Point Of Convergence Research Articles

Shared Molecular Signature in Alzheimer's Disease and Schizophrenia: A Systematic Review of the Reelin Signaling Pathway.

The Reelin signaling pathway, particularly the RELN-APOER2-DAB1 complex, has emerged as a key contributor to the neuropathology of Alzheimer's disease (AD) and Schizophrenia (SZ). Despite being distinct clinical conditions, these disorders exhibit similar patterns of cognitive decline, including early disruptions in synaptic function and memory impairments. Notably, individuals with SZ have a 2-4 fold increased risk of developing AD or other dementias, highlighting potential shared molecular mechanisms, and positioning Reelin as a pivotal link between them. This systematic review explores the role of Reelin and its signaling components across these disorders. In AD, Reelin disruption correlates with hallmark features such as Tau hyperphosphorylation, amyloid-beta accumulation, and cognitive deficits. In SZ, alterations in Reelin signaling, including epigenetic modifications affecting RELN expression, are linked to disruptions in neuronal development and synaptic plasticity, particularly in the parietal and prefrontal cortices. Additionally, genomic studies reveal specific RELN variants and allelic imbalances that may influence disease severity and treatment response in SZ, suggesting RELN's role as a potential biomarker for therapeutic outcomes. Region-specific Reelin alterations in both AD and SZ suggest differing impacts yet underscore a potential common molecular origin. Our findings highlight the Reelin pathway as a molecular convergence point, warranting further investigation as a therapeutic and diagnostic target for AD, SZ, and potentially other neuropsychiatric disorders. The interplay between genetic and epigenetic regulation of RELN may provide novel insights into neurodegeneration, with implications for personalized intervention strategies in AD and SZ.

MTOR Ser1261 is an AMPK-dependent phosphosite in mouse and human skeletal muscle not required for mTORC2 activity.

The kinases AMPK, and mTOR as part of either mTORC1 or mTORC2, are major orchestrators of cellular growth and metabolism. Phosphorylation of mTOR Ser1261 is reportedly stimulated by both insulin and AMPK activation and a regulator of both mTORC1 and mTORC2 activity. Intrigued by the possibilities that Ser1261 might be a convergence point between insulin and AMPK signaling in skeletal muscle, we investigated the regulation and function of this site using a combination of human exercise, transgenic mouse, and cell culture models. Ser1261 phosphorylation on mTOR did not respond to insulin in any of our tested models, but instead responded acutely to contractile activity in human and mouse muscle in an AMPK activity-dependent manner. Contraction-stimulated mTOR Ser1261 phosphorylation in mice was decreased by Raptor muscle knockout (mKO) and increased by Raptor muscle overexpression, yet was not affected by Rictor mKO, suggesting most of Ser1261 phosphorylation occurs within mTORC1 in skeletal muscle. In accordance, HEK293 cells mTOR Ser1261Ala mutation strongly impaired phosphorylation of mTORC1 substrates but not mTORC2 substrates. However, neither mTORC1 nor mTORC2-dependent phosphorylations were affected in muscle-specific kinase-dead AMPK mice with no detectable mTOR Ser1261 phosphorylation in skeletal muscle. Thus, mTOR Ser1261 is an exercise but not insulin-responsive AMPK-dependent phosphosite in human and murine skeletal muscle, playing an unclear role in mTORC1 regulation but clearly not required for mTORC2 activity.

Tidal tails of nearby open clusters. I. Mapping with Gaia DR3

Tidal tails of open clusters are the result of stellar evaporation from the cluster through the Galactic potential and internal dynamics. With the recent availability of high-precision data, tidal tails are being detected for most of the nearby open clusters. We identify the tidal tail members for all open clusters within a distance of 400 pc that are older than 100 Myr and have $>$100 members. To do this, we use model-independent methods. We used the convergent-point (CP) method to identify the co-moving stars near the open clusters using Gaia DR3 data. A new method called the self-compact convergent-point (SCCP) method was proposed and applied to some of the clusters. It performed better overall in tracing the tails. We also analysed the colour-magnitude diagrams and orbital energy to diagnose possible contamination. Nineteen out of 21 clusters have tidal tails. Five of them were discovered for the first time through this work. The typical span of the tidal tails is 20--200 pc, and 30--700 member stars lie in the region inside the tidal radius and the tidal tails. Four out of 19 tidal tails are tilted away from direction of the Galactic centre. This contradicts the known theory of the tidal-tail formation. The luminosity functions of the tails and clusters are consistent with each other and with the canonical stellar interstellar mass function, but systematically higher radial velocities for the trailing tail than for the leading tail were observed for the first time. The CP method is useful for detecting tidal tails on a scale of ≈100 pc for clusters closer than 400 pc. A further analysis of theoretical N-body models is required to understand the incompleteness and biases in the current sample of tidal tails.

