The role of neurocomputational decision processes in affect-based impulsivity in borderline personality

Borderline personality disorder (BPD) portends heightened risk for a variety of negative life outcomes, ranging from broad impairments in social functioning to suicide. People with BPD often engage in impulsive behaviors during states of heightened negative affect. Building on preclinical work on the effect of stress on decision-making, as well as Bayesian models of affect’s role in decision-making, we propose that affect alters the balance of Pavlovian and goal-directed decision systems, favoring Pavlovian influences that heighten the pursuit of rewards. To test this account, we sought to (1) characterize effects of affect and stress on decision processes (Aim 1) and (2) quantify alterations in these decision processes among individuals prone to affect-based impulsivity using computational reinforcement learning models (Aim 2). Following an experimental manipulation of affect, participants completed a social variant of a decision-tree task . Among individuals prone to affect-based impulsivity, exposure to the negative affect induction invigorated pursuit of immediately valuable, though often suboptimal, actions. We further found that affect-based impulsivity was associated with heightened discounting of future rewards. These data provide support the account that affect-based impulsivity is associated with a heightened influence of Pavlovian cues on decision-making and with blunted effects of model-based goal-directed reasoning on decision-making. This research lends initial insights into the neurocomputational mechanisms of affect-based impulsivity in BPD.Doctor of Philosoph

An emerging user-led participatory methodology: Mapping impact pathways of urban food system sustainability innovations

This chapter presents an emerging effort to develop a participatory mapping methodology that will illuminate the pathways through which sustainable urban food systems achieve lasting impact. Carried out in collaboration with Està (Economia e Sostenibilità), the UNESCO Chair in World Food System (at Montpellier SupAgro), CIRAD (French Agricultural Research Centre for International Development) and the LCSFS (Laurier Center for Sustainable Food Systems), this initiative aims to provide an alternative to quantitative tools that lack precision at the local level, and to qualitative approaches holding a narrow focus that may obscure broader systemic dynamics. This URBAL project focuses on innovations in consumer practices, value-chains, and governance by examining 12 case studies in eight cities in the Global South and North

The MOSDEF Survey: Kinematic and Structural Evolution of Star-Forming Galaxies at 1.4≤z≤3.81.4\leq z\leq 3.8

We present ionized gas kinematics for 681 galaxies at $z\sim 1.4-3.8$ from the MOSFIRE Deep Evolution Field survey, measured using models which account for random galaxy-slit misalignments together with structural parameters derived from CANDELS Hubble Space Telescope (HST) imaging. Kinematics and sizes are used to derive dynamical masses. Baryonic masses are estimated from stellar masses and inferred gas masses from dust-corrected star formation rates (SFRs) and the Kennicutt-Schmidt relation. We measure resolved rotation for 105 galaxies. For the remaining 576 galaxies we use models based on HST imaging structural parameters together with integrated velocity dispersions and baryonic masses to statistically constrain the median ratio of intrinsic ordered to disordered motion, $V/\sigma_{V,0}$. We find that $V/\sigma_{V,0}$ increases with increasing stellar mass and decreasing specific SFR (sSFR). These trends may reflect marginal disk stability, where systems with higher gas fractions have thicker disks. For galaxies with detected rotation we assess trends between their kinematics and mass, sSFR, and baryon surface density ($\Sigma_{\mathrm{bar},e}$). Intrinsic dispersion correlates most with $\Sigma_{\mathrm{bar},e}$ and velocity correlates most with mass. By comparing dynamical and baryonic masses, we find that galaxies at $z\sim 1.4-3.8$ are baryon dominated within their effective radii ($R_E$), with Mdyn/Mbaryon increasing over time. The inferred baryon fractions within $R_E$, $f_{\mathrm{bar}}$, decrease over time, even at fixed mass, size, or surface density. At fixed redshift, $f_{\mathrm{bar}}$ does not appear to vary with stellar mass but increases with decreasing $R_E$ and increasing $\Sigma_{\mathrm{bar},e}$. For galaxies at $z\geq2$, the median inferred baryon fractions generally exceed 100%. We discuss possible explanations and future avenues to resolve this tension.Comment: Accepted to ApJ. Added Figure 9, corrected sample size (main results unchanged). 28 pages, 13 figure

Outcomes in patients with gunshot wounds to the brain.

