MFC), 23 (64%) became MRD-. CR/CRi was higher in pts carrying favorable- or intermediate-risk AML compared to poor-risk AML (100% vs. 60% vs. 45%, P=0.029). CR/CRi was 48% in those with complex cytogenetics (N = 31), 45% in monosomal karyotype (N = 22), 36% in KMT2A gene rearrangement (N = 11), 74% in normal karyotype (N = 19), and 25% in inversion 3 (N =4). The CR/CRi rate was not significantly different between newly diagnosed or r/r AML (61% vs. 48%, P = 0.17), nor was there a difference associated with AML type (de novo vs. therapy-related vs. secondary, P= 0.26), patient age (> or ≤ 65 years) at time of therapy (P = 0.13), prior allogeneic HCT (P = 0.29), prior administration of HMA (P = 0.37) and the type or schedule (5- or 10-day decitabine) of HMA (P = 0.52). In multivariate analysis, only favorable- or intermediate-risk cytogenetics was associated with better CR/CRi (P = 0.036). CR/CRi was also comparable regardless of the presence or absence of various analyzed somatic AML mutations. However, in recursive partitioning analysis of detectable somatic mutations and response to therapy, the combined lack of RAS, TP53 and RUNX1 mutations was linked to an improved rate of CR/CRi. When AML cases were stratified into functional gene alteration subgroups (according to the TCGA data set), there was no significant difference in CR/CRi according to the presence or absence of certain functional genes/fusions.Median overall survival (OS) for all pts was 12.5 months and was 14.6 months for pts who achieved CR/CRi, in contrast to 4.6 months for non-responders (P <0.001). Only AML subtype (de novo vs. therapy-related vs. secondary) (P <0.001) and AML genetic risk (favorable/intermediate vs. high) (P = 0.042) independently impacted OS in multivariate analysis. None of the AML individual somatic mutations influenced OS for this cohort, however, in recursive partitioning analysis of detectable mutations, the presence of any of SRSF2, IDH1/2 or RUNX1 were associated with improved OS. Furthermore, the presence of myeloid transcription factor (P = 0.033) and spliceosome complex mutations (P = 0.004) predicted superior OS, whereas the presence of a chromatin modifying mutation predicted inferior OS (P = 0.004). Thirteen (23%) responders subsequently underwent allogeneic HCT.We report remarkable activity with venetoclax and HMA across various high-risk genetics and clinical features in AML patients. Prospective studies are warranted to compare this combination directly with chemotherapy in all AML subsets. This is particularly true for high risk AML where response to conventional chemotherapy is poor. [Display omitted] DisclosuresAli:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Salhotra:Kadmon Corporation, LLC: Consultancy. Khaled:Alexion: Consultancy, Speakers Bureau; Juno: Other: Travel Funding; Daiichi: Consultancy. Stein:Celgene: Speakers Bureau; Amgen Inc.: Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

Whole-Genome Genomics Correlates of Response to Anti-PD1 Therapy in Relapsed/Refractory Natural Killer/T Cell Lymphoma