Duration adaptation depends on the perceived rather than physical duration and can be observed across sensory modalities.

Previous research has indicated that exposure to sensory stimuli of short or long durations influences the perceived duration of subsequent stimuli within the same modality. However, it remains unclear whether this adaptation is driven by the stimulus physical duration or by the perceived duration. We hypothesized that the absence of cross-modal duration adaptation observed in earlier studies was due to the mismatched perceived durations of adapting stimuli. To address this issue, we conducted two experiments to explore cross-modal adaptation and its dependence on perceived duration versus physical duration. Our findings reveal that the duration aftereffect from adapting to a visual stimulus aligns more closely with the perceptually matched stimulus duration rather than the physical duration. Moreover, adapting to a subjectively matched visual stimulus produced a significant aftereffect when the test stimulus was auditory, indicating the existence of the cross-modal adaptation. Thus, duration adaptation relies on perceived duration and can occur across sensory modalities. These results suggest a distinct neural representation of perceived duration, likely located at a convergence point for multisensory information, contributes to a unified temporal experience across different sensory channels.

The effect of low hypermetropia correction and office-based orthoptic training on binocular vision parameters in children with convergence insufficiency.

To determine the effect of low hypermetropia correction and orthoptic exercises on binocular visual function in children with symptomatic convergence insufficiency. This was a prospective, randomized intervention with a 3-month follow-up. Consecutive pediatric patients with convergence insufficiency and hypermetropia who met inclusion criteria were randomly assigned to one of three treatment groups: spectacle correction and orthoptic training (group 1), spectacle correction alone (group 2) and orthoptic training alone (group 3). The correction of hypermetropia ranged from +0.50 D to +2.25 D. All patients underwent an orthoptic examination, and the severity of functional symptoms was assessed. A total of 55 patients (28 females, 27 males) were included. There were no treatment-related changes in visual acuity or angle of phoria. Statistically significant reductions in the near point of convergence occurred in group 1 (-5.5 ± 6.8 cm [P = 0.001]) and in group 2 (-5.1 ± 4.8 cm [P = 0.001]). Fusional convergence for distance improved in groups 1 (P = 0.003), 2 (P = 0.018) and 3 (P = 0.006) but for near only in group 2 (P = 0.004). The largest improvement in the mean accommodative facility occurred in group 1 (P = 0.001). A significant decrease in the severity of functional symptoms was noted in all groups (P < 0.001 in groups 1 and 2 and P = 0.006 in group 3). In our study cohort, correction of low hypermetropia positively influenced binocular vision parameters in patients with convergence insufficiency, suggesting that low hypermetropia correction should be considered for patients who undergo orthoptic training for convergence insufficiency.

The role of the jasmonate signalling transcription factors MYC2/3/4 in circadian clock-mediated regulation of immunity in Arabidopsis.

Plants are exposed to pathogens at specific, yet predictable times of the day-night cycle. In Arabidopsis, the circadian clock influences temporal differences in susceptibility to the necrotrophic pathogen Botrytis cinerea. The jasmonic acid (JA) pathway regulates immune responses against B. cinerea. The paralogous basic helix-loop-helix transcription factors MYC2, MYC3 and MYC4 are primary regulators of the JA pathway, but their role in regulating temporal variation in immunity is untested. This study aimed to investigate the roles of the MYC transcription factors in the temporal defence response to B. cinerea. We inoculated leaves from wild-type, myc single-, double- and triple-knockout mutants, and lines overexpressing MYC2, MYC3 or MYC4, with B. cinerea at two times of day in constant light, and compared lesion sizes. The presence of MYC2, MYC3 or MYC4 alone was sufficient to maintain temporal variation in susceptibility, but this was abolished in the myc234 triple-knockout mutant. Constitutive expression of MYC2, MYC3 or MYC4 abolished time-of-day differences in susceptibility. The data suggest that MYC2, MYC3 and MYC4 function redundantly in regulating temporal defence responses against B. cinerea and are a point of convergence between the JA pathway and the circadian clock in Arabidopsis.This article is part of the Theo Murphy meeting issue 'Circadian rhythms in infection and immunity'.