Introduction:Gunshot wounds to the brain (GSWB) confer high lethality and uncertain recovery. It is unclear which patients benefit from aggressive resuscitation, and furthermore whether patients with GSWB undergoing cardiopulmonary resuscitation (CPR) have potential for survival or organ donation. Therefore, we sought to determine the rates of survival and organ donation, as well as identify factors associated with both outcomes in patients with GSWB undergoing CPR. Methods:We performed a retrospective, multicenter study at 25 US trauma centers including dates between June 1, 2011 and December 31, 2017. Patients were included if they suffered isolated GSWB and required CPR at a referring hospital, in the field, or in the trauma resuscitation room. Patients were excluded for significant torso or extremity injuries, or if pregnant. Binomial regression models were used to determine predictors of survival/organ donation. Results:825 patients met study criteria; the majority were male (87.6%) with a mean age of 36.5 years. Most (67%) underwent CPR in the field and 2.1% (n=17) survived to discharge. Of the non-survivors, 17.5% (n=141) were considered eligible donors, with a donation rate of 58.9% (n=83) in this group. Regression models found several predictors of survival. Hormone replacement was predictive of both survival and organ donation. Conclusion:We found that GSWB requiring CPR during trauma resuscitation was associated with a 2.1% survival rate and overall organ donation rate of 10.3%. Several factors appear to be favorably associated with survival, although predictions are uncertain due to the low number of survivors in this patient population. Hormone replacement was predictive of both survival and organ donation. These results are a starting point for determining appropriate treatment algorithms for this devastating clinical condition. Level of evidence:Level II

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

The Epoch of Disk Settling: z~1 to Now

We present evidence from a sample of 544 galaxies from the DEEP2 Survey for evolution of the internal kinematics of blue galaxies with stellar masses ranging 8.0 < log M* (M_Sun) < 10.7 over 0.2<z<1.2. DEEP2 provides galaxy spectra and Hubble imaging from which we measure emission-line kinematics and galaxy inclinations, respectively. Our large sample allows us to overcome scatter intrinsic to galaxy properties in order to examine trends in kinematics. We find that at a fixed stellar mass galaxies systematically decrease in disordered motions and increase in rotation velocity and potential well depth with time. Massive galaxies are the most well-ordered at all times examined, with higher rotation velocities and less disordered motions than less massive galaxies. We quantify disordered motions with an integrated gas velocity dispersion corrected for beam smearing (sigma_g). It is unlike the typical pressure-supported velocity dispersion measured for early type galaxies and galaxy bulges. Because both seeing and the width of our spectral slits comprise a significant fraction of the galaxy sizes, sigma_g integrates over velocity gradients on large scales which can correspond to non-ordered gas kinematics. We compile measurements of galaxy kinematics from the literature over 1.2<z<3.8 and do not find any trends with redshift, likely for the most part because these datasets are biased toward the most highly star-forming systems. In summary, over the last ~8 billion years since z=1.2, blue galaxies evolve from disordered to ordered systems as they settle to become the rotation-dominated disk galaxies observed in the Universe today, with the most massive galaxies being the most evolved at any time.Comment: submitted to ApJ and responded to referee repor

Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors

SummaryNovel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal cells to identify compounds that overcome stromal resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered to be an unusual ATP non-competitive kinesin-5 (Eg5) inhibitor. A novel mutation caused resistance, suggesting a binding site distinct from known Eg5 inhibitors, and BRD9876 inhibited only microtubule-bound Eg5. Eg5 phosphorylation, which increases microtubule binding, uniquely enhanced BRD9876 activity. MM cells have greater phosphorylated Eg5 than hematopoietic cells, consistent with increased vulnerability specifically to BRD9876’s mode of action. Thus, differences in Eg5-microtubule binding between malignant and normal blood cells may be exploited to treat multiple myeloma. Additional steps are required for further therapeutic development, but our results indicate that unbiased chemical biology approaches can identify therapeutic strategies unanticipated by prior knowledge of protein targets

Differential Inhibitory Effects of CysLT1 Receptor Antagonists on P2Y6 Receptor-Mediated Signaling and Ion Transport in Human Bronchial Epithelia

