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PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology
No full textBackground: Phospholipase C gamma 2 (PLCG2) is an intracellular effector of microglial cell surface receptors, including triggering receptor expressed on myeloid cells 2 (TREM2). Variants which alter PLCG2 activity impact Alzheimer's disease (AD) risk, but the effects of PLCG2 deficiency in AD remain unclear.
Methods: 5xFAD mice were crossed with PLCG2- and TREM2-deficient mice to assess the role of PLCG2 in response to amyloid pathology. Human bulk RNA-sequencing data were used to validate findings in AD patients.
Results: In 5xFAD mice, the absence of PLCG2 resulted in reduced TREM2 expression and impaired microglial associations with amyloid beta plaques. Transcriptomic analysis revealed perturbations in immune-related pathways shared between PLCG2 and TREM2 deficiencies, as well as distinct differences. Human transcriptomics revealed positive correlations between PLCG2 and TREM2 independent of pathological scores.
Discussion: PLCG2 is a critical component of TREM2 signal transduction and may play an upstream role in TREM2 regulation. These findings clarify the mechanisms of risk and protective PLCG2 variants.
Highlights: The role of phospholipase C gamma 2 (PLCG2) deficiency in response to amyloid beta (Aβ) pathology was investigated in 5xFAD mice and with human cortical transcriptomics. PLCG2 deficiency significantly reduces triggering receptor expressed on myeloid cells 2 (TREM2) expression, while TREM2 deficiency increases PLCG2 expression. PLCG2 expression predicts TREM2 expression in human cortex independent of pathology. PLCG2 and TREM2 deficiencies similarly impair microglial responses to Aβ plaques, exacerbate neuronal pathology, and impair gene expression associated with immune responses. PLCG2 deficiency confers distinct transcriptional perturbations from TREM2 deficiency. PLCG2 may play an upstream role in the regulation of the TREM2-mediated immune response
540. Inflammation and Aging in Psychosis – A Transdiagnostic Proteomics Study Using the Human Connectome Project for Early Psychosis (HCP-EP)
No full textBackground:
Since protein expression plays a key role in mediating genetic risk, the field of proteomics—the in-depth analysis of proteins—has gained renewed importance in neuropsychiatric research. Recent technical advancements now allow for the simultaneous examination of multiple proteins, revealing complex pathological processes in mental illnesses. Various studies have demonstrated that proteomics can elucidate underlying molecular mechanisms, identify clinically relevant biomarkers, and suggest novel treatment strategies, particularly in neurodegenerative disorders. Although its application in psychiatry remains less explored, proteins have proven to be promising transdiagnostic markers for understanding disease heterogeneity. In psychosis, proteomic studies support the “inflamm-aging” hypothesis, wherein chronic low-grade inflammation accelerates biological aging and contributes to disease onset and progression. These insights underscore the importance of integrating protein-based approaches to detect inflammatory subtypes.
Aims & Objectives:
This study examines whether psychosis exhibits a unique proteomic profile derived from 374 peripheral proteins and seeks to clarify the affected pathways. Additionally, it evaluates cellular aging indices based on senescence-associated secretory phenotype (SASP) proteins.
Method:
Data was obtained from the Human Connectome Project for Early Psychosis (HCP-EP), which recruited participants aged 16 to 35 years across four institutions. Out of 303 participants of the original cohort, 120 individuals were included in the analyses. This sample consists of 35 healthy controls and 85 individuals with transdiagnostic psychosis (schizophrenia, schizophreniform disorder, schizoaffective disorder, psychosis not otherwise specified, delusional disorder, brief psychotic disorder, major depression with psychosis, or bipolar disorder with psychosis). Proteomic plasma analyses were performed using the Olink platform across four panels relevant to “inflamm-aging.” We conducted analyses comparing individual protein expression levels between groups using ANCOVAs (controlling for age, sex, and storage time). Subsequent Gene Set Enrichment Analysis (GSEA) identified enriched pathways between the groups, and principal component analyses (PCA) were used to derive composite measures for the significant protein sets and the SASP indices.
Results:
Our analysis revealed significant differences in the expression of proteins associated with inflammation, cell communication, and cardiometabolic regulation between individuals with psychosis and healthy controls (pFDR-corrected < 0.1). GSEA demonstrated significant enrichment in pathways related to the cellular response to tumor necrosis factor and monocyte chemotaxis in the psychosis group (qFDR < 0.05). PCA of the SASP indices indicated that individuals with psychosis exhibited a significantly higher SASP index compared to controls (p < 0.05). Moreover, these indices were associated with age, sex, body mass index, alcohol consumption and psychological well-being (p < 0.05).