The genetic landscape of Natural killer/T-cell nasal-type lymphoma (NKTL) has been recently unraveled by discoveries describing recurring mutations altering the JAK-STAT pathway, epigenetic modifiers, the DDX3X gene and genetic predisposition in the HLA-DPB1 gene but none has employed whole-genome sequencing (WGS).Whole-genome sequencing was performed for 11 pairs of tumor-blood samples to study the association between somatic mutations and response to pembrolizumab. Interestingly, recurrent PD-L1 SRs were validated in four of the seven complete responders (CR) cases. JAK3-activating (p.A573V) mutations were also validated in another two pembrolizumab-treated patients who have achieved CR. Lastly, we also found a homozygous 3 bp insertion (p.Q131_H132insQ) in the ARID1B gene, a chromatin remodeler gene and a subunit in the SWI/SNF complex in the last remaining CR case. A recent study has also reported PBRM1-deficient and ARID2-deficient tumors correlated with better response to anti-PD1/PD-L1 therapy renal cell carcinoma. There seems to be a relationship between truncating alterations in the subunits of the SWI/SNF complex and response to PD1/PD-L1 therapy. However, the exact mechanisms behind these associations remain to be elucidated for NKTL.Analysis of the WGS data from the four remaining progressive disease (PD) patients' tumors did not reveal similar alterations in the PD-L1 and JAK3 genes. A careful inspection was also carried out on the genes associated with major histocompatibility complex and interferon gamma pathways, which are known to associate with resistance to immune checkpoint blockade in melanoma, but no further mutation in these groups of genes was found in our cohort. Furthermore, a TP53 (p.W14X) stop-gain mutation, a hallmark tumor suppressor gene, was detected in a patient who had progressive disease after given pembrolizumab.We went on to check if PD-L1 IHC staining could explain the response of these NKTL patients to pembrolizumab. In this study, tumors were stained and assessed for PD-L1 positivity by the same pathologist. All cases, except two cases, have greater than 20% of tumor cells stained positive for PD-L1. Interesting, both cases are CR. In addition, all four PD cases were strongly stained for PD-L1 with an average of 69% PD-L1 positive cells (range, 50% - 90%) but their outcomes were dismal. This suggests that there could be a companion biomarker that could be added to PD-L1 IHC positivity for better predictive power of response to PD1 blockade therapy.Here we report retrospectively, for the first time, the genomic mutational profiles of anti-PD1 blockade in 11 relapsed/refractory NKTL patients using WGS data, which provide proof-of-concept data that the response to anti-PD1 is relevant and correlates with recurrent PD-L1 and JAK3 genomic alterations in this malignancy. DisclosuresNo relevant conflicts of interest to declare.

Paradox-Breaker Pan-RAF Inhibitors Induce an AML-Specific Cytotoxic Response and Synergize with Venetoclax to Display Superior Antileukemic Activity

The RAS-RAF-MEK-ERK (MAPK) pathway is deregulated in many cancers including acute myeloid leukemia (AML), where it facilitates cancer progression, chemo-resistance and cancer relapse. Therefore, the inhibition of this pathway has been explored for the treatment of AML, especially in the ~10% of AML cases where the leukemic cells carry activating mutations of the NRAS or KRAS oncogenes. However, MEK inhibitors, the best explored class of MAPK inhibitors, have not proven effective in the clinical setting. A novel clinically investigated drug class in this context are the paradox-breaker pan-RAF inhibitors that prevent the reactivation of the MAPK-pathway and have exhibited single agent efficacy in preclinical testing for solid cancers. Therefore, it is relevant to explore the utility of this class of drugs for AML treatment.We found that the paradox breaker pan-RAF inhibitors LY3009120 (currently in clinical testing), AZ-628 and TAK-632 as well as other MAPK inhibitors effectively downregulated MAPK signaling activity (ERK phosphorylation) in AML cells. However, when comparing cell viability (CellTiter Glo) and cell death (CellTox Green) responses in 101 AML patient sample cohort, only the pan-RAF inhibitors induced cytotoxicity while the other MAPK-pathway inhibitors generally induced a temporary cytostatic response. Specifically, LY3009120 induced cell death in 42 samples out of 101 (42 %) whereas only 9/101 (9 %) underwent cell death in response to trametinib (MEK-inhibitor) (Fig. panel A). Importantly, LY3009120 did not induce cell death in mononuclear bone marrow cells obtained from healthy individuals (5 samples) or in non-hematopoietic cell lines (Fig. panel A).To get insight into the mechanism regulating cell death in response to pan-RAF inhibition we first characterized that cells underwent rapid caspase-3/7 mediated apoptotic cell death in response to pan-RAF inhibitors (Fig. panel B). Therefore, we analyzed the proteins involved in apoptosis pathways and found that MCL-1 protein, but not mRNA levels, were downregulated upon treatment with pan-RAF inhibitors but not with MEK-inhibitors. This suggests that pan-RAF inhibition negatively regulated the translation of MCL-1, thus uncovering a new mode of MCL-1 regulation by RAF kinases. Importantly, pan-RAF inhibitors downregulated MCL-1 levels independently of caspase activity, indicating that MCL-1 downregulation precedes the apoptotic response.We explored the link between somatic mutation status and response to LY3009120 in our AML patient sample cohort. KRAS, KIT, FLT3-TKD, BCOR, JAK2 and PTPN11 mutations were found to correlate positively with pan-RAF inhibitor response, while SRSF2, RUNX1, GATA2 and STAG2 mutations negatively correlated with response and appeared to override positively correlating mutations.As pan-RAF inhibition downregulates MCL-1, an important survival protein whose increased expression is known to cause resistance to BCL-2 inhibitors, we hypothesized that inhibition of RAF kinases can overcome the resistance to BCL-2 inhibitors. In order to test the hypothesis, we generated venetoclax (BCL-2 inhibitor) resistant MOLM-13 cells and treated them with single and combined doses of venetoclax and LY3009120. As expected, combined inhibition of BCL-2 and RAF kinases significantly increased cytotoxicity as compared to either of the drugs alone (Fig. panel C). Conversely, to see if BCL-2 inhibition can overcome resistance to pan-RAF inhibitors, we treated pan-RAF inhibitor resistant HL-60 and THP-1 cells with single and combined doses of venetoclax and LY3009120. Interestingly, the drug combination exhibited synergistic cytotoxicity in HL-60 cells (where LY3009120 alone downregulates MCL-1) but not in THP-1 cells (where LY3009120 alone does not downregulate MCL-1). This indicates that MCL-1 downregulation upon pan-RAF inhibitor treatment is critical for the observed combination cytotoxicity.In summary, our results show that paradox breaker pan-RAF inhibitors are effective as single agents to induce cell death in AML blasts, likely through a combined MAPK pathway and MCL-1 dependent mechanism. Moreover, combined inhibition of RAF kinases and BCL-2 can overcome resistance of AML cells to either drug alone and lead to superior anti-leukemic activity. [Display omitted] DisclosuresHeckman:Celgene: Research Funding; Novartis: Research Funding; Orion Pharma: Research Funding. Porkka:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wennerberg:Novartis: Research Funding.

