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Distractibility determines the propensity to have one's attention captured by irrelevant information; it relies on a balance between voluntary and involuntary attention. We report a cross-sectional study that uses the competitive attention test to characterize patterns of attention across the adult life span from 21 to 86 years old. Several distractibility components were measured in 186 participants distributed within seven age groups. Results indicate that distractibility components follow distinct trajectories with aging: Voluntary orienting remains stable from 21 to 86 years old, sustained attention decreases after 30 years old, distraction progressively increases between 26 and 86 years old, and impulsivity is lower in older compared to younger adults. Increased distractibility in older age thus seems to result from a dominance of involuntary over voluntary attention processes, whose detrimental effect on performance is partly compensated by enhanced motor control. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

CAR (chimeric antigen receptor) T cell therapy has shown clinical success in treating hematological malignancies, but its treatment of solid tumors has been limited. One major challenge is on-target, off-tumor toxicity, where CAR T cells also damage normal tissues that express the targeted antigen. To reduce this detrimental side-effect, Boolean-logic gates like AND-NOT gates have utilized an inhibitory CAR (iCAR) to specifically curb CAR T cell activity at selected nonmalignant tissue sites. However, the strategy seems inefficient, requiring high levels of iCAR and its target antigen for inhibition. Using a TROP2-targeting iCAR with a single PD1 inhibitory domain to inhibit a CEACAM5-targeting CAR (CEACAR), we observed that the inefficiency was due to a kinetic delay in iCAR inhibition of cytotoxicity. To improve iCAR efficiency, we modified three features of the iCAR-the avidity, the affinity, and the intracellular signaling domains. Increasing the avidity but not the affinity of the iCAR led to significant reductions in the delay. iCARs containing twelve different inhibitory signaling domains were screened for improved inhibition, and three domains (BTLA, LAIR-1, and SIGLEC-9) each suppressed CAR T function but did not enhance inhibitory kinetics. When inhibitory domains of LAIR-1 or SIGLEC-9 were combined with PD-1 into a single dual-inhibitory domain iCAR (DiCARs) and tested with the CEACAR, inhibition efficiency improved as evidenced by a significant reduction in the inhibitory delay. These data indicate that a delicate balance between CAR and iCAR signaling strength and kinetics must be achieved to regulate AND-NOT gate CAR T cell selectivity.

In vowel discrimination, commonly found discrimination patterns are directional asymmetries where discrimination is faster (or easier) if differing vowels are presented in a certain sequence compared to the reversed sequence. Different models of speech sound processing try to account for these asymmetries based on either phonetic or phonological properties. In this study, we tested and compared two of those often-discussed models, namely the Featurally Underspecified Lexicon (FUL) model (Lahiri and Reetz, 2002) and the Natural Referent Vowel (NRV) framework (Polka and Bohn, 2011). While most studies presented isolated vowels, we investigated a large stimulus set of German vowels in a more naturalistic setting within minimal pairs. We conducted an mismatch negativity (MMN) study in a passive and a reaction time study in an active oddball paradigm. In both data sets, we found directional asymmetries that can be explained by either phonological or phonetic theories. While behaviorally, the vowel discrimination was based on phonological properties, both tested models failed to explain the found neural patterns comprehensively. Therefore, we additionally examined the influence of a variety of articulatory, acoustical, and lexical factors (e.g., formant structure, intensity, duration, and frequency of occurrence) but also the influence of factors beyond the well-known (perceived loudness of vowels, degree of openness) in depth via multiple regression analyses. The analyses revealed that the perceptual factor of perceived loudness has a greater impact than considered in the literature and should be taken stronger into consideration when analyzing preattentive natural vowel processing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Riedinger, Nagels, Werth and Scharinger.)

