tbuckley/cabot-search huggingface dataset:
Predicting the outcome of psychotherapy for chronic depression by person‐specific symptom networks
Authors: Lea Schumacher, Jan Philipp Klein, Martin Hautzinger, Martin Härter, Elisabeth Schramm, Levente Kriston
Journal: World Psychiatry (2024)

Psychotherapies are efficacious in the treatment of depression, albeit only with a moderate effect size. It is hoped that personalization of treatment can lead to better outcomes. The network theory of psychopathology offers a novel approach suggesting that symptom interactions as displayed in person‐specific symptom networks could guide treatment planning for an individual patient. In a sample of 254 patients with chronic depression treated with either disorder‐specific or non‐specific psychotherapy for 48 weeks, we investigated if person‐specific symptom networks predicted observer‐rated depression severity at the end of treatment and one and two years after treatment termination. Person‐specific symptom networks were constructed based on a time‐varying multilevel vector autoregressive model of patient‐rated symptom data. We used statistical parameters that describe the structure of these person‐specific networks to predict therapy outcome. First, we used symptom centrality measures as predictors. Second, we used a machine learning approach to select parameters that describe the strength of pairwise symptom associations. We found that information on person‐specific symptom networks strongly improved the accuracy of the prediction of observer‐rated depression severity at treatment termination compared to common covariates recorded at baseline. This was also shown for predicting observer‐rated depression severity at one‐ and two‐year follow‐up. Pairwise symptom associations were better predictors than symptom centrality parameters for depression severity at the end of therapy and one year later. Replication and external validation of our findings, methodological developments, and work on possible ways of implementation are needed before person‐specific networks can be reliably used in clinical practice. Nevertheless, our results indicate that the structure of person‐specific symptom networks can provide valuable information for the personalization of treatment for chronic depression.
Social connection as a critical factor for mental and physical health: evidence, trends, challenges, and future implications
Authors: Julianne Holt‐Lunstad
Journal: World Psychiatry (2024)

Rising concerns about social isolation and loneliness globally have highlighted the need for a greater understanding of their mental and physical health implications. Robust evidence documents social connection factors as independent predictors of mental and physical health, with some of the strongest evidence on mortality. Although most data are observational, evidence points to directionality of effects, plausible pathways, and in some cases a causal link between social connection and later health outcomes. Societal trends across several indicators reveal increasing rates of those who lack social connection, and a significant portion of the population reporting loneliness. The scientific study on social isolation and loneliness has substantially extended over the past two decades, particularly since 2020; however, its relevance to health and mortality remains underappreciated by the public. Despite the breadth of evidence, several challenges remain, including the need for a common language to reconcile the diverse relevant terms across scientific disciplines, consistent multi‐factorial measurement to assess risk, and effective solutions to prevent and mitigate risk. The urgency for future health is underscored by the potentially longer‐term consequences of the COVID‐19 pandemic, and the role of digital technologies in societal shifts, that could contribute to further declines in social, mental and physical health. To reverse these trends and meet these challenges, recommendations are offered to more comprehensively address gaps in our understanding, and to foster social connection and address social isolation and loneliness.
Chronic Activation of Tubulin Tyrosination Improves Heart Function
Authors: Niels Pietsch, Christina Y. Chen, Svenja Kupsch, Lucas Bacmeister, Birgit Geertz, Marisol Herrera-Rivero, Bente Siebels, Hannah Voß, Elisabeth Krämer, Ingke Braren, Dirk Westermann, Hartmut Schlüter, Giulia Mearini, Saskia Schlossarek, Jolanda van der Velden, Matthew A. Caporizzo, Diana Lindner, Benjamin L. Prosser, Lucie Carrier
Journal: Circulation Research (2024)