Identification of ARHGEF11 (PDZ-RhoGEF) as an in vivo regulator of synapses and cognition

Given the influence of cognitive abilities on life outcomes, there is inherent value in identifying genes involved in controlling learning and memory. Further, cognitive dysfunction is a core feature of many neuropsychiatric disorders. Here, we use a combinatory in silico approach to identify human gene targets that will have an especially high likelihood of individually and directly impacting cognition. This broad and unbiased screen led to the specific identification of ARHGEF11, which encodes PDZ-RhoGEF. PDZ-RhoGEF is a largely RhoA-specific activator that is highly enriched in dendritic spines, and recent work identified hyperexpression of PDZ-RhoGEF in the prefrontal cortex of bipolar disorder subjects, a disease characterized by an early emergence and persistence of broad scope cognitive dysfunction. Here, we characterize the effects of PDZ-RhoGEF on synaptic and behavioral phenotypes, and we identify molecular and biochemical mechanisms that control PDZ-RhoGEF's expression, synaptic spatial localization, and enzymatic activity. Importantly, our identified direct regulators of PDZ-RhoGEF (miR-132 and DISC1) have themselves been repeatedly implicated in controlling cognitive phenotypes in humans, including those caused by several neuropsychiatric disorders. Taken together, our findings indicate that PDZ-RhoGEF is a key convergence point among multiple synaptic and cognition-relevant signaling cascades with potential translational significance.

Evaluation of Accommodation Amplitude and Convergence Insufficiency in Patients with Multiple Sclerosis

ABSTRACT Purpose To evaluate the near reflex components, including accommodation, convergence, and binocular fusional vergences in patients with multiple sclerosis (MS). Material-Method MS patients under 35 years of age without visual evoked potential (VEP) abnormalities (MS Group) and age-matched healthy individuals of (Control Group) were included in the study. Fusional vergence amplitudes, the amplitude of accommodation (AA), stereopsis measurements, near-object fixation and near point of convergence (NPC) measurements, Convergence Insufficiency Symptoms Survey (CISS) results, and the presence of nystagmus were recorded retrospectively from the files of the cases. Statistical comparison was made between the groups. Results The mean age was 28.04 ± 3.7 years in the MS group (20 females, 4 males) and 27.16 ± 3.1 years in the control group (20 females, 5 males) (p = .763). There was no statistically significant difference between groups in stereopsis (p = .395), mean convergence (p = .666), and divergence amplitudes (p = .773) at a distance, and mean convergence and (p = .836) divergence amplitudes (p = .877) at near, and NPC measurements (p = .908). The mean AA was 5.31 ± 0.7 D in the MS group and 6.1 ± 0.8 D in the control group (p < .001). CISS results were lower in the control group (p < .001). In addition, gaze-evoked nystagmus was statistically significantly higher in the MS group (p < .001). Conclusion Compared to the healthy control group, MS patients under 35 who did not have optic neuritis had lower accommodation amplitude and more signs in favor of convergence insufficiency symptoms. In addition, gaze evoked nystagmus was observed at a higher rate in the MS group. These findings may guide us in understanding the asthenopia findings of MS patients without optic neuritis.

Is the convergence insufficiency symptom survey applicable to elderly individuals?

BackgroundThe psychometric properties of the Convergence Insufficiency Symptom Survey (CISS) have been previously determined across the younger adult population. This study investigated the psychometric properties of the CISS in presbyopic adults via classical and Rasch analysis.MethodsA total of 100 presbyopic individuals (40–60 years) were selected with far and near acuity of 20/20 with their habitual spectacles; 50 had convergence insufficiency and 50 had normal binocular vision. Refraction, cover test, near point of convergence, and positive fusional ranges were examined. The Persian translated CISS was administered twice, once in the first session and 7 to 14 days later. Classical and Rasch analyses were conducted.ResultsThe mean ages and gender ratios in the CI group and normal group were 49.70 ± 5.96 and 49.82 ± 5.64 years with a 50% female distribution among individuals. The mean CISS scores for presbyopes with CI and normal groups were 19.24 ± 5.33 and 13.26 ± 3.53 respectively (p < 0.001). Effective discrimination was achieved with a score greater than 15, yielding a sensitivity of 72%, a specificity of 69%, and an Area Under the Curve (AUC) of 0.813. For internal consistency, Cronbach’s α coefficient was 0.82. For test-retest reliability in CISS scores, ICC was 0.91 (confidence interval 0.88–0.93) with the 95% limits of agreement in CI group being − 3.91 to 2.59. The Rasch analysis demonstrated a satisfactory model fit, as all items had infit and outfit mean square values ranging between 0.6 and 1.4. The measurement precision was good, with a person separation value of 2.30. Additionally, the first contrast eigenvalue of 2.34 and a raw variance of less than 50% indicated multidimensionality. The CI group reported headaches (item 3) more frequently than the normal binocular vision group did. However, eye discomfort scores (item 10) were similar for both groups.ConclusionsThe CISS is a valid and reliable tool for assessing the symptoms in presbyopic adults. However, due to this survey’s multidimensionality, we recommend additional objective examinations in presbyopic adults with CI.

