NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance.

The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically1,2. This results in substantial accumulation of lacate, the end product of anaerobic glycolysis, in cancer cells3. However, how cancer metabolism affects chemotherapy response and DNA repair in general remains incompletely understood. Here we report that lactate-driven lactylation of NBS1 promotes homologous recombination (HR)-mediated DNA repair. Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11-RAD50-NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks. Furthermore, we identify TIP60 as the NBS1 lysine lactyltransferase and the 'writer' of NBS1 K388 lactylation, and HDAC3 as the NBS1 de-lactylase. High levels of NBS1 K388 lactylation predict poor patient outcome of neoadjuvant chemotherapy, and lactate reduction using either genetic depletion of lactate dehydrogenase A (LDHA) or stiripentol, a lactate dehydrogenase A inhibitor used clinically for anti-epileptic treatment, inhibited NBS1 K388 lactylation, decreased DNA repair efficacy and overcame resistance to chemotherapy. In summary, our work identifies NBS1 lactylation as a critical mechanism for genome stability that contributes to chemotherapy resistance and identifies inhibition of lactate production as a promising therapeutic cancer strategy.

Discontinuation of anti-tumour necrosis factor alpha treatment owing to blood test abnormalities, and cost-effectiveness of alternate blood monitoring strategies.

BACKGROUND: There is no evidence base to support the use of 6-monthly monitoring blood tests for the early detection of liver, blood and renal toxicity during established anti-tumour necrosis factor alpha (TNFα) treatment. OBJECTIVES: To evaluate the incidence and risk factors of anti-TNFα treatment cessation owing to liver, blood and renal side-effects, and to estimate the cost-effectiveness of alternate intervals between monitoring blood tests. METHODS: A secondary care-based retrospective cohort study was performed. Data from the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR) were used. Patients with at least moderate psoriasis prescribed their first anti-TNFα treatment were included. Treatment discontinuation due to a monitoring blood test abnormality was the primary outcome. Patients were followed-up from start of treatment to the outcome of interest, drug discontinuation, death, 31 July 2021 or up to 5 years, whichever came first. The incidence rate (IR) and 95% confidence intervals (CIs) of anti-TNFα discontinuation with monitoring blood test abnormality was calculated. Multivariate Cox regression was used to examine the association between risk factors and outcome. A mathematical model evaluated costs and quality-adjusted life years (QALYs) associated with increasing the length of time between monitoring blood tests during anti-TNFα treatment. RESULTS: The cohort included 8819 participants [3710 (42.1%) female, mean (SD) age 44.76 (13.20) years] that contributed 25 058 person-years (PY) of follow-up and experienced 125 treatment discontinuations owing to a monitoring blood test abnormality at an IR of 5.85 (95% CI 4.91-6.97)/1000 PY. Of these, 64 and 61 discontinuations occurred within the first year and after the first year of treatment start, at IRs of 8.62 (95% CI 6.74-11.01) and 3.44 (95% CI 2.67-4.42)/1000 PY, respectively. Increasing age (in years), diabetes and liver disease were associated with anti-TNFα discontinuation after a monitoring blood test abnormality [adjusted hazard ratios of 1.02 (95% CI 1.01-1.04), 1.68 (95% CI 1.00-2.81) and 2.27 (95% CI 1.26-4.07), respectively]. Assuming a threshold of £20 000 per QALY gained, no monitoring was most cost-effective, but all extended periods were cost-effective vs. 3- or 6-monthly monitoring. CONCLUSIONS: Anti-TNFα drugs were uncommonly discontinued owing to abnormal monitoring blood tests after the first year of treatment. Extending the duration between monitoring blood tests was cost-effective. Our results produce evidence for specialist society guidance to reduce patient monitoring burden and healthcare costs.

Risk of Suicide and Suicidality in Patients with Moderate to Severe Psoriasis: results from the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR).