Objective: To determine factors that may lead physicians not to comply with clinical practice guidelines.Design: Retrospective analysis of patients whose physicians were not compliant with discharge recommendations from a prospective, controlled interventional trial of a guideline to reduce hospital length of stay for patients admitted for chest pain.Setting: A large community teaching hospital.Participants: Patients admitted with chest pain who were not discharged according to a practice guideline.Results: 79 (34%) of 230 patients with chest pain classified as being at low risk by concurrent or retrospective review were not discharged by day 3 (the guideline recommendation). Of these 79 patients, 33 (42%) were misclassified at concurrent review (10 were falsely classified as being at high risk and 23 were falsely classified as being at low risk). Of 46 correctly classified patients, 11 (14%) were classified as having noncompliant physicians because of health care system inefficiencies. The status of 7 (9%) patients was changed to high risk between initial classification and potential discharge. For 15 patients (19%), no obvious reason for delayed discharge was found, but they had a higher severity of illness than did low-risk patients discharged according to the guideline as measured by mean time-insensitive predictive instrument scores (41.3% +/- [SD] 14.1% compared with 31.5% +/- 14.3%; P = 0.017). In 13 patients (16%), physicians refused to follow the guideline recommendations.Conclusions: In measuring and attempting to improve physician compliance with a length-of-stay guideline, physician refusal accounts for a small percentage (16%) of noncompliance. Implementation issues, health care system inefficiency, and severity of illness were the predominant reasons why physicians did not comply with guidelines. Our study further supports the principle that clinical practice guidelines should complement rather than be a substitute for physician judgment. [ABSTRACT FROM AUTHOR]

Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of prostate adenocarcinoma. These tumors display features of epithelial-to-mesenchymal transition, a cellular state associated with increased tumor aggressiveness. Consistent with its activation in clinical CRPC, tumors driven by Notch1 intracellular domain in combination with multiple pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Our study provides functional evidence that the Notch1 signaling axis synergizes with alternative pathways in promoting metastatic CRPC and may represent a new therapeutic target for advanced prostate cancer., Competing Interests: The authors declare no conflict of interest.

Background: Psychocardiology explores the impact of symbolic, emotional, behavioral, and social factors on cardiovascular functions and vice versa. This holistic approach focuses on managing psychosocial predisposing factors, comorbidities, and interventions within cardiology. The guideline development involved a thorough literature review on psychocardiology, encompassing studies on psychosocial influences, communication strategies, and cultural competence in cardiovascular care. Methods: Data were collected from peer-reviewed journals, clinical trials, and meta-analyses to create an evidence-based framework. Expert panels comprising cardiologists, psychologists, and communication specialists provided insights and validated the recommendations. The methodology also incorporated qualitative feedback from patient interviews and focus groups to ensure the guidelines address real-world challenges and patient perspectives. Results: The guidelines highlight the importance of effective physician-patient communication, emphasizing the role of psychological factors in managing and treating cardiovascular diseases (CVDs). Psychosocial elements such as psychological flexibility, attachment styles, coping mechanisms, existential anxiety, and obsessive beliefs are closely linked to cardiovascular health, influencing both the incidence and progression of CVDs. Conclusion: Addressing personality traits, emotion regulation, health and illness behaviors, and the communicative context, as well as fostering communication and cultural sensitivity in clinical settings, can improve diagnostic accuracy, treatment adherence, and overall patient satisfaction. [ABSTRACT FROM AUTHOR]