Acute stress responses after indirect exposure to the MH17 airplane crash.

People can experience disasters vicariously (indirectly) via conversation, social media, radio, and television, even when not directly involved in a disaster. This study examined whether vicarious exposure to the MH17‐airplane crash in Ukraine, with 196 Dutch victims, elicited affective and somatic responses in Dutch adults about 2,600 km away, who happened to participate in an ongoing diary study. Participants (n = 141) filled out a diary three times a day for 30 days on their smartphones. Within‐person changes in positive affect (PA) and negative affect (NA) and somatic symptoms after the crash were studied. Additionally, we tested whether between‐person differences in response could be explained by age, baseline personality (NEO‐FFI‐3), and media exposure. The MH17 crash elicited a small within‐person decrease in PA and an increase in NA and somatic symptoms. This response waned after 3 days and returned to baseline at day four. The decrease in PA was larger in more extraverted participants but smaller in those higher on neuroticism or conscientiousness. The NA response was smaller in elderly. Personality did not seem to moderate the NA and somatic response, and neither did media exposure. Dutch participants showed small acute somatic and affective responses up till 3 days to a disaster that they had not directly witnessed. Vicariously experienced disasters can thus elicit affective‐visceral responses indicative of acute stress reactions. Personality and age explained some of the individual differences in this reaction.

Global and Multiplexed Dendritic Computations under In Vivo-like Conditions

SummaryDendrites integrate inputs nonlinearly, but it is unclear how these nonlinearities contribute to the overall input-output transformation of single neurons. We developed statistically principled methods using a hierarchical cascade of linear-nonlinear subunits (hLN) to model the dynamically evolving somatic response of neurons receiving complex, in vivo-like spatiotemporal synaptic input patterns. We used the hLN to predict the somatic membrane potential of an in vivo-validated detailed biophysical model of a L2/3 pyramidal cell. Linear input integration with a single global dendritic nonlinearity achieved above 90% prediction accuracy. A novel hLN motif, input multiplexing into parallel processing channels, could improve predictions as much as conventionally used additional layers of local nonlinearities. We obtained similar results in two other cell types. This approach provides a data-driven characterization of a key component of cortical circuit computations: the input-output transformation of neurons during in vivo-like conditions.