Discussion & Conclusions:
Our findings provide preliminary evidence that psychosis is characterized by a transdiagnostic proteomic profile marked by increased levels of inflammatory and aging-related proteins. The enrichment of specific inflammatory pathways and the elevation of the SASP index support the concept of premature biological aging in psychosis. These results underscore the potential of protein-based biomarkers to enhance our understanding of psychosis as a whole-body disorder and may inform future efforts in developing targeted therapeutic interventions. However, larger and longitudinal studies are needed to confirm these associations and to further delineate the clinical utility of these proteomic signatures
Memorial Stained-Glass Window Inventories
No full textInventories of the stained-glass memorial windows located on the “Old Lobby” side of the Edward A. Block Family Library in Riley Hospital for Children. The initial inventory was created by Thomas D. Lund in 2014 and updated by Karen Bruner Stroup in 2017. The more detailed, updated inventory featuring additional background information about each window was compiled by Karen Bruner Stroup and Richard L. Schreiner in 2025. Photos included in updated inventory of stained-glass window panels provided courtesy of Thomas D. Lund
Unfolded Protein Response (UPR) Signaling in Hepatic Stellate Cells (HSC) as a Key Regulator of Liver Fibrosis
No full textIUILiver cirrhosis is a leading cause of death worldwide, with the prevalence of cirrhosis on
the rise. Cirrhosis is driven by various etiologies, including liver injuries from diabetes,
obesity, metabolic disorders, and alcohol use. Central to the progression of chronic liver
disease to cirrhosis is the activation of hepatic stellate cells (HSCs), which secrete
extracellular matrix (ECM) proteins such as collagen to form fibrotic scars. Activated HSCs
produce vast amounts of fibrotic proteins that require folding and processing prior to
secretion. Increased protein folding demands cause endoplasmic reticulum (ER) stress
and initiate the Unfolded Protein Response (UPR). The UPR allows HSCs to adapt to ER
stress and restore proteostasis to maintain fibrogenic secretion, while failure to restore
proteostasis leads to apoptosis. All three arms of the UPR are activated in fibrogenic HSCs,
propagated by ATF6α, PERK, and IRE1α, but how activated HSCs manage elevated UPR
signaling while remaining viable is not well understood. This gap in knowledge limits
therapeutic development to limit fibrosis progression. We identified Protein Kinase R-like
ER Kinase (PERK) as a crucial factor for fibrogenesis, but the mechanisms of PERK signaling
in HSCs are largely unknown. Our research aims to understand how PERK regulates HSC
activation and fibrogenesis and to target these mechanisms in order to promote HSC
inactivation and mitigate fibrogenesis. Importantly, we demonstrated that PERK
activation stimulates its downstream target, a stress-responsive gene named GADD45A, which serves as a regulator of HSC activation. Finally, we show that HSC-specific deletion
of GADD45A limits CCl₄-driven fibrogenesis in vivo with reduced collagen deposition and
limited HSC activation, likely through increased HSC senescence. In conclusion, our
findings highlight the pivotal role of the PERK–GADD45A axis in limiting liver fibrosis and
underscore its potential as a therapeutic target to modulate HSC fate and attenuate
fibrogenesis in chronic liver disease
Open, laparoscopic, and robotic radical nephroureterectomy for upper tract urothelial carcinoma: Comparing outcomes and the tetrafecta as a composite marker of surgery quality
No full textIntroduction: The purpose of this study was to compare surgical outcomes and costs between robotic radical nephroureterectomy (RNU), laparoscopic radical nephroureterectomy (LNU), and open radical nephroureterectomy (ONU), and to assess the relevance of the tetrafecta as a composite outcome on survival parameters after nephroureterectomy (NU).
Methods: Operative and oncologic followup data was retrospectively collected on patients who underwent NU from 2006-2022 at our institution. The tetrafecta was defined as a true bladder cuff, lymph node dissection, negative surgical margins, and no postoperative complications. Cox proportional hazards regression was used to assess the impact of surgical approach on survival outcomes.
Results: A total of 248 patients were included in the analysis (145 RNU, 61 LNU, and 42 ONU). The complication rate differed by approach and was lowest in RNU (p<0.01). Cancer-specific survival (CSS) differed between ONU and RNU patients, with ONU patients 2.51 times as likely to die from their cancer. Retroperitoneal recurrence-free survival (RPFS) differed between ONU and RNU patients, with ONU patients 7.22 times more likely to experience a retroperitoneal recurrence (p=0.0013). Variable surgical costs were lower in LNU compared to ONU (p=0.028) and direct inpatient hospital costs were lowest with RNU (p<0.01). Eighty-one patients met criteria for the tetrafecta. RNU patients were more likely to achieve the tetrafecta compared to LNU (p<0.01) and ONU (p<0.01) patients. No differences in survival parameters existed between patients who did and did not achieve the tetrafecta.