Background: Circulating metabolite levels are altered in multiple sclerosis (MS) and are associated with MS severity. However, how metabolic profiles shift following highly efficacious therapies, like ocrelizumab remains unclear. Objective: Circulating metabolite levels are altered in multiple sclerosis (MS) and are associated with MS severity. However, how metabolic profiles shift following highly efficacious therapies, like ocrelizumab remains unclear. To assess changes in the circulating metabolome produced by ocrelizumab treatment in people with relapsing–remitting MS (RRMS). Methods: Thirty‐one individuals with RRMS eligible for beginning treatment with ocrelizumab were recruited and followed with demographic, clinical, quality‐of‐life, and global metabolomics data collected at each visit. Modules of highly correlated metabolites were identified using the weighted correlation network analysis approach. Changes in each module's eigenmetabolite values and individual metabolites during the study were evaluated using linear mixed‐effects models. Results: Patients with a mean age of 40.8 (SD = 10.30) years, and median disease duration of 4.0 (IQR = 8.5) years, were monitored for a median of 3.36 (IQR = 1.43) years. Two out of twelve identified sets of metabolites were altered significantly. The first module mainly contained androgenic and pregnenolone steroids (p‐value <0.001, coefficient: −0.10). The second module primarily consisted of several lysophospholipids, arachidonic acid, some endocannabinoids, and monohydroxy fatty acid metabolites (p‐value = 0.016, coefficient: −0.12), which its reduction was significantly associated with improvement based on overall disability response score (OR 3.09e‐01, 95% CI: 6.83e‐02, 9.09e‐01, p‐value = 3.15E‐02). Interpretation: In this longitudinal observational study, using a global untargeted metabolomics approach, we showed significant alteration in circulating metabolome in RRMS patients undergoing ocrelizumab treatment. In particular, we observed a significant reduction in metabolites involved in the lysophospholipid pathway, which was associated with patients' improvement. [ABSTRACT FROM AUTHOR]

The precise regulation of pH homeostasis is crucial for normal physiology. However, in tissue microenvironments, it can be impacted by pathological conditions such as inflammation and cancer. Due to the overproduction and accumulation of acids (protons), the extracellular pH is characteristically more acidic in inflamed tissues and tumors in comparison to normal tissues. A family of proton-sensing G-protein-coupled receptors (GPCRs) has been identified as molecular sensors for cells responding to acidic tissue microenvironments. Herein, we review the current research progress pertaining to these proton-sensing GPCRs, including GPR4, GPR65 (TDAG8), and GPR68 (OGR1), in inflammation and cancer. Growing evidence suggests that GPR4 and GPR68 are mainly pro-inflammatory, whereas GPR65 is primarily anti-inflammatory, in various inflammatory disorders. Both anti- and pro-tumorigenic effects have been reported for this family of receptors. Moreover, antagonists and agonists targeting proton-sensing GPCRs have been developed and evaluated in preclinical models. Further research is warranted to better understand the roles of these proton-sensing GPCRs in pathophysiology and is required in order to exploit them as potential therapeutic targets for disease treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Liposarcoma is a rare cancer of adipose tissue with limited treatment options. Here, we studied the fuel used by liposarcoma to develop a new strategy for treatment. Liposarcoma was found to rely on the amino acid Asparagine for tumor growth, especially in its most aggressive form. By combining treatments that limit both synthesis and uptake of Asparagine within liposarcoma cells, we demonstrated a unique sensitivity that reduced tumor growth in animal models. Altogether, findings from this study suggest that targeting Asparagine could be a promising new therapy in liposarcoma. Background: mTORC1 activity is dependent on the presence of micronutrients, including Asparagine (Asn), to promote anabolic cell signaling in many cancers. We hypothesized that targeting Asn metabolism would inhibit tumor growth by reducing mTORC1 activity in well-differentiated (WD)/dedifferentiated (DD) liposarcoma (LPS). Methods: Human tumor metabolomic analysis was utilized to compare abundance of Asn in WD vs. DD LPS. Gene set enrichment analysis (GSEA) compared relative expression among metabolic pathways upregulated in DD vs. WD LPS. Proliferation assays were performed for LPS cell lines and organoid models by using the combination treatment of electron transport chain (ETC) inhibitors with Asn-free media. 13C-Glucose-labeling metabolomics evaluated the effects of combination treatment on nucleotide synthesis. Murine xenograft models were used to assess the effects of ETC inhibition combined with PEGylated L-Asparaginase (PEG-Asnase) on tumor growth and mTORC1 signaling. Results: Asn was enriched in DD LPS compared to WD LPS. GSEA indicated that mTORC1 signaling was upregulated in DD LPS. Within available LPS cell lines and organoid models, the combination of ETC inhibition with Asn-free media resulted in reduced cell proliferation. Combination treatment inhibited nucleotide synthesis and promoted cell cycle arrest. In vivo, the combination of ETC inhibition with PEG-Asnase restricted tumor growth. Conclusions: Asn enrichment and mTORC1 upregulation are important factors contributing to WD/DD LPS tumor progression. Effective targeting strategies require limiting access to extracellular Asn and inhibition of de novo synthesis mechanisms. The combination of PEG-Asnase with ETC inhibition is an effective therapy to restrict tumor growth in WD/DD LPS. [ABSTRACT FROM AUTHOR]