BACKGROUND: Psoriasis is associated with poor mental health and reduced quality of life. Although the high risk for depression in patients with psoriasis is well-established, their suicidality risk is uncertain. Previous studies provide contrasting results and have not included patients with clinically-confirmed severe disease. OBJECTIVES: Our aim was to determine risk of suicide among patients with moderate to severe psoriasis compared with the general population, and investigate if psychiatric comorbidity or history of suicidality increases future suicidality risk in psoriasis. We further estimated the incidence of suicidal and self-injurious behaviours in patients. METHODS: Analysis was performed using the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR). As controls, general population mortality and suicide data were used. RESULTS: There were 9 suicides in BADBIR. The incidence rate of suicide was 12.5 per 100,000 person-years (95% CI 6.53, 24.11) in BADBIR versus 11.0 per 100,000 person-years (95% CI 10.7, 11.3) in the general population in England and Wales. Among patients, psychiatric comorbidity or past suicidality was associated with higher risk for suicidal ideation, suicide attempts and self-injurious behaviours. CONCLUSIONS: Suicide rates among patients with moderate to severe psoriasis were not significantly higher compared with the general population. Suicide is a rare event and our results are limited by the uncertainty in the estimate reliability. However, considering the high depression prevalence in psoriasis, our findings support the need for prompt assessment of patients for psychiatric comorbidities and suicidality history. Further research is required on suicidal behaviours and the role of psoriasis severity.

METTL3 promotes oxaliplatin resistance of gastric cancer CD133+ stem cells by promoting PARP1 mRNA stability.

Oxaliplatin is the first-line regime for advanced gastric cancer treatment, while its resistance is a major problem that leads to the failure of clinical treatments. Tumor cell heterogeneity has been considered as one of the main causes for drug resistance in cancer. In this study, the mechanism of oxaliplatin resistance was investigated through in vitro human gastric cancer organoids and gastric cancer oxaliplatin-resistant cell lines and in vivo subcutaneous tumorigenicity experiments. The in vitro and in vivo results indicated that CD133+ stem cell-like cells are the main subpopulation and PARP1 is the central gene mediating oxaliplatin resistance in gastric cancer. It was found that PARP1 can effectively repair DNA damage caused by oxaliplatin by means of mediating the opening of base excision repair pathway, leading to the occurrence of drug resistance. The CD133+ stem cells also exhibited upregulated expression of N6-methyladenosine (m6A) mRNA and its writer METTL3 as showed by immunoprecipitation followed by sequencing and transcriptome analysis. METTTL3 enhances the stability of PARP1 by recruiting YTHDF1 to target the 3'-untranslated Region (3'-UTR) of PARP1 mRNA. The CD133+ tumor stem cells can regulate the stability and expression of m6A to PARP1 through METTL3, and thus exerting the PARP1-mediated DNA damage repair ability. Therefore, our study demonstrated that m6A Methyltransferase METTL3 facilitates oxaliplatin resistance in CD133+ gastric cancer stem cells by Promoting PARP1 mRNA stability which increases base excision repair pathway activity.

Neuropilin 1 mediates epicardial activation and revascularization in the regenerating zebrafish heart.

Unlike adult mammals, zebrafish can regenerate their heart. A key mechanism for regeneration is the activation of the epicardium, leading to the establishment of a supporting scaffold for new cardiomyocytes, angiogenesis and cytokine secretion. Neuropilins are co-receptors that mediate signaling of kinase receptors for cytokines with crucial roles in zebrafish heart regeneration. We investigated the role of neuropilins in response to cardiac injury and heart regeneration. All four neuropilin isoforms (nrp1a, nrp1b, nrp2a and nrp2b) were upregulated by the activated epicardium and an nrp1a-knockout mutant showed a significant delay in heart regeneration and displayed persistent collagen deposition. The regenerating hearts of nrp1a mutants were less vascularized, and epicardial-derived cell migration and re-expression of the developmental gene wt1b was impaired. Moreover, cryoinjury-induced activation and migration of epicardial cells in heart explants were reduced in nrp1a mutants. These results identify a key role for Nrp1 in zebrafish heart regeneration, mediated through epicardial activation, migration and revascularization.