Flow and intuition: a systems neuroscience comparison.

This paper explores the relationship between intuition and flow from a neurodynamics perspective. Flow and intuition represent two cognitive phenomena rooted in nonconscious information processing; however, there are clear differences in both their phenomenal characteristics and, more broadly, their contribution to action and cognition. We propose, extrapolating from dual processing theory, that intuition serves as a rapid, nonconscious decision-making process, while flow facilitates this process in action, achieving optimal cognitive control and performance without [conscious] deliberation. By exploring these points of convergence between flow and intuition, we also attempt to reconcile the apparent paradox of the presence of enhanced intuition in flow, which is also a state of heightened cognitive control. To do so, we utilize a revised dual-processing framework, which allows us to productively align and differentiate flow and intuition (including intuition in flow). Furthermore, we draw on recent work examining flow from an active inference perspective. Our account not only heightens understanding of human cognition and consciousness, but also raises new questions for future research, aiming to deepen our comprehension of how flow and intuition can be harnessed to elevate human performance and wellbeing.

Effect of Smartphone use on Convergence among Undergraduate Students

Aim: This study aimed to determine the effect of smartphone usage on convergence among undergraduate students. Study Design: Cross-sectional study. Duration and Setting of the Study: This study was conducted from July 2019 to December 2019 at Pakistan Institute of Community Ophthalmology, Hayatabad Medical Complex, Peshawar. Methods: A non-probability sampling technique was used to include students. The subjects were taken as per the inclusion criteria. Visual acuity was recorded with log MAR at 4 meters, and retinoscopy was performed to rule out refractive error in the subjects. The researcher asked the questions given in the structured questionnaire and recorded the responses. The near point of convergence was determined with the help of the RAF ruler. The Convergence Insufficiency Symptom Survey (CISS) questionnaire was used to record the convergence insufficiency score. Results: A total of 100 students participated, in which 49% were male and 51% were female. The use of Android smartphones was more (82%) than iOS (16%) and others (2%). Most of the subjects used smartphones during the night (54%). It also showed that hours spent on smartphones were interrupted (70%). Smartphone users used their smartphones with dull screens (62%). The near point of convergence was 5cm in (63%). CISS score was noted (&gt;21) was noted in (73%) of students. There was a strong correlation between near point of convergence and CISS scores (p=0.000), with significant associations between smartphone usage patterns and convergence issues (p=0.02). Conclusion: In this study it is concluded that those subjects whose usage of mobile was more than 4 hours had an excess of convergence along with worse symptoms. CISS scores indicated a high prevalence of symptoms, particularly among those with poor near point of convergence (NPC).

Reprocessing of Single-Use Medical Devices: Viewpoints and Perceptions of Cardiologists and Hospital Pharmacists

A pilot initiative on the reprocessing of medical devices (MD), particularly in electrophysiology, is expected to be launched in France in November 2024. Reprocessing single-use medical devices (SUDs) presents potential benefits and challenges, with differing perspectives among healthcare professionals. This study aims to compare the knowledge and positions of hospital pharmacists (HP) and cardiologists (CA) regarding the use of reprocessed single-use devices (R-SUDs), in order to identify their concerns as well as points of convergence and divergence. A directive and mixed electronic questionnaire consisting of 27 questions was sent to HPs and CAs from the Assistance Publique-Hôpitaux de Paris (AP-HP). Responses from 32 HPs and 30 CAs were analyzed using statistical methods via R software. The results revealed that CAs overwhelmingly support reprocessing, while HPs show significantly more reservations (p<0.0001). Among HPs, 56% (n=18) favored an "open" supply chain model for reprocessing, compared to 28% (n=9) who preferred a "closed" one. CAs show a more balanced distribution of their preferences, with 30% (n=9) favoring the "open" chain and 40% (n=12) the "closed" model. Both groups raised concerns about the safety and quality of reprocessed devices, but the majority would accept R-SUDs if clinical trials validated their safety and effectiveness compared to original SUDs. Reprocessing is nevertheless seen as a means to reduce hospital costs and carbon footprint in hospitals.