Efficient and adequate generation of deoxyribonucleotides is critical to successful DNA repair. We show that ataxia telangiectasia mutated (ATM) integrates the DNA damage response with DNA metabolism by regulating the salvage of deoxyribonucleosides. Specifically, ATM phosphorylates and activates deoxycytidine kinase (dCK) at serine 74 in response to ionizing radiation (IR). Activation of dCK shifts its substrate specificity toward deoxycytidine, increases intracellular dCTP pools post IR, and enhances the rate of DNA repair. Mutation of a single serine 74 residue has profound effects on murine T and B lymphocyte development, suggesting that post-translational regulation of dCK may be important in maintaining genomic stability during hematopoiesis. Using [(18)F]-FAC, a dCK-specific positron emission tomography (PET) probe, we visualized and quantified dCK activation in tumor xenografts after IR, indicating that dCK activation could serve as a biomarker for ATM function and DNA damage response in vivo. In addition, dCK-deficient leukemia cell lines and murine embryonic fibroblasts exhibited increased sensitivity to IR, indicating that pharmacologic inhibition of dCK may be an effective radiosensitization strategy.

In a retrospective study in an academic, acute-care community hospital, we studied the possible safety and effectiveness of a practice guideline recommending early discharge from the hospital for patients having uncomplicated total knee replacement. Of 206 patients receiving knee replacements, 162 (79%) were classified by the guideline as being at low risk for complications between the 4th and 7th postoperative days. Use of the guideline could have reduced the postoperative length of stay from 7.3 +/- 2.6 days to 4 days for the 112 patients (54%) who became low risk on the 4th postoperative day. Explicit and implicit review of the quality of care determined that 157 patients (96.9%; 95% confidence interval, (92.9%, 99.0%) could have been safely transferred from the acute-care hospital to an appropriate setting when they became classified at low risk between the 4th and 7th postoperative days. Clinical practice guidelines can possibly be used to reduce the postoperative length of acute-care hospital stay for patients having knee replacements. This guideline requires further study in a controlled clinical trial before it can be recommended for use. [ABSTRACT FROM AUTHOR]

Objective: The acceptability, safety, and efficacy of practice guidelines have rarely been evaluated. Moreover, despite the recent development of guidelines and decision aids for patients admitted to coronary care and intermediate care units, few have been tested in clinical practice.Design: A prospective, controlled clinical trial with an alternate-month design.Setting: A large teaching community hospital.Patients: Patients admitted to coronary care and intermediate care units with chest pain who were considered at low risk for complications according to a practice guideline (n = 375).Intervention: Physicians caring for patients with chest pain who were at low risk for complications received concurrent, personalized written and verbal reminders regarding a guideline that recommended a 2-day hospital stay.Results: Use of the practice guideline recommendation with concurrent reminders was associated with a 50% to 69% increase in guideline compliance (P < 0.001) and a decrease in length of stay from 3.54 +/- 4.1 to 2.63 +/- 3.0 days (0.91-day reduction, 95% CI, 0.18 to 1.63; P = 0.02) for all patients with chest pain considered at low risk for complications. The intervention was associated with a total (direct and indirect) cost reduction of $1397 per patient (CI, $176 to $2618; P = 0.03). No significant difference was found in the hospital complication rate between patients admitted to the hospital during control and intervention periods, and no significant difference was noted in complications, patient health status, or patient satisfaction when measured 1 month after hospital discharge.Conclusion: These results suggest that implementation of this practice guideline through concurrent reminders reduced hospital costs for patients with chest pain considered at low risk for complications. Further study of the guideline is warranted. [ABSTRACT FROM AUTHOR]

