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Identification of the tyrosine phosphorylation (pY)-dependent interactome of immune co-receptors is crucial for understanding signal pathways involved in immunotherapy. However, identifying the motif-specific interactome for each pY commonly found on these multi-phosphorylated membrane proteins remains challenging. Here, we describe a photoaffinity-based chemical proteomic approach to dissect the motif-specific cytoplasmic interactomes of the critical immune co-receptor CD28. Various full-length CD28 cytoplasmic tails (CD28cyto) with defined pY and selectively replaced photo-methionine were synthesized and applied to explore three pY-motif-dependent CD28cyto interactomes. We identified a stand-alone interaction of phospholipase PLCG1 with the Y191 motif with enhanced affinity for the sequence neighboring the transmembrane domain. Importantly, taking advantage of native top-down mass spectrometry with a 193-nm laser, we discovered the direct association of a previously undefined pY218 motif with the kinase PKCθ through its C2 domain. This synthetic CD28cyto-based photoaffinity proteomic approach is generically applicable to the study of other immune co-receptors with multiple pY sites on their linear cytoplasmic tail.

In the version of this Letter initially published, the Acknowledgements section omitted the following note of support from Geoffrey M. Wahl: “Work in the laboratory of G.M.W. was supported, in part, by the Cancer Center Core Grant (CA014195), National Institutes of Health/National Cancer Institute (R35 CA197687), National Institutes of Health Cancer Training Grant (T32 CA009370), the Isacoff Research Foundation Gastrointestinal (ICOF) and the Freeberg Foundation.”.

Studies have shown that both short-term and long-term cold exposures disturb the biological process. The aim of the present study is to investigate the effects of intermittent cold exposure on proteomic profiles in the hypothalamus and pituitary of female Sprague-Dawley (SD) rats.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology1,2. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance3-7. Furthermore, PSC activation occurs very early during PDAC tumorigenesis8-10, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.

Background: Kinesiophobia is common in patients after total knee arthroplasty and is an important risk factor for post-operative recovery outcomes. Little is known about the complex intercorrelations between different components of pain catastrophizing, self-efficacy, and kinesiophobia. This study aimed to identify the central components of kinesiophobia and to explore the interconnectedness between components of pain catastrophizing, self-efficacy, and kinesiophobia. Methods: A total of 216 patients after total knee arthroplasty were recruited in this study. Pain Catastrophizing Scale, Self-efficacy of Rehabilitation Outcome Scale and Tampa Scale for Kinesiophobia were used to assess pain catastrophizing, self-efficacy and kinesiophobia. R software was used to visualize the networks and analyze the centrality of the networks. The index "strength" and "bridge expected influence" were employed to identify the central components and the bridge components of the networks. Results: In the item network of kinesiophobia, three items ("Simply being careful that I do not make any unnecessary movements is the safest thing I can do to prevent my pain from worsening", "My accident has put my body at risk for the rest of my life", and "My body is telling me I have something dangerously wrong") had the highest strength centrality. In the pain catastrophizing/self-efficacy–kinesiophobia network, rumination had the highest positive bridge expected influence, while coping self-efficacy had the highest negative value. Conclusion: The three central components of kinesiophobia identified in this study, as well as two bridge variables (rumination and coping self-efficacy), could be promising and effective targets for prevention and intervention of kinesiophobia. [ABSTRACT FROM AUTHOR]

BACKGROUND: Moringa oleifera (M. oleifera) leaves are rich in nutrients and bioactive ingredients. This study was aimed at evaluating the anti‐fatigue effect of the ethanol extract of M. oleifera leaves (MLEE) on mice and its primary mechanism of action using a weight‐loaded forced swimming test. In the present study, MLEE was prepared by ultrasound‐assisted extraction, and its anti‐fatigue effect and antioxidant capacity were evaluated in mice. Mice were administrated MLEE (320 mg kg−1 body weight) for 15 days. RESULTS: MLEE supplementation significantly increased levels of glucose and non‐esterified fatty acids (NEFA), while decreasing levels of lactate and blood urea nitrogen in serum (P < 0.05); the levels of glycogen in the liver and muscle were also increased, as was the activity of glycogen synthase and the level of NEFA in muscle (P < 0.05). According to a Western blot analysis, MLEE increased the expression of AMPKα1, JNK, AKT and STAT3 in the muscle of mice. CONCLUSION: Our findings indicate that MLEE has an anti‐fatigue effect via the AMPK‐linked route, which enables it to control energy metabolism and enhance antioxidant enzyme activity. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]