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common cardiac genetic disorder caused by sarcomeric gene variants and associated with left ventricular hypertrophy and diastolic dysfunction. The role of the microtubule network has recently gained interest with the findings that microtubule detyrosination (dTyr-MT) is markedly elevated in heart failure. Acute reduction of dTyr-MT by inhibition of the detyrosinase (VASH [vasohibin]/SVBP [small VASH-binding protein] complex) or activation of the tyrosinase (TTL [tubulin tyrosine ligase]) markedly improved contractility and reduced stiffness in human failing cardiomyocytes and thus posed a new perspective for HCM treatment. In this study, we tested the impact of chronic tubulin tyrosination in an HCM mouse model ( Mybpc3 knock-in), in human HCM cardiomyocytes, and in SVBP-deficient human engineered heart tissues (EHTs). METHODS: Adeno-associated virus serotype 9–mediated TTL transfer was applied in neonatal wild-type rodents, in 3-week-old knock-in mice, and in HCM human induced pluripotent stem cell–derived cardiomyocytes. RESULTS: We show (1) TTL for 6 weeks dose dependently reduced dTyr-MT and improved contractility without affecting cytosolic calcium transients in wild-type cardiomyocytes; (2) TTL for 12 weeks reduced the abundance of dTyr-MT in the myocardium, improved diastolic filling, compliance, cardiac output, and stroke volume in knock-in mice; (3) TTL for 10 days normalized cell area in HCM human induced pluripotent stem cell–derived cardiomyocytes; (4) TTL overexpression activated transcription of tubulins and other cytoskeleton components but did not significantly impact the proteome in knock-in mice; (5) SVBP-deficient EHTs exhibited reduced dTyr-MT levels, higher force, and faster relaxation than TTL-deficient and wild-type EHTs. RNA sequencing and mass spectrometry analysis revealed distinct enrichment of cardiomyocyte components and pathways in SVBP-deficient versus TTL-deficient EHTs. CONCLUSIONS: This study provides the first proof of concept that chronic activation of tubulin tyrosination in HCM mice and in human EHTs improves heart function and holds promise for targeting the nonsarcomeric cytoskeleton in heart disease.
<scp>TLR7</scp>/8 Activation in Immune Cells and Muscle by <scp>RNA</scp>‐Containing Immune Complexes: Role in Inflammation and the Pathogenesis of Myositis
Authors: Yin Wu, Aditee Deshpande, Nicholas Geraci, Petra Budde, Vera Sellers, Phanindra Velisetty, Chia‐Chi Sun, Fatima Strand, Carmina Bhavsar, Timothy B. Niewold, Mark A. Jensen, Irina Kalatskaya, Kavita Y. Sarin, David Fiorentino, Andrew T. Bender
Journal: Arthritis & Rheumatology (2024)

Objective Activation of endosomal toll‐like receptors (TLRs) is one possible driver of inflammation in idiopathic inflammatory myopathies (IIM). We investigated the potential contribution of TLR7 and TLR8 to IIM pathogenesis. Methods Activation of TLR7/8 in healthy donor peripheral blood mononuclear cells (PBMCs) by immune complexes from patients with IIM and lupus was tested. Autoantibody profiling of patient IgG samples was performed using a 1581‐antigen array. TLR7 and/or TLR8 activation by RNA molecules associated with autoantibodies was assessed. Gene expression in human myoblasts and satellite cells following treatment with supernatants from TLR7/8‐activated PBMCs was evaluated by NanoString. C57BL/6 mice were dosed intramuscularly with the TLR7/8 agonist R848 and single‐cell RNA‐sequencing was performed on the muscle to ascertain the cell types responding to TLR7/8 activation and the downstream effects. Results Overall, 69 patients with IIM were included with representation of dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM) subsets. Immune complexes from patients with IIM, as well as autoantibody‐associated RNAs His‐tRNA, Y1, Y4 and U1, activated PBMCs to produce IFN‐α and IL‐6 via TLR7/8. Several canonical (Ro60, Ro52, HIST1H4A) and novel (IL‐36RN) autoreactivities correlated highly with TLR7/8 activation. Supernatants from TLR7/8‐activated PBMCs had a negative impact on human myoblasts and satellite cells. Endothelial cells were activated by R848 in mouse muscle in vivo , in addition to immune cells such as monocytes and macrophages. Conclusion Our results suggest that patients with IIM have autoantibodies in their blood causing TLR7/8 activation, which leads to inflammation in muscles with potential deleterious effects. image
The <scp>WHO</scp> Flexible Interview for <scp>ICD</scp>‐11 (<scp>FLII</scp>‐11)
Authors: Geoffrey M. Reed, Karen T. Maré, Michael B. First, T.S. Jaisoorya, Girish N. Rao, John‐Joe Dawson‐Squibb, Christine Lochner, Mark van Ommeren, Dan J. Stein
Journal: World Psychiatry (2024)
Nutrient Levels and Nutrient Sources in Pancreatic Tumors
Authors: Sven Groessl, Wilhelm Palm
Journal: Cancer Research (2024)