Objective: To determine whether providing private practitioners with triage criteria for their low-risk chest pain patients would safely enhance bed utilization efficiency in coronary and intermediate care units.Design: Prospective, controlled, interventional trial using an alternate month study design.Setting: A large teaching community hospital.Patients: Cohort of 404 low-risk patients with chest pain for whom a diagnosis of myocardial infarction has been excluded and who have not sustained complications, required interventions, or developed unstable comorbidity.Interventions: During intervention months, private practitioners caring for low-risk patients in the coronary and intermediate care units were contacted 24 hours after admission. Physicians were informed that the transfer of low-risk patients to nonmonitored beds could probably be done safely, based on the results of a pilot study. The practitioner had the option of agreeing to or deferring patient transfer. During control months, physicians were not contacted in this way.Measurements and Main Results: Use of the triage criteria by private practitioners reduced lengths of stay in the intermediate and coronary care units by 36% and 53%, respectively. Bed availability increased by 744 intermediate and 372 coronary care unit bed-days per year. Charges decreased by $2.6 million per year and profits improved by $390,000 per year. There were not significant differences in complications between control and intervention patients and in no case (95% CI, 0% to 1.6%) did the triage criteria adversely affect quality of care.Conclusions: The early transfer triage criteria may be a safe and efficacious decision aid for improving bed utilization in intermediate and coronary care units. In addition, this study shows the feasibility of and potential benefits from applying practice guidelines at a community hospital. [ABSTRACT FROM AUTHOR]

Cation exchange is a versatile post-synthetic method to explore a wide range of nanoparticle compositions, phases, and morphologies. Recently, several studies have expanded the scope of cation exchange to magic-size clusters (MSCs). Mechanistic studies indicated that MSC cation exchange undergoes a two-stage reaction pathway instead of the continuous diffusion-controlled mechanism found in nanoparticle cation exchange reactions. The cation exchange intermediate, however, has not been well-identified despite it being the key to understanding the reaction mechanism. Only indirect evidence, such as exciton peak shifts and powder x-ray diffraction, has been used to indicate the formation of the cation exchange intermediate. In this paper, we investigate the unusual nature of cation exchange in nanoclusters using our previously reported CdS MSC. High-resolution mass spectra reveal two cation exchanged reaction intermediates [Ag2Cd32S33(L) and AgCd33S33(L), L: oleic acid] as well as the fully exchanged Ag2S cluster. Crystal and electronic structure characterizations also confirm the two-stage reaction mechanism. Additionally, we investigate the Cu/CdS MSC cation exchange reaction and find a similar two-stage reaction mechanism. Our study shows that the formation of dilutely exchanged intermediate clusters can be generally found in the first stage of the MSC cation exchange reaction. By exchanging different cations, these intermediate clusters can access varying properties compared to their unexchanged counterparts. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) reporter genes allow noninvasive whole-body imaging of transplanted cells by detection with radiolabeled probes. We used a human deoxycytidine kinase containing three amino acid substitutions within the active site (hdCK3mut) as a reporter gene in combination with the PET probe [(18)F]-L-FMAU (1-(2-deoxy-2-(18)fluoro-β-L-arabinofuranosyl)-5-methyluracil) to monitor models of mouse and human hematopoietic stem cell (HSC) transplantation. These mutations in hdCK3mut expanded the substrate capacity allowing for reporter-specific detection with a thymidine analog probe. Measurements of long-term engrafted cells (up to 32 wk) demonstrated that hdCK3mut expression is maintained in vivo with no counter selection against reporter-labeled cells. Reporter cells retained equivalent engraftment and differentiation capacity being detected in all major hematopoietic lineages and tissues. This reporter gene and probe should be applicable to noninvasively monitor therapeutic cell transplants in multiple tissues.