Convergence of orphan quality control pathways at a ubiquitin chain-elongating ligase.

Unassembled and partially assembled subunits of multi-protein complexes have emerged as major quality control clients, particularly under conditions of imbalanced gene expression such as stress, aging, and aneuploidy. The factors and mechanisms that eliminate such orphan subunits to maintain protein homeostasis are incompletely defined. Here, we show that the UBR4-KCMF1 ubiquitin ligase complex is required for the efficient degradation of multiple unrelated orphan subunits from the chaperonin, proteasome cap, proteasome core, and a protein targeting complex. Epistasis analysis in cells and reconstitution studies invitro show that the UBR4-KCMF1 complex acts downstream of a priming ubiquitin ligase that first mono-ubiquitinates orphans. UBR4 recognizes both the orphan and its mono-ubiquitin and builds a K48-linked poly-ubiquitin degradation signal. The discovery of a convergence point for multiple quality control pathways may explain why aneuploid cells are especially sensitive to loss of UBR4 or KCMF1 and identifies a potential vulnerability across many cancers.

Diagnostika a trénink neurovizuálních funkcí v rehabilitaci a ve sportu

Sensory integration plays a crucial role in the smooth execution of movements. However, the repeated intake of suboptimal information from our surroundings can disrupt the motor learning process. Sight stands out as the dominant human sense, providing visual information that is integrated at the central nervous system (CNS) level. This integration occurs alongside inputs from other sensory organs, constantly influencing motor activity. The term “neuro-visual system” (NVS) is now widely recognized in the fields of rehabilitation and sports, highlighting the crucial eye–brain–body axis connection. This article provides an overview of recent findings on the NVS exploring diagnostic procedures relevant to NVS in clinical settings. These procedures include tests for visual acuity, eye motility, and the near point of convergence. Drawing on existing literature, it identifies specific patient groups for whom neuro-visual training (NVT) could significantly enhance rehabilitation outcomes. Additionally, it discusses the potential benefits of NVT for athletes as an integral part of their sports training regimen. Included in the publication are two case studies illustrating NVS assessment and the application of NVT in clinical practice. The first case involves an adolescent with attention disorder and congenital diplopia, and the second, a young tennis player suffering from headaches. These examples underscore the practical value of NVS diagnostics and neuro-visual training in addressing specific health and performance issues.

FLEX-AS: ESTRATÉGIA DIDÁTICA PARA O ENSINO DE CIÊNCIAS NAS PERSPECTIVAS DA aPRENDIZAGEM SIGNIFICATIVA E FLEXIBILIDADE COGNITIVA

This study is a segment of a broader research project aimed at identifying connections between the Theory of Meaningful Learning (TML), its critical perspective (CML), and the Theory of Cognitive Flexibility (TCF). Based on this dialogue, the study sought to design a didactic strategy for science teaching in basic education to facilitate the promotion of meaningful and critical learning. Analyzing the principles of these theories led to the identification of five points of convergence, or descriptors, namely: Emphasis on Knowledge Construction, Relevance of Prior Knowledge, Focus on Deep Understanding, Contextualized Learning, and Learning Progressivity. These descriptors guided the development of a didactic strategy for science teaching. The strategy, titled FLEX-AS, consists of four stages: Planning, Preparation, Experience, and Evaluation. Each stage is detailed and theoretically and methodologically grounded. Reflections on the creation of FLEX-AS demonstrated the conceptual coherence of integrating the underlying theories into a less theoretical and more practical framework for educators.

On Being and Becoming Human Through Accompaniment and Telos: Ontological Convergences Between Christian Anthropology and the Science of Human Development

We discuss several points of convergence in ontological concepts within Christian anthropology and the contemporary dynamic, relational, developmental systems (RDS)-based approach within developmental science. Both approaches uphold the significance of relationality, particularly of mutually beneficial (nurturing) relationships between every individual and others, as both the means and the ends of human development and thriving. Both magisteriums build similarly on the fundamental significance of dynamic, relational development that provides a goal, or telos, for each individual to live with and for others and that leads to becoming a more fully reciprocating self. We discuss several concepts present in both contemporary developmental science and Christian anthropology: embodiment, holism, specificity of mutually influential individual ⇔ context coactions, relationality, and telos. We argue that the ontological convergences between Christian anthropology and RDS-based developmental science provide means for enacting mutually beneficial collaborations between religion and science, which, if enacted, could promote thriving lives for individuals and support social justice movements.