Conclusions: Most oncologic outcomes after NU do not differ by approach on long-term followup; however, CSS and RPFS appear to differ between RNU and ONU. ONU has traditionally been considered the approach with the lowest cost; however, our analysis demonstrates both RNU and LNU require lower costs than ONU, depending on the cost parameter analyzed. Among all approaches, the tetrafecta is best achieved with RNU
Healthcare provider perspectives on HPV vaccinations at ages 9-10 in the United States
Get PDFThis study investigated health care providers' (HCPs') attitudes and experiences with initiating HPV vaccination at 9-10 y old instead of 11-12 y old. We conducted a cross-sectional online survey with 500 US HCPs who reported recommending and/or administering HPV vaccination to pediatric patients, recruited from a membership-based panel. The survey focused on providers' experiences with, and attitudes toward, routine HPV vaccination at age 9-10. Participants included pediatricians (n = 175), family medicine physicians (n = 175), nurse practitioners (n = 75), and physician assistants (n = 75). HCPs were mostly female (56%), white (79%), with a mean age of 43 y. HCPs reported mentioning the HPV vaccine to boys and girls before age 11 72% and 77% of the time, respectively, but recommending it prior to age 11 less frequently (38% and 51% of the time). Few HCPs (11%) reported introducing the vaccine at the same visit at which it was given; 36% reported multiple discussions before acceptance. A substantial proportion of HCPs (23%) would not administer HPV vaccine when children were <11 y old, even if asked by parents. HCPs reported that a majority of parents who were offered HPV vaccination for their children at 9-10 y of age accepted. HCPs identified benefits of earlier vaccination; the top three were improving on-time completion, completion prior to other adolescent vaccines and increased opportunities to vaccinate. Top concerns included parent misconception about the duration of protection and difficulty explaining HPV vaccination to a younger child. Findings suggest most HCPs would support earlier HPV vaccination and see potential for improved completion
The heterogeneity of type 1 diabetes: implications for pathogenesis, prevention, and treatment-2024 Diabetes, Diabetes Care, and Diabetologia Expert Forum
Get PDFThis article summarises the current understanding of the heterogeneity of type 1 diabetes from a June 2024 international Expert Forum organised by the editors of Diabetes, Diabetes Care, and Diabetologia. The Forum reviewed key factors contributing to the development and progression of type 1 diabetes and outlined specific, high-priority research questions. Knowledge gaps were identified and, notably, opportunities to harness disease heterogeneity to develop personalised therapies were outlined. Herein, we summarise our discussions and review the heterogeneity of genetic risk and immunologic and metabolic phenotypes that influence and characterise type 1 diabetes progression (presented as a palette of risk factors). We discuss how these age-related factors determine disease aggressiveness (along gradients) and describe how variable immunogenetic pathways aggregate (into networks) to affect beta cell and other pancreatic pathologies to cause clinical disease at different ages and with variable severity (described as disease-related thresholds). Heterogeneity of pathogenesis and clinical severity opens avenues to prevention and intervention, including the potential of disease-modifying immunotherapy and islet cell replacement. We conclude with a call for (1) continued research to identify more factors contributing to the disease, both overall and in specific subgroups; (2) investigations focusing on both individuals who surpass metabolic and immune thresholds and develop diabetes and those who remain disease free with the same level of immunogenetic risk; and (3) efforts to identify where the current type 1 diabetes staging system may fall short and determine how it can be improved to capture and leverage heterogeneity in prevention and intervention strategies
Nonlinear steepest descent on a torus: a case study of the Landau–Lifshitz equation
Get PDFWe obtain rigorous large time asymptotics for the Landau–Lifshitz (LL) equation in the soliton free case by extending the nonlinear steepest descent method to genus 1 surfaces. The methods presented in this paper pave the way to a rigorous analysis of other integrable equations on the torus and enable asymptotic analysis on different regimes of the LL equation
Isabella and the Puzzle Pirates
Get PDFThis is an adaptation of a story mutually told in our family during the early years of the pandemic. It involves a young girl's discoveries about moral identity formation, woven into her fantasy life, during a time of uncertainty and social isolation. This adaptation is intended for classroom and performative readings as well as staged enactments in intimate spaces accommodating young children with teachers and parents present. The readings or enactments may be conducted over consecutive storytelling periods. Audience participation is welcomed during several scenes. The author anticipates that creative puppetry as well as pantomime may be used liberally