‘It definitely made a difference’: A grounded theory study of yoga for pregnancy and women's self-efficacy for labour

ObjectiveTo explore women's experience of attending yoga for pregnancy classes in order to generate a theory about which aspects, if any, are effective in enhancing self-efficacy for labour and birth. DesignA longitudinal grounded theory study. MethodsSemi-structured interviews were undertaken with women before they started yoga for pregnancy classes, after they had attended at least six classes, and finally, postnatally. Interview transcripts were analysed using constructive grounded theory and a self-efficacy framework. SettingThree yoga for pregnancy teachers' classes in England. ParticipantsTwenty two women attending yoga for pregnancy classes. FindingsAnalysis of interviews with women at three time points led to a propositional theory that yoga for pregnancy enhances women's self-efficacy for labour by building their confidence and competence through a combination of techniques. These include repeated practice of a variety of pain management strategies, use of affirming language and the telling of positive labour stories, underpinned by yoga practice to lower somatic response to stress.

GLP-1 neurons form a local synaptic circuit within the rodent nucleus of the solitary tract.

Glutamatergic neurons that express pre‐proglucagon (PPG) and are immunopositive (+) for glucagon‐like peptide‐1 (i.e., GLP‐1+ neurons) are located within the caudal nucleus of the solitary tract (cNTS) and medullary reticular formation in rats and mice. GLP‐1 neurons give rise to an extensive central network in which GLP‐1 receptor (GLP‐1R) signaling suppresses food intake, attenuates rewarding, increases avoidance, and stimulates stress responses, partly via GLP‐1R signaling within the cNTS. In mice, noradrenergic (A2) cNTS neurons express GLP‐1R, whereas PPG neurons do not. In this study, confocal microscopy in rats confirmed that prolactin‐releasing peptide (PrRP)+ A2 neurons are closely apposed by GLP‐1+ axonal varicosities. Surprisingly, GLP‐1+ appositions were also observed on dendrites of PPG/GLP‐1+ neurons in both species, and electron microscopy in rats revealed that GLP‐1+ boutons form asymmetric synaptic contacts with GLP‐1+ dendrites. However, RNAscope confirmed that rat GLP‐1 neurons do not express GLP‐1R mRNA. Similarly, Ca2+ imaging of somatic and dendritic responses in mouse ex vivo slices confirmed that PPG neurons do not respond directly to GLP‐1, and a mouse crossbreeding strategy revealed that <1% of PPG neurons co‐express GLP‐1R. Collectively, these data suggest that GLP‐1R signaling pathways modulate the activity of PrRP+ A2 neurons, and also reveal a local “feed‐forward” synaptic network among GLP‐1 neurons that apparently does not use GLP‐1R signaling. This local GLP‐1 network may instead use glutamatergic signaling to facilitate dynamic and potentially selective recruitment of GLP‐1 neural populations that shape behavioral and physiological responses to internal and external challenges.

C - 65Evaluating MMPI-2-RF Infrequent Somatic Responses (Fs) Item Endorsement Rates Across Ethnic, Gender, and Age Groups with a Forensic Inpatient Sample

C - 65Evaluating MMPI-2-RF Infrequent Somatic Responses (Fs) Item Endorsement Rates Across Ethnic, Gender, and Age Groups with a Forensic Inpatient Sample

Brain activation patterns in response to complex triggers in the Word Association Test: results from a new study in the United States

AbstractC.G. Jung's theory of psychological complexes lies at the root of analytical psychology theory and practice. Functional magnetic resonance imaging (fMRI) provides a powerful tool to validate the theory of complexes and eludicate the neuropsychologic mechanisms underlying the unconscious activation of significant memories. In this study, using fMRI, we identify two brain circuits which are activated in response to complex triggering words. Circuit one involves brain regions involved in episodic memory and somatic (body) responses and the experience of uncertainty. A second circuit involves episodic memory, emotion, visual and language association, and semiotic meaning. Specific brain regions include the right prefrontal cortex, SMA cortex, left temporal cortex, and the caudate and cingulate. These brain circuits may be thought of as the biological form in which complexes are experienced. Implications for analytic psychology practice and theory are discussed.

Spatially dispersed synapses yield sharply-tuned place cell responses through dendritic spike initiation.