Retinal and Cortical Contributions to Phosphenes During Transcranial Electrical Current Stimulation.

It is generally believed that the phosphenes induced by transcranial electric current stimulation (tECS) are a product of retinal activation, even when electrode placement is directly over the primary visual cortex. However, the origins of these tECS-induced phosphenes have not yet been conclusively determined. In this study, phosphene detection thresholds using an FPz-Oz montage were compared with those from (i) an Oz-Cz montage to determine whether prefrontal regions, such as the retina, contribute to phosphenes and (ii) an FPz-Cz montage to determine whether the visual cortex in the occipital lobe contributes to phosphenes. Twenty-two participants received transcranial current stimulation with each of these montages (as well as a T3-T4 montage included for exploratory purposes) at 6, 10, 16, 20, 24, 28, and 32 Hz. To estimate differences in current density at the retina and occipital lobe across montages, modeling of current density at phosphene thresholds was measured across 20 head models. Consistent with the proposal that tECS-induced phosphenes are generated in the retina, increasing current density near the retina (FPz-Oz relative to Oz-Cz montage) reduced phosphene thresholds. However, increasing current density near the occipital cortex (FPz-Oz relative to FPz-Cz montage) also reduced phosphene thresholds while also requiring less current density at the retina according to the modeling estimates. This suggests that tECS of this occipital cortex also contributed to phosphene perception. © 2020 Bioelectromagnetics Society.

HLA-C*06:02 genotype is a predictive biomarker of biologic treatment response in psoriasis.

BACKGROUND: Biologic therapies can be highly effective for the treatment of severe psoriasis, but response for individual patients can vary according to drug. Predictive biomarkers to guide treatment selection could improve patient outcomes and treatment cost-effectiveness. OBJECTIVE: We sought to test whether HLA-C*06:02, the primary genetic susceptibility allele for psoriasis, predisposes patients to respond differently to the 2 most commonly prescribed biologics for psoriasis: adalimumab (anti-TNF-α) and ustekinumab (anti-IL-12/23). METHODS: This study uses a national psoriasis registry that includes longitudinal treatment and response observations and detailed clinical data. HLA alleles were imputed from genome-wide genotype data for 1326 patients for whom 90% reduction in Psoriasis Area and Severity Index score (PASI90) response status was observed after 3, 6, or 12 months of treatment. We developed regression models of PASI90 response, examining the interaction between HLA-C*06:02 and drug type (adalimumab or ustekinumab) while accounting for potentially confounding clinical variables. RESULTS: HLA-C*06:02-negative patients were significantly more likely to respond to adalimumab than ustekinumab at all time points (most strongly at 6 months: odds ratio [OR], 2.95; P = 5.85 × 10-7), and the difference was greater in HLA-C*06:02-negative patients with psoriatic arthritis (OR, 5.98; P = 6.89 × 10-5). Biologic-naive patients who were HLA-C*06:02 positive and psoriatic arthritis negative demonstrated significantly poorer response to adalimumab at 12 months (OR, 0.31; P = 3.42 × 10-4). Results from HLA-wide analyses were consistent with HLA-C*06:02 itself being the primary effect allele. We found no evidence for genetic interaction between HLA-C*06:02 and ERAP1. CONCLUSION: This large observational study suggests that reference to HLA-C*06:02 status could offer substantial clinical benefit when selecting treatments for severe psoriasis.

Smooth muscle cell-specific knockout of neuropilin-1 impairs postnatal lung development and pathological vascular smooth muscle cell accumulation.