BACKGROUND: Cysteinyl leukotriene (CysLT) is one of the proinflammatory mediators released by the bronchi during inflammation. CysLTs exert their biological effects via specific G-protein-coupled receptors. CysLT(1) receptor antagonists are available for clinical use for the treatment of asthma. Recently, crosstalk between CysLT(1) and P2Y(6) receptors has been delineated. P2Y receptors are expressed in apical and/or basolateral membranes of virtually all polarized epithelia to control the transport of fluid and electrolytes. Previous research suggests that CysLT(1) receptor antagonists inhibit the effects of nucleotides acting at P2Y receptors. However, the detailed molecular mechanism underlying the inhibition remains unresolved. METHODOLOGY/PRINCIPAL FINDINGS: In this study, western blot analysis confirmed that both CysLT(1) and P2Y(6) receptors were expressed in the human bronchial epithelial cell line 16HBE14o-. All three CysLT(1) antagonists inhibited the uridine diphosphate (UDP)-evoked I(SC), but only montelukast inhibited the UDP-evoked [Ca(2+)](i) increase. In the presence of forskolin or 8-bromoadenosine 3'5' cyclic monophosphate (8-Br-cAMP), the UDP-induced I(SC) was potentiated but was reduced by pranlukast and zafirlukast but not montelukast. Pranlukast inhibited the UDP-evoked I(SC) potentiated by an Epac activator, 8-(4-Chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate (8-CPT-2'-O-Me-cAMP), while montelukast and zafirlukast had no such effect. Pranlukast inhibited the real-time increase in cAMP changes activated by 8-CPT-2'-O-Me-cAMP as monitored by fluorescence resonance energy transfer imaging. Zafirlukast inhibited the UDP-induced I(SC) potentiated by N(6)-Phenyladenosine-3',5'-cyclic monophosphorothioate, Sp-isomer (Sp-6-Phe-cAMP; a PKA activator) and UDP-activated PKA activity. CONCLUSIONS/SIGNIFICANCE: In summary, our data strongly suggest for the first time that in human airway epithelia, the three specific CysLT(1) receptor antagonists exert differential inhibitory effects on P2Y(6) receptor-coupled Ca(2+) signaling pathways and the potentiating effect on I(SC) mediated by cAMP and Epac, leading to the modulation of ion transport activities across the epithelia

Recruitment and Activation of Pancreatic Stellate Cells from the Bone Marrow in Pancreatic Cancer: A Model of Tumor-Host Interaction

BACKGROUND AND AIMS: Chronic pancreatitis and pancreatic cancer are characterised by extensive stellate cell mediated fibrosis, and current therapeutic development includes targeting pancreatic cancer stroma and tumor-host interactions. Recent evidence has suggested that circulating bone marrow derived stem cells (BMDC) contribute to solid organs. We aimed to define the role of circulating haematopoietic cells in the normal and diseased pancreas. METHODS: Whole bone marrow was harvested from male β-actin-EGFP donor mice and transplanted into irradiated female recipient C57/BL6 mice. Chronic pancreatitis was induced with repeat injections of caerulein, while carcinogenesis was induced with an intrapancreatic injection of dimethylbenzanthracene (DMBA). Phenotype of engrafted donor-derived cells within the pancreas was assessed by immunohistochemistry, immunofluorescence and in situ hybridisation. RESULTS: GFP positive cells were visible in the exocrine pancreatic epithelia from 3 months post transplantation. These exhibited acinar morphology and were positive for amylase and peanut agglutinin. Mice administered caerulein developed chronic pancreatitis while DMBA mice exhibited precursor lesions and pancreatic cancer. No acinar cells were identified to be donor-derived upon cessation of cerulein treatment, however rare occurrences of bone marrow-derived acinar cells were observed during pancreatic regeneration. Increased recruitment of BMDC was observed within the desmoplastic stroma, contributing to the activated pancreatic stellate cell (PaSC) population in both diseases. Expression of stellate cell markers CELSR3, PBX1 and GFAP was observed in BMD cancer-associated PaSCs, however cancer-associated, but not pancreatitis-associated BMD PaSCs, expressed the cancer PaSC specific marker CELSR3. CONCLUSIONS: This study demonstrates that BMDC can incorporate into the pancreas and adopt the differentiated state of the exocrine compartment. BMDC that contribute to the activated PaSC population in chronic pancreatitis and pancreatic cancer have different phenotypes, and may play important roles in these diseases. Further, bone marrow transplantation may provide a useful model for the study of tumor-host interactions in cancer and pancreatitis