Unlabelled: Unlike many cancers that exhibit glycolytic metabolism, high-grade liposarcomas often exhibit low 2[18F]fluoro-2-deoxy-D-glucose uptake by positron emission tomography (PET), despite rapid tumor growth. Here, we used liquid chromatography tandem mass spectrometry to identify carbon sources taken up by liposarcoma cell lines derived from xenograft tumors in patients. Interestingly, we found that liposarcoma cell lines consume nucleosides from culture media, suggesting nucleoside salvage pathway activity. The nucleoside salvage pathway is dependent on deoxycytidine kinase (dCK) and can be imaged in vivo by PET with 1-(2'-deoxy-2'-[18F]fluoroarabinofuranosyl) cytosine (FAC). We found that liposarcoma cell lines and xenograft tumors exhibit dCK activity and dCK-dependent FAC uptake in vitro and in vivo. In addition, liposarcoma cell lines and xenograft tumors are sensitive to treatment with the nucleoside analogue prodrug gemcitabine, and gemcitabine sensitivity is dependent on dCK expression. Elevated dCK activity is evident in 7 of 68 clinical liposarcoma samples analyzed. These data suggest that a subpopulation of liposarcoma patients have tumors with nucleoside salvage pathway activity that can be identified noninvasively using [18F]-FAC-PET and targeted using gemcitabine., Significance: Patients with high-grade liposarcoma have poor prognoses and often fail to respond to chemotherapy. This report identifies elevated nucleoside salvage activity in a subset of liposarcomas that are identifiable using noninvasive PET imaging with FAC and that are sensitive to gemcitabine. Thus, we suggest a new treatment paradigm for liposarcoma patients that uses [18F]-FAC-PET in the clinic to delineate gemcitabine responders from nonresponders., (©2012 AACR.)

The steroid hormone signaling axis is thought to play a central role in initiation and progression of many hormonally regulated epithelial tumors. It is unclear whether all cancer-initiating signals depend on an intact hormone receptor signaling machinery. To ascertain whether cell autonomous androgen receptor (AR) is essential for initiation of prostate intraepithelial neoplasia (PIN), the response of AR-null prostate epithelia to paracrine and cell autonomous oncogenic signals was assessed in vivo by using the prostate regeneration model system. Epithelial-specific loss of AR blocked paracrine FGF10-induced PIN, whereas the add back of exogenous AR restored this response. In contrast, PIN initiated by cell-autonomous, chronic-activated AKT developed independent of epithelial AR signaling. Our findings demonstrate a selective role for AR in the initiation of PIN, dependent on the signaling pathways driving tumor formation. Insights into the role of hormone receptor signaling in the initiation of epithelial tumors may help define this axis as a target for chemoprevention of carcinomas.

Clinical tools that measure changes in immune cell metabolism would improve the diagnosis and treatment of immune dysfunction. PET, utilizing probes for specific metabolic processes, detects regions of immune activation in vivo. In this study we investigated the immune cell specificity of PET probes for two different metabolic pathways: [18F]-2-fluorodeoxyglucose ([18F]-FDG) for glycolysis and [18F]-2-fluoro-D-(arabinofuranosyl)cytosine ([18F]-FAC) for deoxycytidine salvage. We isolated innate and adaptive immune cells from tissues of mice challenged with a retrovirus-induced sarcoma and measured their ability to accumulate FDG and FAC. We determined that the two probes had distinct patterns of accumulation: FDG accumulated to the highest levels in innate immune cells, while FAC accumulated predominantly in CD8+ T cells in a manner that correlated with cellular proliferation. This study demonstrates that innate and adaptive cell types differ in glycolytic and deoxycytidine salvage demands during an immune response and that these differential metabolic requirements can be detected with specific PET probes. Our findings have implications for the interpretation of clinical PET scans that use [18F]-FDG or [18F]-FAC to assess immune function in vivo and suggest potential applications of metabolic PET to monitor the effects of targeted immune modulation.