Key points The generation of dendritic spikes and the consequent sharp tuning of neuronal responses are together attainable even when iso‐feature synapses are randomly dispersed across the dendritic arbor.Disparate combinations of channel conductances with distinct configurations of randomly dispersed place field synapses concomitantly yield similar sharp tuning profiles and similar functional maps of several intrinsic properties.Targeted synaptic plasticity converts silent cells to place cells for specific place fields in models with disparate channel combinations that receive dispersed synaptic inputs from multiple place field locations.Dispersed localization of iso‐feature synapses is a strong candidate for achieving sharp feature selectivity in neurons across sensory‐perceptual systems, with several degrees of freedom in relation to synaptic locations.Quantitative evidence for the possibility that degeneracy (i.e. the ability of disparate structural components to yield similar functional outcomes) could act as a broad framework that effectively accomplishes the twin goals of input‐feature encoding and homeostasis of intrinsic properties without cross interferences. A prominent hypothesis spanning several sensory‐perceptual systems implicates spatially clustered synapses in the generation of dendritic spikes that mediate sharply‐tuned neuronal responses to input features. In this conductance‐based morphologically‐precise computational study, we tested this hypothesis by systematically analysing the impact of distinct synaptic and channel localization profiles on sharpness of spatial tuning in hippocampal pyramidal neurons. We found that the generation of dendritic spikes, the emergence of an excitatory ramp in somatic voltage responses, the expression of several intrinsic somatodendritic functional maps and sharp tuning of place‐cell responses were all attainable even when iso‐feature synapses are randomly dispersed across the dendritic arbor of models with disparate channel combinations. Strikingly, the generation and propagation of dendritic spikes, reliant on dendritic sodium channels and N‐methyl‐d‐asparate receptors, mediated the sharpness of spatial tuning achieved with dispersed synaptic localization. To ensure that our results were not artefacts of narrow parametric choices, we confirmed these conclusions with independent multiparametric stochastic search algorithms spanning thousands of unique models for each synaptic localization scenario. Next, employing virtual knockout models, we demonstrated a vital role for dendritically expressed voltage‐gated ion channels, especially the transient potassium channels, in maintaining sharpness of place‐cell tuning. Importantly, we established that synaptic potentiation targeted to afferents from one specific place field was sufficient to impart place field selectivity even when intrinsically disparate neurons received randomly dispersed afferents from multiple place field locations. Our results provide quantitative evidence for disparate combinations of channel and synaptic localization profiles to concomitantly yield similar tuning and similar intrinsic properties.

Evaluation of Endogenous Sugars, Chlorogenic Acid and Caffeine Associated with Direct Somatic Embryogenesis of Coffee (Coffea arabica L.)

Coffee is one of the most important cash crops cultivated in the world with great economic importance. During the induction of somatic embryogenesis, there are different endogenous compounds involved in the success or failure of the somatic embryogenesis response and these compounds determine the specificity of cellular responses. This present experiment identified and quantified endogenous sugars, chlorogenic acid and caffeine present during somatic embryogenesis of ‘Ruiru 11’. Laboratory experiments were set up at Coffee Research Institute, Ruiru-Kenya between 2014 and 2016. Third leaf pair explants were excised from 8-monthold greenhouse-grown mother plants and cultured in half strength Murashige and Skoog basal salts augmented with Thidiazuron. Once embryos had developed, the cultures were analysed for endogenous sugars, caffeine and chlorogenic acid using HPLC. Generally, green embryogenic cultures contained more and higher quantities of the compounds. Glucose and fructose were highest (38.95 mg/g and 45.43 mg/g respectively) in leaf discs of brown non-embryogenic cultures. Sucrose was highest (62.15 mg/g) in embryos of green embryogenic cultures. Embryos of green embryogenic cultures had the highest chlorogenic acid (5.3 mg/g), whereas caffeine was highest (0.55 mg/g) in embryos of brown embryogenic cultures. Endogenous fructose and glucose inhibited embryogenesis, while sucrose, chlorogenic acids and caffeine promoted embryogenesis and are potential biomarkers for embryogenesis. Other biochemical compounds such as organic acids should be identified and their role in coffee somatic embryogenesis determined.

Efficacy and tolerability of short-term duloxetine treatment in adults with generalized anxiety disorder: A meta-analysis.