Neuropilin 1 (NRP1) is important for neuronal and cardiovascular development due to its role in conveying class 3 semaphorin and vascular endothelial growth factor signaling, respectively. NRP1 is expressed in smooth muscle cells (SMCs) and mediates their migration and proliferation in cell culture and is implicated in pathological SMC remodeling in vivo. To address the importance of Nrp1 for SMC function during development, we generated conditional inducible Nrp1 SMC-specific knockout mice. Induction of early postnatal SMC-specific Nrp1 knockout led to pulmonary hemorrhage associated with defects in alveogenesis and revealed a specific requirement for Nrp1 in myofibroblast recruitment to the alveolar septae and PDGF-AA-induced migration in vitro. Furthermore, SMC-specific Nrp1 knockout inhibited PDGF-BB-stimulated SMC outgrowth ex vivo in aortic ring assays and reduced pathological arterial neointima formation in vivo. In contrast, we observed little significant effect of SMC-specific Nrp1 knockout on neonatal retinal vascularization. Our results point to a requirement of Nrp1 in vascular smooth muscle and myofibroblast function in vivo, which may have relevance for postnatal lung development and for pathologies characterized by excessive SMC and/or myofibroblast proliferation.

VEGF (Vascular Endothelial Growth Factor) Induces NRP1 (Neuropilin-1) Cleavage via ADAMs (a Disintegrin and Metalloproteinase) 9 and 10 to Generate Novel Carboxy-Terminal NRP1 Fragments That Regulate Angiogenic Signaling.

Objective- NRP1(neuropilin-1) acts as a coreceptor for VEGF (vascular endothelial growth factor) with an essential role in angiogenesis. Recent findings suggest that posttranslational proteolytic cleavage of VEGF receptors may be an important mechanism for regulating angiogenesis, but the role of NRP1 proteolysis and the NRP1 species generated by cleavage in endothelial cells is not known. Here, we characterize NRP1 proteolytic cleavage in endothelial cells, determine the mechanism, and investigate the role of NRP1 cleavage in regulation of endothelial cell function. Approach and Results- NRP1 species comprising the carboxy (C)-terminal and transmembrane NRP1 domains but lacking the ligand-binding A and B regions are constitutively expressed in endothelial cells. Generation of these C-terminal domain NRP1 proteins is upregulated by phorbol ester and Ca2+ ionophore, and reduced by pharmacological inhibition of metalloproteinases, by small interfering RNA-mediated knockdown of 2 members of ADAM (a disintegrin and metalloproteinase) family, ADAMs 9 and 10, and by a specific ADAM10 inhibitor. Furthermore, VEGF upregulates expression of these NRP1 species in an ADAM9/10-dependent manner. Transduction of endothelial cells with adenoviral constructs expressing NRP1 C-terminal domain fragments inhibited VEGF-induced phosphorylation of VEGFR2 (VEGF receptor tyrosine kinase)/KDR (kinase domain insert receptor) and decreased VEGF-stimulated endothelial cell motility and angiogenesis in coculture and aortic ring sprouting assays. Conclusions- These findings identify novel NRP1 species in endothelial cells and demonstrate that regulation of NRP1 proteolysis via ADAMs 9 and 10 is a new regulatory pathway able to modulate VEGF angiogenic signaling.

Vascular Endothelial Growth Factor (VEGF) Promotes Assembly of the p130Cas Interactome to Drive Endothelial Chemotactic Signaling and Angiogenesis.

p130Cas is a polyvalent adapter protein essential for cardiovascular development, and with a key role in cell movement. In order to identify the pathways by which p130Cas exerts its biological functions in endothelial cells we mapped the p130Cas interactome and its dynamic changes in response to VEGF using high-resolution mass spectrometry and reconstruction of protein interaction (PPI) networks with the aid of multiple PPI databases. VEGF enriched the p130Cas interactome in proteins involved in actin cytoskeletal dynamics and cell movement, including actin-binding proteins, small GTPases and regulators or binders of GTPases. Detailed studies showed that p130Cas association of the GTPase-binding scaffold protein, IQGAP1, plays a key role in VEGF chemotactic signaling, endothelial polarization, VEGF-induced cell migration, and endothelial tube formation. These findings indicate a cardinal role for assembly of the p130Cas interactome in mediating the cell migratory response to VEGF in angiogenesis, and provide a basis for further studies of p130Cas in cell movement.

Frequency-dependent and montage-based differences in phosphene perception thresholds via transcranial alternating current stimulation.