Abstract It has been known that poor tumor perfusion and dysregulated cancer cell metabolism give rise to tumor microenvironments with unphysiologic nutrient levels, but the precise alterations in metabolite abundance are not well defined. In a 2015 study in Cancer Research, Kamphorst and colleagues published a detailed comparison of the metabolome from human pancreatic tumors and benign tissues. Tumors were depleted in glucose and various nonessential amino acids but, surprisingly, enriched in essential amino acids. The authors attributed these nutrient imbalances to macropinocytosis of extracellular proteins, a RAS-driven amino acid acquisition pathway that was found to be increased in human tumors and supports pancreatic cancer cell growth during amino acid starvation. These findings substantially contributed to the understanding of altered nutrient levels in tumors and extracellular proteins as noncanonical nutrients. Intratumoral nutrient levels in different cancer contexts and signaling pathways that regulate nutrient acquisition by cancer cells remain a focus of current research. See related article by Kamphorst and colleagues, Cancer Res 2015;75:544–53
An update from the <scp>WPA</scp> Section on Anxiety and <scp>Obsessive‐Compulsive</scp> Disorders
Authors: Naomi A. Fineberg, Dan J. Stein, Katharina Domschke, Eric Hollander, Susanne Walitza, Michael Van Ameringen, Bernardo Dell'Osso, Joseph Zohar
Journal: World Psychiatry (2024)
Enhanced browning of adipose tissue by mirabegron-microspheres
Authors: Zheming Niu, Staffan Hildebrand, Sebastian Kappes, Mohamed Ehab Ali, Matthias Vogel, Mickel Mikhael, Danli Ran, Jan Kozak, Maria Wiedner, Dirk F Richter, Alf Lamprecht, Alexander Pfeifer
Journal: Journal of Controlled Release (2024)
Hope on the Horizon: A Revolution in KRAS Inhibition Is Creating a New Treatment Paradigm for Patients with Pancreatic Cancer
Authors: Andrew J. Aguirre, Ben Z. Stanger, Anirban Maitra
Journal: Cancer Research (2024)

Abstract KRAS is the most frequently altered oncogene in pancreatic ductal adenocarcinoma, in which the aberrantly activated RAS signaling pathway plays pleiotropic roles in tumor initiation and maintenance. Nearly four decades after the discovery of the RAS oncoprotein, a multitude of pharmacologic inhibitors are now available that directly target mutant KRAS. This In Focus commentary, published simultaneously with the 2024 AACR Special Conference on Pancreatic Cancer, summarizes the current state of this rapidly changing field, including preclinical data and emerging clinical trends with respect to therapeutic efficacy, mechanisms of resistance, and potential combinations to maximize clinical benefit from this promising class of therapies.
Topical Transdermal Administration of Supramolecular Self‐Assembled Carnosine for Anti‐Melanin and Anti‐Aging
Authors: De Bai, Zhenyuan Wang, Lin Xie, Beibei Lu, Mi Wang, Jiaheng Zhang
Journal: Advanced Healthcare Materials (2024)