ObjectiveTo investigate the efficacy and tolerability of duloxetine during short-term treatment in adults with generalized anxiety disorder (GAD).MethodsWe conducted a comprehensive literature review of the PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials databases for randomized controlled trials(RCTs) comparing duloxetine or duloxetine plus other antipsychotics with placebo for the treatment of GAD in adults. Outcome measures were (1) efficacy, assessed by the Hospital Anxiety and Depression Scale(HADS) anxiety subscale score, the Hamilton Rating Scale for Anxiety(HAM-A) psychic and somatic anxiety factor scores, and response and remission rates based on total scores of HAM-A; (2) tolerability, assessed by discontinuation rate due to adverse events, the incidence of treatment emergent adverse events(TEAEs) and serious adverse events(SAEs). Review Manager 5.3 and Stata Version 12.0 software were used for all statistical analyses.ResultsThe meta-analysis included 8 RCTs. Mean changes in the HADS anxiety subscale score [mean difference(MD) = 2.32, 95% confidence interval(CI) 1.77–2.88, P<0.00001] and HAM-A psychic anxiety factor score were significantly greater in patients with GAD that received duloxetine compared to those that received placebo (MD = 2.15, 95%CI 1.61–2.68, P<0.00001). However, there was no difference in mean change in the HAM-A somatic anxiety factor score (MD = 1.13, 95%CI 0.67–1.58, P<0.00001). Discontinuation rate due to AEs in the duloxetine group was significantly higher than the placebo group [odds ratio(OR) = 2.62, 95%CI 1.35–5.06, P = 0.004]. The incidence of any TEAE was significantly increased in patients that received duloxetine (OR = 1.76, 95%CI 1.36–2.28, P<0.0001), but there was no significant difference in the incidence of SAEs (OR = 1.13, 95%CI 0.52–2.47, P = 0.75).ConclusionDuloxetine resulted in a greater improvement in symptoms of psychic anxiety and similar changes in symptoms of somatic anxiety compared to placebo during short-term treatment in adults with GAD and its tolerability was acceptable.

The Influence of University Students' Stress Mindsets on Health and Performance Outcomes.

Emerging evidence indicates that holding particular stress mindsets has favorable implications for peoples' health and performance under stress. The aim of the current study was to examine the processes by which implicit and explicit stress mindsets relate to health- and performance-related outcomes. Specifically, we propose a stress beliefs model in which somatic responses to stress and coping behaviors mediate the effect of stress mindsets on outcomes. Undergraduate university students (N = 218, n = 144 females) aged 17- 25 years completed measures of stress mindset, physical and psychological wellbeing, perceived stress, perceived somatic responses to stress, proactive behaviors under stress, and an implicit association test assessing an implicit stress mindset. At the end of the semester, students' academic performance was collected from university records. Path analysis indicated significant indirect effects of stress mindset on psychological wellbeing and perceived stress through proactive coping behaviors and perceived somatic symptoms. Stress mindset directly predicted perceived stress and physical wellbeing, and physical wellbeing and academic performance were predicted by stress mindset through perceived somatic symptoms. Implicit stress mindset did not predict proactive behavior as anticipated. Current findings indicate that behaviors with the goal of proactively meeting demands under stress and perceived somatic symptoms are important mediators of the effect of stress mindset on health- and performance-related outcomes. The findings from this study provide formative data that can inform the development of future interventions aiming to encourage more adaptive responses to stress.

Explant origin and culture media factors drive the somatic embryogenesis response in Acrocomia aculeata (Jacq.) Lodd. ex Mart., an emerging oil crop in the tropics