It is well known that applying transcranial alternating current stimulation (tACS) to the scalp can generate artefactual visual perceptions of flashing or shimmering light known as phosphenes. The thresholds for generating these phosphenes have been used by international standards bodies to provide conservative estimates of the field strength required to interfere with human neural functioning and set safety limits accordingly. However, the precise relationship between electric currents and phosphene perception thresholds remains uncertain. The present study used tACS to systematically investigate the effects of the location and the frequency of stimulation on phosphene perception thresholds. These thresholds were obtained from 24 participants using a within-subject design as a function of scalp stimulation sites (FPz-Cz versus Oz-Cz) and stimulation frequency (2-30 Hz in steps of 2 Hz). Phosphene perception thresholds were consistently lower for FPz-Cz stimulation, and regardless of tACS location were lowest for 16 Hz stimulation. Threshold variation between participants was very small, which is meaningful when setting standards based on phosphenes. Bioelectromagnetics. 2019;40:365-374. © 2019 Bioelectromagnetics Society.

A crucial role for DOK1 in PDGF-BB-stimulated glioma cell invasion through p130Cas and Rap1 signalling.

DOK1 regulates platelet-derived growth factor (PDGF)-BB-stimulated glioma cell motility. Mechanisms regulating tumour cell motility are essential for invasion and metastasis. We report here that PDGF-BB-mediated glioma cell invasion and migration are dependent on the adaptor protein downstream of kinase 1 (DOK1). DOK1 is expressed in several glioma cell lines and in tumour biopsies from high-grade gliomas. DOK1 becomes tyrosine phosphorylated upon PDGF-BB stimulation of human glioma cells. Knockdown of DOK1 or expression of a DOK1 mutant (DOK1FF) containing Phe in place of Tyr at residues 362 and 398, resulted in inhibition of both the PDGF-BB-induced tyrosine phosphorylation of p130Cas (also known as BCAR1) and the activation of Rap1. DOK1 colocalises with tyrosine phosphorylated p130Cas at the cell membrane of PDGF-BB-treated cells. Expression of a non-tyrosine-phosphorylatable substrate domain mutant of p130Cas (p130Cas15F) inhibited PDGF-BB-mediated Rap1 activation. Knockdown of DOK1 and Rap1 inhibited PDGF-BB-induced chemotactic cell migration, and knockdown of DOK1 and Rap1 and expression of DOK1FF inhibited PDGF-mediated three-dimensional (3D) spheroid invasion. These data show a crucial role for DOK1 in the regulation of PDGF-BB-mediated tumour cell motility through a p130Cas-Rap1 signalling pathway. [Corrected]

N-terminal modification of VEGF-A C terminus-derived peptides delineates structural features involved in neuropilin-1 binding and functional activity.

The interaction between VEGF-A and its neuropilin (NRP) receptors mediates a number of important biological effects. NRP1 and the related molecule NRP2 are widely expressed on multiple tumour types and throughout the tumour vasculature, and are emerging as critical molecules required for the progression of angiogenic diseases. Given the increasing evidence supporting a role for NRP1 in tumour development, there is growing interest in developing inhibitors of NRP1 interactions with VEGF and its other ligands. In order to probe the interaction we synthesised a number of exon 7- and 8-derived bicyclic peptides with N-terminal lipophilic groups and found a simple N-octanoyl derivative (EG00086) to be the most potent and functionally active. Detailed modelling studies indicated that new intramolecular hydrogen bonds were formed, stabilising the structure and possibly contributing to the potency. Removal of a salt bridge between D142 and R164 implicated in VEGF-A binding to neuropilin-1 had a minor effect on potency. Isothermal calorimetry was used to assess binding of EG00086 to NRP1 and NRP2, and the stability of the peptide in serum and in vivo was investigated. EG00086 is a potent blocker of VEGF-promoted cellular adhesion to extracellular matrices, and phosphorylation of p130Cas contributes to this effect.

Novel processing and staining methodology of bottlenose dolphin (Tursiops truncatus) teeth for age determination.