Background & Aims: Uptake of [18F]1-(2'-deoxy-2'-arabinofuranosyl)cytosine (D-FAC) is a trait of activated lymphocytes; its biodistribution predominates in the spleen, thymus, and bone marrow. In addition, D-FAC is taken up at high levels by the intestine. We analyzed the regional specificity of uptake and cell types that mediate it., Methods: In mice, 3-dimensional isocontour regions of interest were drawn based on computed tomographic images to quantify intestinal signals from micro-positron emission tomography scans. To ascertain the cell type responsible, intestinal epithelium and immune cells were isolated and D-FAC uptake was analyzed in vitro. Mice deficient in mucosal homing (beta7 integrin-/-), enteric microbiota (germ-free), or active for immune colitis (G alpha i2-/- CD3+ transferred into Rag-/- recipients) were studied., Results: Strong uptake of D-FAC was detected throughout the intestine, with greatest signal per region of interest in the duodenum. Fractionation of intestinal cell types after in vivo uptake revealed that the signal was almost entirely from epithelial cells. Among resident immune cell types, CD4+ T cells showed the greatest per-cell and total uptake. D-FAC uptake increased in both intestinal and systemic lymphoid sites during colitis. Compared with fluorodeoxyglucose, increased uptake of D-FAC in the small and large intestine occurred at an earlier stage of disease development., Conclusions: Uptake of D-FAC is a prominent trait of normal mouse intestinal epithelial cells, which is useful for their noninvasive visualization by positron emission tomography. Increased uptake of D-FAC reflects the activity of the epithelium and lymphocytes, providing a unique early marker of intestinal inflammation., (2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Although abnormal metabolism plays a critical role in the pathogenesis of psoriasis, the details are unclear., Objectives: Here, we identified to explore the role and mechanism of lysophosphatidylcholine (LPC) on the pathogenesis of psoriasis., Methods: The level of LPC in plasma and skin lesions and the expression of G2A on skin lesions of psoriasis patients were detected by enzyme-linked immunosorbent assay, liquid chromatography-tandem mass spectrometry, or immunohistochemistry, respectively. The glycolysis in the skin lesions of imiquimod (IMQ)-induced psoriasis-like mouse model was detected by extracellular acidification rate. LPC was subcutaneously injected into IMQ-treated mouse ears, and the phenotype as well as the glycolysis were evaluated. Exploring the effects and mechanism of LPC on keratinocytes and CD4 + T cells by culturing primary keratinocytes and CD4 + T in vitro., Results: We found that LPC was significantly increased both in the plasma and skin lesions of psoriatic patients, while G2A, exerting an essential role in LPC-inducing biological functions, was increased in psoriatic lesions. The abundance of LPC was positively correlated with glycolytic activity in the psoriasis-like mouse model. LPC treatment facilitated psoriasis-like inflammation and glycolytic activity in skin lesions. Mechanistically, the LPC/G2A axis significantly triggered glycolytic activity and produced inflammatory factors in keratinocytes, and blockade of glycolysis abrogated LPC-induced expression of inflammatory mediators in keratinocytes. LPC activated STAT1, resulting in recognition and binding to the promoters of GCK and PKLR, which are glycolytic rate-limiting enzymes. Furthermore, the LPC/G2A axis directly benefited Th1 differentiation, which was dependent on LPC-induced glycolytic activity. Notably, LPC indirectly facilitated Th17 differentiation by inducing the secretion of IL-1β in keratinocytes-T cells coculture system., Conclusions: Taken together, our findings revealed the role of the LPC/G2A axis in the pathogenesis of psoriasis; targeting LPC/G2A is a potential strategy for psoriasis therapy., (© 2023 European Academy of Dermatology and Venereology.)