The explant origin and the factors in the culture medium are responsible for the response to somatic embryogenesis in most plant species, including palms. Acrocomia aculeata is a neotropical palm currently undergoing domestication due to its sustainability and profitability as an alternative oil crop. The attainment of productive cultivars of this palm may be speed up by somatic embryogenesis. Thus, this study sought to refine an existing somatic embryogenesis cloning protocol for A. aculeata and to investigate the possible genetic influence on the in vitro propagation response, using zygotic embryos from 19 matrices or open-pollinated families. The embryos were inoculated in modified induction media. The following characteristics were evaluated in this phase: swollen embryos, percentage of zygotic embryos that formed callus, embryogenic calli and oxidation. Afterwards the resulting pro embryogenic masses were subsequently cultivated in modified multiplication, maturation and gemination media. In those phases the open-pollinated families’ response was measured by the growth of their embryogenic mass and the quantity of regenerated and germinated somatic embryos. The refined micropropagation protocol was successful in establishing embryogenic lines and maintaining their cyclic multiplication for a long period; all without the loss of their potential to maturate and regenerate somatic embryos. In general, the multiplication of pro embryogenic masses was effective even in the lowest dose of Picloram (18 μM). The addition of activated charcoal in the medium favored the maturation of somatic embryos. Plantlets regeneration, although defective in some lineages, was promoted by GA3 (0.55 μM). The zygotic embryos’ responsiveness to somatic embryogenesis varied according to their matrices, indicating that if micropropagation is to be used as a mass propagation technique for the species, the explant́s genotype must be considered.

Impact of dietary phosphorous in diploid and triploid Atlantic salmon (Salmo salar L.) with reference to early skeletal development in freshwater

In order to assess the effect of dietary phosphorus (P) in reducing vertebral malformations and improving freshwater (FW) performance in triploid Atlantic salmon (Salmo salar), both triploid and diploid Atlantic salmon were fed three different dietary P inclusion levels (low: 4.9, medium: 7.7, and high: 9.7 g available P kg−1) from first feeding until smolt. Somatic and skeletal response was assessed at fry (~0.5 g), parr (~5 g) and smolt (~45 g) stages. Triploid parr initially grew faster on the high P diet, while groups fed low P resulted in a significantly higher weight at smolt. Image analysis of double stained Alcian blue and Alizarin red S fry revealed that low P fed triploid fish presented less well mineralised vertebrae, and significantly more malformed vertebrae in both parr and smolt stages following x-ray radiographic assessment. Triploid parr fed high and medium P had similar numbers of malformed vertebrae relative to their diploid counterparts but greater numbers than at smolt. Low P fed triploids had the highest prevalence of jaw and vertebral malformations as well as the highest number of deformed vertebrae in the central caudal vertebral region, which was more pronounced at parr than at smolt. Shorter vertebrae dorso-ventral lengths were observed throughout the spinal column (R1–R4) in parr fed low P and only in the caudal region (R3) at smolt. In parr, both ploidies showed reduced phosphate homeostasis protein fgf23 gene expression in vertebrae when fed low P diets, while triploids showed greater down-regulation of osteogenic factors (alp, opn and igf1r) between diets relative to diploids, suggesting possible greater active suppression of mineralisation and reduced osteogenic potential in triploids. No effects of diet or ploidy on gene expression were evident at smolt. Comparisons between development stages suggest early P supplementation in triploids is crucial for skeletal development. Ultimately, reducing vertebral deformities observed at smolt with higher P supplementation in triploids could contribute towards improving skeletal performance and welfare of the stocks in the marine phase.

Standardised noxious stimulation-guided individual adjustment of remifentanil target-controlled infusion to prevent haemodynamic responses to laryngoscopy and surgical incision: A randomised controlled trial.

The surgical plethysmographic index (SPI) is one of the available indexes of the nociception-antinociception (NAN) balance. Individually adjusting the NAN balance to prevent somatic responses to noxious stimulation remains a challenge. To assess whether guiding remifentanil administration according to the SPI response to a calibrated noxious stimulus (NANCAL) can blunt the haemodynamic response to tracheal intubation and surgical incision. Randomised multicentre study. Two Belgian university hospitals from January 2014 to April 2015. After ethic review board approval and informed consent, 48 American Society of Anesthesiologists I or II adult patients scheduled for surgery under general anaesthesia were enrolled. Patients were randomly assigned to a SPI group, where remifentanil effect-site concentration was adjusted according to NANCAL, or a control group, where it was fixed at 4 ng ml. Propofol concentration was always adjusted to maintain the bispectral index close to 40. NANCAL consisted of a 100 Hz, 60 mA electrical tetanic stimulation during 30 s at the wrist before tracheal intubation and before surgical incision. The primary endpoint was the efficacy of the NANCAL-guided remifentanil administration to prevent the haemodynamic response to tracheal intubation and surgical incision. The secondary aim was to compare the ability of SPI, analgesia nociception index, pupil diameter and mean arterial pressure response to NANCAL to predict the haemodynamic response to tracheal intubation and surgical incision. Our SPI response to NANCAL-based correcting scheme for remifentanil administration was not superior to a fixed remifentanil concentration at blunting the haemodynamic response to tracheal intubation or surgical incision. Among all tested NAN balance indices, only mean arterial pressure had significant predictive ability with regard to the haemodynamic response to surgical incision. Further research is needed to define the best NANCAL stimulus and the best remifentanil correcting scheme to help individualised tailoring of antinociception for each specific subpopulation of surgical patients. Clinicaltrials.gov NCT: 02884310; https://clinicaltrials.gov/ct2/show/NCT02884310.