Abstract The structure of natural proteins has inspired the hypothesis that L‐carnosine (LC), acetyl carnosine (AC), and decarboxy carnosine (DC) self‐assemble into highly bioactive carnosine with supramolecular structures. These structures are proposed to combat skin pigmentation and aging through the coordination of weak interactions between molecules. Simulations are conducted to ascertain the precise free energies of the potential supramolecular structures and to identify the equilibrium structure. The mechanism of transdermal action of supramolecular carnosine is investigated through experiments and molecular dynamics simulations. The results demonstrate that supramolecular carnosine exhibits a more pronounced reactivity with the skin than LC, primarily due to the interaction of AC and DC with the lipid matrix, which reduces interfacial resistance. The anti‐photoaging and anti‐glycation cell models demonstrate that supramolecular carnosine upregulates the expression of the Nrf2 protein, activates the antioxidant defense system of melanocytes, inhibits the expression of the receptor for advanced glycosylation end products (AGEs), and reduces the level of AGEs in vivo. Moreover, supramolecular carnosine has demonstrated satisfactory whitening efficacy in cells and clinical efficacy tests, thereby underscoring its considerable potential for biomedical and aesthetic applications.
Hypoxia Promotes the Expression of <scp>ADAM9</scp> by Tubular Epithelial Cells which Enhances <scp>TGF</scp>‐β1 Activation and Promotes Tissue Fibrosis in Lupus Nephritis
Authors: Masataka Umeda, Kohei Karino, Abhigyan Satyam, Nobuya Yoshida, Ryo Hisada, Rhea Bhargava, Theodoros Vichos, Ana Laura Kunzler, Takashi Igawa, Kunihiro Ichinose, Kenta Torigoe, Tomoya Nishino, Takahiro Maeda, Caroline A Owen, Reza Abdi, Atsushi Kawakami, George C Tsokos
Journal: Arthritis & Rheumatology (2024)

Objective Enhanced expression of transforming growth factor (TGF) β in the kidneys of patients with lupus nephritis (LN) can lead to progressive fibrosis, resulting in end‐organ damage. ADAM9 activates TGFβ1 by cleaving the latency‐associated peptide (LAP). We hypothesized that ADAM9 in the kidney may accelerate fibrogenesis by activating TGFβ1. Methods We assessed the expression of ADAM9 in the kidneys of mice and humans who were lupus prone. In vitro experiments were conducted using tubular epithelial cells (TECs) isolated from mice and explored the mechanisms responsible for the up‐regulation of ADAM9 and the subsequent activation of TGFβ1. To assess the role of ADAM9 in the development of tubular‐intestinal fibrosis in individuals with LN, we generated MRL/ lpr mice who were Adam9 deficient. Results ADAM9 was highly expressed in tubules from MRL /lpr mice. The transcription factor hypoxia‐inducible factor–1α was found to promote the transcription of ADAM9 in TECs. TECs from mice who were Adam9 deficient and exposed to the hypoxia mimetic agent dimethyloxalylglycine failed to cleave the LAP to produce bioactive TGFβ1 from latent TGFβ1. Coculture of TECs from mice who were Adam9 deficient with fibroblasts in the presence of dimethyloxalylglycine and latent TGFβ1 produced decreased amounts of type I collagen and α–smooth muscle actin (SMA) by fibroblasts. MRL/ lpr mice who were Adam9 deficient showed reduced interstitial fibrosis. At the translational level, ADAM9 expression in tissues and urine of patients with LN was found to increase. Conclusion Hypoxia promotes the expression of ADAM9 by TECs, which is responsible for the development of interstitial fibrosis in patients with LN by enhancing the TGFβ1 activation, which promotes fibroblasts to produce collagen and α‐SMA. image
Prevention, treatment and care of substance use disorders among adolescents. Statement by the <scp>UNODC</scp>‐<scp>WHO</scp> Informal Scientific Network, 2024
Authors: Nora D. Volkow, Michael P. Schaub, Anja Busse, Vladimir Poznyak, Dzmitry Krupchanka, Giovanna Campello
Journal: World Psychiatry (2024)
Unveiling Hierarchical Self‐Assembly of Triazolylferrocenyl Dendrimers: Producing Non‐Traditional Intrinsically Green Fluorescent Vesosomes for Nanotheranostics
Authors: Carolyne B. Braga, Gabriel Perli, Qi Wang, Luke Wylie, Diego L. Bertuzzi, Marco C. P. Soares, Miguel D. Ramos, Jaime Ruiz, Agilio Padua, Didier Astruc, Catia Ornelas
Journal: Advanced Healthcare Materials (2024)