Individual Variations in Vergence and Accommodation Responses Following Virtual Reality Gameplay.

Virtual reality (VR) can challenge the visual system, leading to temporary oculomotor changes, though the degree of change varies among individuals. While the vergence and accommodation system plays a crucial role in VR perception, it remains unclear whether individuals whose visual functions fall outside clinical norms experience larger changes. Thus, our study aimed to investigate whether changes in vergence and accommodation responses following VR gameplay differ between individuals with and without non-strabismic binocular and accommodative disorders. To assess this, both subjective and objective measurements were conducted before and after 20 min of playing Beat Saber. Results revealed significant alterations across both subjective measurements-near point of convergence and near point of accommodation-and objective measurements, including eye refraction, accommodation lag, and accommodative microfluctuations at far. Moreover, individuals with non-strabismic binocular and accommodative disorders exhibited larger accommodative microfluctuations at far compared to the control group. Overall, these findings indicate that considering individual differences in vergence and accommodation responses is important when evaluating the impact of VR on the visual system and can be helpful in the design and use of VR systems, particularly for individuals with binocular and accommodative disorders.

The Spiral of Attention, Arousal, and Release: A Comparative Phenomenology of Jhāna Meditation and Speaking in Tongues.

Buddhist Jhāna meditation and the Christian practice of speaking in tongues appear wildly distinct. These spiritual techniques differ in their ethical, theological, and historical frames and seem, from the outside, to produce markedly different states of consciousness-one a state of utter calm and the other of high emotional arousal. Yet, our phenomenological interviews with experienced practitioners in the USA found significant points of convergence. Practitioners in both traditions describe a dynamic relationship between focused attention, aroused joy, and a sense of letting go or release that they describe as crucial to their practice. This paper highlights these shared phenomenological features and theorizes possible underlying mechanisms. Analyzing our phenomenological data through the lens of various theories of brain function, including sensory gating and predictive processing, we propose that these practices both engage an autonomic field built through a spiral between attention, arousal, and release (AAR).

A subgradient projection method for quasiconvex multiobjetive optimization

We discuss a subgradient projection method for dealing with the nonconvex nonsmooth multiobjective optimization problem when every component of the vector-valued function is strongly quasiconvex in the sense of Polyak [Existence theorems and convergence of minimizing sequences in extremum problems with restrictions. Soviet Math. 1966;7:72–75]. Under mild assumptions, we ensure that the generated sequence converges to an efficient solution point of the multiobjective optimization problem and we provide a kind of linear convergence rate. The algorithm is based on a specific generalized subdifferential that was recently introduced for strongly quasiconvex functions, this approach provides new and valuable information on the generated sequence and its convergent point. Finally, we present numerical experiments for classes of quadratic fractional programming problems.

Stress and obesity signaling converge on CREB phosphorylation to promote pancreatic cancer.

One of the deadliest types of cancer is pancreatic ductal adenocarcinoma (PDAC). Chronic stress and obesity are recognized as risk factors for PDAC. We hypothesized that the combination of stress and obesity strongly promotes pancreatic cancer development and growth. Here, we show that the stress mediator norepinephrine and the beta adrenergic receptor agonist isoproterenol rapidly stimulate CREB phosphorylation at Ser133 in human PDAC cells. Exposure to the non-selective beta adrenergic receptor antagonist propranolol or selective antagonists, including nebivolol, atenolol, or ICI118551 blocked CREB phosphorylation elicited by norepinephrine or isoproterenol in PDAC cells. Stimulation of PDAC cells with neurotensin, a neuropeptide implicated in obesity and PDAC, also stimulated CREB phosphorylation at Ser133. Mechanistically, norepinephrine induced CREB phosphorylation at Ser133 via PKA whereas neurotensin promoted CREB phosphorylation predominantly through protein kinase D (PKD). Our results indicate that CREB is a point of signal convergence that mediates proliferation in PDAC cells and raised the possibility that stress and diet cooperate in promoting PDAC in vivo. To test this notion, mice expressing KrasG12D in all pancreatic lineages (KC mice) and fed an obesogenic high fat, calorie diet (HFCD) that promotes early PDAC development were subjected to social isolation stress (SIS). We show that SIS induced a significant increase in the proportion of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia [PanIN]-3) in KC mice subjected to an obesogenic HFCD. Implications: Our data imply that chronic (social isolation) stress cooperates with diet-induced obesity in accelerating the development of pancreatic cancer.