Systematic generation of biophysically detailed models for diverse cortical neuron types

The cellular components of mammalian neocortical circuits are diverse, and capturing this diversity in computational models is challenging. Here we report an approach for generating biophysically detailed models of 170 individual neurons in the Allen Cell Types Database to link the systematic experimental characterization of cell types to the construction of cortical models. We build models from 3D morphologies and somatic electrophysiological responses measured in the same cells. Densities of active somatic conductances and additional parameters are optimized with a genetic algorithm to match electrophysiological features. We evaluate the models by applying additional stimuli and comparing model responses to experimental data. Applying this technique across a diverse set of neurons from adult mouse primary visual cortex, we verify that models preserve the distinctiveness of intrinsic properties between subsets of cells observed in experiments. The optimized models are accessible online alongside the experimental data. Code for optimization and simulation is also openly distributed.

Exploring Efficient Callusing and Rapid Regeneration System in Upland Rice (&lt;i&gt;Oryza sativa&lt;/i&gt; L.)

An efficient callusing and rapid regeneration system is all time needed for successful genetic transformation in rice. Therefore, mature healthy dehulled kernels of a popular upland rice variety Khandagiri was used for in vitro culture using four callus induction media and various hormone recipes singly or in combination. MS medium was equivalent to LS medium for callusing response while, BM and B5 media had shown delayed and poor callusing response without inducing somatic embryos. MS with 2.5mg/l 2, 4-D + 0.5mg/l Kn induced fast growing creamy, embryogenic and nodular calli with minimum necrosis. MS with 2.0mg/l BAP + 0.5mg/l NAA revealed excellent somatic embryogenic regeneration response with on an average 8.8 shoots per responsive callus as compared to any other combinations of BAP/Kn with NAA. The regenerated shoots were rooted on MS medium with NAA(1.0mg/l) + BAP (0.2mg/l) with highest rhizogenetic response within a week. The present reproducible in vitro culture system is amenable for rapid plantlet regeneration in upland rice.

Chapter 10 - Shivering and nonshivering thermogenesis in skeletal muscles

Humans have inherited complex neural circuits which drive behavioral, somatic, and autonomic thermoregulatory responses to defend their body temperature. While they are well adapted to dissipate heat in warm climates, they have a reduced capacity to preserve it in cold environments. Consequently, heat production is critical to defending their core temperature. As in other large mammals, skeletal muscles are the primary source of heat production recruited in cold-exposed humans. This is achieved voluntarily in the form of contractions from exercising muscles or involuntarily in the form of contractions from shivering muscles and the recruitment of nonshivering mechanisms. This review describes our current understanding of shivering and nonshivering thermogenesis in skeletal muscles, from the neural circuitry driving their recruitment to the metabolic substrates that fuel them. The presence of these heat-producing mechanisms can be measured in vivo by combining indirect respiratory calorimetry with electromyography or biomedical imaging modalities. Indeed, much of what is known regarding shivering in humans and other animal models stems from studies performed using these methods combined with in situ and in vivo neurologic techniques. More recent investigations have focused on understanding the metabolic processes that produce the heat from both contracting and noncontracting mechanisms. With the growing interest in the potential therapeutic benefits of shivering and nonshivering skeletal muscle to counter the effects of neuromuscular, cardiovascular, and metabolic diseases, we expect this field to continue its growth in the coming years.