Abstract Dendrimers and supramolecular chemistry continue to fascinate researchers due to the endless unrevealed potential of their combination. This study investigates the self‐assembly process of a series of hydrophobic triazolylferrocenyl dendrimers in aqueous medium. Deep investigation through NMR spectroscopy, absorption UV–vis spectroscopy along with theoretical simulations demonstrates that the ferrocenyl moieties interact intramolecularly and intermolecularly driving the self‐assembly process. Data obtained by DLS, NTA, SEM, TEM, and EF‐TEM demonstrate that these dendrimers, in water, spontaneously self‐assemble through a hierarchical process. The dendrimers first self‐assemble into uniform nanovesicles, which in turn self‐assemble into larger vesosomes. The resulting vesosomes emit green non‐traditional intrinsic fluorescence, which is a property that emerged from the self‐assembled architectures. The vesosomes are efficiently uptaken by cancer cells and induce significant cytotoxic activity against the cancer cell line MCF‐7, up to the submicromolar concentration. Positive dendritic effects are identified in the fluorescence intensity and in the cytotoxic activity of the vesosomes, which follow the trend G0‐9Fc &lt; G1‐27Fc &lt; G2‐81Fc. This work showcases the remarkable potential of combining the two dynamic fields of dendrimers and supramolecular chemistry, which resulted in green fluorescent vesosomes capable of performing the dual role of cell imaging and killing, with potential applications in nanotheranostics.
Eumelanin‐Enhanced Photothermal Disinfection of Contact Lenses Using a Sustainable Marine Nanoplatform Engineered with Electrospun Nanofibers
Authors: Magdalena Bartolewska, Alicja Kosik‐Kozioł, Zbigniew Korwek, Zuzanna Krysiak, Devis Montroni, Maciej Mazur, Giuseppe Falini, Filippo Pierini
Journal: Advanced Healthcare Materials (2024)

Abstract Bacterial keratitis (BK) is a severe eye infection commonly associated with Staphylococcus aureus (S. aureus) , posing a significant risk to vision, especially among contact lens wearers. This research introduces a novel smart nanoplatform (deMS@cNF), developed from demineralized mussel shells (deMS) and reinforced with chitin (CT) nanofibrils, specifically designed for portable photothermal disinfection of contact lenses. The nanoplatform leverages the photothermal properties of eumelanin in mussel shells (MS), which, when activated by a simple bike flashlight, rapidly heats to temperatures up to 95 °C, effectively destroying bacterial contamination. In vitro tests demonstrate that the nanoplatform is biocompatible and non‐toxic, making it suitable for medical applications. This study highlights an innovative approach to converting marine biowaste into a safe, effective, and low‐cost portable method for disinfecting contact lenses, showcasing the potential of the deMS@cNF platform for broader antimicrobial applications.
Metabolic reprogramming by mutant GNAS creates an actionable dependency in intraductal papillary mucinous neoplasms of the pancreas
Authors: Yuki Makino, Kimal I Rajapakshe, Benson Chellakkan Selvanesan, Takashi Okumura, Kenjiro Date, Prasanta Dutta, Lotfi Abou-Elkacem, Akiko Sagara, Jimin Min, Marta Sans, Nathaniel Yee, Megan J Siemann, Jose Enriquez, Paytience Smith, Pratip Bhattacharya, Michael Kim, Merve Dede, Traver Hart, Anirban Maitra, Fredrik Ivar Thege
Journal: Gut (2024)