2-arachidonoylglycerol (2-AG) is the most abundant endocannabinoid (EC), acting as a full agonist at both CB1 and CB2 cannabinoid receptors. It is synthesized on demand in postsynaptic membranes through the sequential action of phosphoinositide-specific phospholipase Cβ1 (PLCβ1) and diacylglycerol lipase α (DAGLα), contributing to retrograde signaling upon interaction with presynaptic CB1. However, 2-AG production might also involve various combinations of PLC and DAGL isoforms, as well as additional intracellular pathways implying other enzymes and substrates. Three other alternative pathways of 2-AG synthesis rest on the extracellular cleavage of 2-arachidonoyl-lysophospholipids by three different hydrolases: glycerophosphodiesterase 3 (GDE3), lipid phosphate phosphatases (LPPs), and two members of ecto-nucleotide pyrophosphatase/phosphodiesterases (ENPP6–7). We propose the names of AlterAG-1, -2, and -3 for three pathways sharing an ectocellular localization, allowing them to convert extracellular lysophospholipid mediators into 2-AG, thus inducing typical signaling switches between various G-protein-coupled receptors (GPCRs). This implies the critical importance of the regioisomerism of both lysophospholipid (LPLs) and 2-AG, which is the object of deep analysis within this review. The precise functional roles of AlterAGs are still poorly understood and will require gene invalidation approaches, knowing that both 2-AG and its related lysophospholipids are involved in numerous aspects of physiology and pathology, including cancer, inflammation, immune defenses, obesity, bone development, neurodegeneration, or psychiatric disorders. [ABSTRACT FROM AUTHOR]

The tunability of the lower critical solution temperature (LCST) of poly(N‐isopropylacrylamide) (PNIPAM) to lower or higher temperatures, as well as the ease of modulation of the LCST phase transition kinetics broadens the scope of application of PNIPAM‐based materials in biomedical fields. This work reports a facile approach to formulate a smart, injectable cellulose nanofibril (CNF)/PNIPAM hybrid gel. Hofmeister salts are used to induce ion‐mediated gelation of the nanofibrils and PNIPAM chains, resulting in an interpenetrating network (IPN) structure. From rheological measurements, the hybrid material displays excellent structural integrity at room temperature and tunable thermo‐stiffening around body temperature. De‐swelling kinetics can be modulated by varying the nature and concentration of the Hofmeister ion used. The successful realization of the IPN hybrid gel structure is dependent on the molecular weight of PNIPAM used. Moreover, the hybrid gels show good thermo‐reversibility during thermal cycling, as well as excellent injectability and remarkable self‐healing post‐injection, owing to shear‐thinning and thixotropic characters. Since rheology is a crucial technique in the analysis of soft matter and flow behavior is fundamental for the design and synthesis of application‐specific viscoelastic materials, the work reported herein provides a rheological basis for careful design and synthesis of smart gels. [ABSTRACT FROM AUTHOR]

Copyright of Forensische Psychiatrie, Psychologie, Kriminologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Forensische Psychiatrie, Psychologie, Kriminologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Prostate cancer (PCa) is commonly occurred with high incidence in men worldwide, and many patients will be eventually suffered from the dilemma of castration-resistance with the time of disease progression. Castration-resistant PCa (CRPC) is an advanced subtype of PCa with heterogeneous carcinogenesis, resulting in poor prognosis and difficulties in therapy. Currently, disorders in androgen receptor (AR)-related signaling are widely acknowledged as the leading cause of CRPC development, and some non-AR-based strategies are also proposed for CRPC clinical analyses. The initiation of CRPC is a consequence of abnormal interaction and regulation among molecules and pathways at multi-biological levels. In this study, CRPC-associated genes, RNAs, proteins, and metabolites were manually collected and integrated by a comprehensive literature review, and they were functionally classified and compared based on the role during CRPC evolution, i.e., drivers, suppressors, and biomarkers, etc. Finally, translational perspectives for data-driven and artificial intelligence-powered CRPC systems biology analysis were discussed to highlight the significance of novel molecule-based approaches for CRPC precision medicine and holistic healthcare. [ABSTRACT FROM AUTHOR]