Age determination of bottlenose dolphins (Tursiops truncatus) is a critical tool in understanding both individual and population health. There are many methods of aging bottlenose dolphins including analysis of teeth, pectoral flipper radiographs, and epigenetics. The most common and oldest method for aging toothed cetaceans is the counting of growth layer groups (GLGs) in the teeth. Current techniques have technical and repeatability challenges. Therefore, a processing technique that results in better resolution of GLGs is needed. This study compares different decalcifications and different histochemical staining techniques. Decalcification was done using 10% EDTA, Kristensen's decalcification, and Rapid Decalcification Solution (RDO). Following decalcification and routine processing, GLGs were assessed using Hematoxylin and Eosin (H&E), hematoxylin, Giemsa, Wright-Giemsa, Toluidine Blue (T-Blue), Masson's Trichrome, and Congo Red staining techniques. Decalcification with Kristensen's and staining with Masson's Trichrome and Congo Red were determined to best highlight GLGs. This processing and staining was then applied to a sample population of 102 bottlenose dolphins that were evaluated independently and blindly by two observers. Of the 102 dolphin samples, 13 (12.7%) were unable to age due to no clear distinction or distortion between GLGs.

Neurological Validation of ASD Diagnostic Criteria Using Frontal Alpha and Theta Asymmetry.

Background/Objectives: Diagnosis of Autism Spectrum Disorder (ASD) relies on the observation of difficulties in social communication and interaction, plus the presence of repetitive and restrictive behaviors. The identification of neurological correlates of these symptoms remains a high priority for clinical research, and has the potential to increase the validity of diagnosis of ASD as well as provide greater understanding of how the autistic brain functions. This study focused on two neurological phenomena that have been previously associated with psychiatric disorders (alpha- and theta-wave asymmetry across the frontal region of the brain), and tested for their association with the major diagnostic criteria for ASD. Methods: A total of 41 male autistic youth underwent assessment with the Autism Diagnostic Observation Schedule (ADOS-2) and 3 min of eyes-closed resting EEG to collect alpha- and theta-wave data from right and left frontal brain sites. Results: Different associations were found for theta versus alpha asymmetry and the ADOS-2 subscales, across different brain regions responsible for a varying range of cognitive functions. In general, theta asymmetry was associated with conversation with others, sharing of enjoyment, and making social overtures, whereas alpha asymmetry was linked with making eye contact, reporting events to others, and engaging in reciprocal social communication. Specific brain regions involved are identified, as well as implications for clinical practice. Conclusions: Specific autism symptoms may be associated with selected brain region activity, providing a neurological basis for diagnosis and treatment.

Depression Severity, Slow- versus Fast-Wave Neural Activity, and Symptoms of Melancholia.

Melancholia is a major and severe subtype of depression, with only limited data regarding its association with neurological phenomena. To extend the current understanding of how particular aspects of melancholia are correlated with brain activity, electroencephalographic data were collected from 100 adults (44 males and 56 females, all aged 18 y or more) and investigated for the association between symptoms of melancholia and the ratios of alpha/beta activity and theta/beta activity at parietal-occipital EEG sites PO1 and PO2. The results indicate differences in these associations according to the depressive status of participants and the particular symptom of melancholia. Depressed participants exhibited meaningfully direct correlations between alpha/beta and theta/beta activity and the feeling that "Others would be better off if I was dead" at PO1, whereas non-depressed participants had significant inverse correlations between theta/beta activity and "Feeling useless and not needed" and "I find it hard to make decisions" at PO1. The results are discussed in terms of the relative levels of fast-wave (beta) versus slow-wave (alpha, theta) activity exhibited by depressed and non-depressed participants in the parietal-occipital region and the cognitive activities that are relevant to that region.

Functional Network Connectivity for Components of Depression-Related Psychological Fragility.