Background Oncogenic ‘hotspot’ mutations of KRAS and GNAS are two major driver alterations in intraductal papillary mucinous neoplasms (IPMNs), which are bona fide precursors to pancreatic ductal adenocarcinoma. We previously reported that pancreas-specific Kras G12D and Gnas R201C co-expression in p48 Cre ; Kras LSL-G12D ; Rosa26 LSL-rtTA ; Tg (TetO-Gnas R201C ) mice ( ‘Kras;Gnas ’ mice) caused development of cystic lesions recapitulating IPMNs. Objective We aim to unveil the consequences of mutant Gnas R201C expression on phenotype, transcriptomic profile and genomic dependencies. Design We performed multimodal transcriptional profiling (bulk RNA sequencing, single-cell RNA sequencing and spatial transcriptomics) in the ‘Kras;Gnas ’ autochthonous model and tumour-derived cell lines ( Kras;Gnas cells), where Gnas R201C expression is inducible. A genome-wide CRISPR/ Cas 9 screen was conducted to identify potential vulnerabilities in Kras G12D ;Gnas R201C co-expressing cells. Results Induction of Gnas R201C —and resulting G (s) alpha signalling—leads to the emergence of a gene signature of gastric (pyloric type) metaplasia in pancreatic neoplastic epithelial cells. CRISPR screening identified the synthetic essentiality of glycolysis-related genes Gpi1 and Slc2a1 in Kras G12D ; Gnas R201C co-expressing cells. Real-time metabolic analyses in Kras;Gnas cells and autochthonous Kras;Gnas model confirmed enhanced glycolysis on Gnas R201C induction. Induction of Gnas R201C made Kras G12D expressing cells more dependent on glycolysis for their survival. Protein kinase A-dependent phosphorylation of the glycolytic intermediate enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) was a driver of increased glycolysis on Gnas R201C induction. Conclusion Multiple orthogonal approaches demonstrate that Kras G12D and Gnas R201C co-expression results in a gene signature of gastric pyloric metaplasia and glycolytic dependency during IPMN pathogenesis. The observed metabolic reprogramming may provide a potential target for therapeutics and interception of IPMNs.
Sensitivity of the familial high‐risk approach for the prediction of future psychosis: a total population study
Authors: Colm Healy, Ulla Lång, Kirstie O’Hare, Juha Veijola, Karen O'Connor, Marius Lahti‐Pulkkinen, Eero Kajantie, Ian Kelleher
Journal: World Psychiatry (2024)

Children who have a parent with a psychotic disorder present an increased risk of developing psychosis. It is unclear to date, however, what proportion of all psychosis cases in the population are captured by a familial high‐risk for psychosis (FHR‐P) approach. This is essential information for prevention research and health service planning, as it tells us the total proportion of psychosis cases that this high‐risk approach would prevent if an effective intervention were developed. Through a prospective cohort study including all individuals born in Finland between January 1, 1987 and December 31, 1992, we examined the absolute risk and total proportion of psychosis cases captured by FHR‐P and by a transdiagnostic familial risk approach (TDFR‐P) based on parental inpatient hospitalization for any mental disorder. Outcomes of non‐affective psychosis (ICD‐10: F20‐F29) and schizophrenia (ICD‐10: F20) were identified in the index children up to December 31, 2016. Of the index children (N=368,937), 1.5% (N=5,544) met FHR‐P criteria and 10.3% (N=38,040) met TDFR‐P criteria. By the study endpoint, 1.9% (N=6,966) of the index children had been diagnosed with non‐affective psychosis and 0.5% (N=1,846) with schizophrenia. In terms of sensitivity, of all non‐affective psychosis cases in the index children, 5.2% (N=355) were captured by FHR‐P and 20.6% (N=1,413) by TDFR‐P approaches. The absolute risk of non‐affective psychosis was 6.4% in those with FHR‐P, and 3.7% in those with TDFR‐P. There was notable variation in the sensitivity and total proportion of FHR‐P and TDFR‐P cases captured based on the age at which FHR‐P/TDFR‐P were determined. The absolute risk for psychosis, however, was relatively time invariant. These metrics are essential to inform intervention strategies for psychosis risk requiring pragmatic decision‐making.