Psychological resilience (PR) is known to be inversely associated with depression. While there is a growing body of research examining how depression alters activity across multiple functional neural networks, how differences in PR affect these networks is largely unexplored. This study examines the relationship between PR and functional connectivity in the alpha and beta bands within (and between) eighteen established cortical nodes in the default mode network, the central executive network, and the salience network. Resting-state EEG data from 99 adult participants (32 depressed, 67 non-depressed) were used to measure the correlation between the five factors of PR sourced from the Connor-Davidson Resilience Scale and eLORETA-based measures of coherence and phase synchronisation. Distinct functional connectivity patterns were seen across each resilience factor, with a notable absence of overlapping positive results across the depressed and non-depressed samples. These results indicate that depression may modulate how resilience is expressed in terms of fundamental neural activity.

Conflict and control in cortical responses to inconsistent emotional signals in a face-word Stroop.

Social communication is fraught with ambiguity. Negotiating the social world requires interpreting the affective signals we receive and often selecting between channels of conflicting affective information. The affective face-word Stroop (AFWS) provides an experimental paradigm which may identify cognitive-affective control mechanisms underpinning essential social-affective skills. Initial functional magnetic resonance imaging (fMRI) study of the AFWS identified right amygdala as driving this affective conflict and left rostral anterior cingulate cortex (rACC) as the locus of conflict control. We employed electroencephalogram (EEG) and eLORETA source localization to investigate the timing, location, and sequence of control processes when responding to affective conflict generated during the AFWS. However we designated affective word as the response target and affective face as the distractor to maximize conflict and control effects. Reaction times showed slowed responses in high vs. low control conditions, corresponding to a Rabbitt type control effect rather than the previously observed Grattan effect. Control related activation occurred in right rACC 96-118 ms post-stimulus, corresponding to the resolution of the P1 peak in the Visual Evoked Potential (VEP). Face distractors elicit right hemisphere control, while word distractors elicit left hemisphere control. Low control trials require rapid "booting up" control resources observable through VEPs. Incongruent trial activity in right fusiform face area is suppressed 118-156 ms post stimulus corresponding to onset and development of the N170 VEP component. Results are consistent with a predicted sequence of rapid early amygdala activation by affective conflict, then rACC inhibition of amygdala decreasing facilitation of affective face processing (however, amygdala activity is not observable with EEG).

USP7 controls NGN3 stability and pancreatic endocrine lineage development.

Understanding the factors and mechanisms involved in beta-cell development will guide therapeutic efforts to generate fully functional beta cells for diabetes. Neurogenin 3 (NGN3) is the key transcription factor that marks endocrine progenitors and drives beta-cell differentiation. Here we screen for binding partners of NGN3 and identify the deubiquitylating enzyme USP7 as a key regulator of NGN3 stability. Mechanistically, USP7 interacts with, deubiquitinates and stabilizes NGN3. In vivo, conditional knockout of Usp7 in the mouse embryonic pancreas causes a dramatic reduction in islet formation and hyperglycemia in adult mice, due to impaired NGN3-mediated endocrine specification during pancreatic development. Furthermore, pharmacological inhibition of USP7 during endocrine specification in human iPSC models of beta-cell differentiation decreases NGN3 expressing progenitor cell numbers and impairs beta cell differentiation. Thus, the USP7-NGN3 axis is an essential mechanism for driving endocrine development and beta-cell differentiation, which can be therapeutically exploited.

Frontal Alpha Asymmetry Argues for the Heterogeneity of Psychological Resilience.

Depression is associated with frontal alpha asymmetry (FAA) and Psychological Resilience (PR), although in different ways. Only cursory attention has been given to how these three constructs interact despite the possible clinical and research implications of those associations. One limitation of recent research into these associations has been conceptualising PR as a unitary construct, whereas it has been shown to be multi-component. This study investigated the underlying components of PR, their correlations with FAA, and the effect that participants' depressive status had upon those correlations in a community sample of 54 males and 46 females aged between 18 yr and 75 years. Results confirmed the overall inverse association between total PR and depression for four of the original five PR components and for one of the two components found in this sample. Similarly, there were differences between the ways that FAA and PR components were associated, depending upon the depressive status of participants. Source localisation data indicated that the PR components were not uniformly correlated with alpha activity in the same brain regions. These findings of content, efficacy, and neurophysiological differences between the five components of PR and their associations with FAA argue against consideration of PR as a unitary construct.