Engineered CD47 protects T cells for enhanced antitumour immunity.

Adoptively transferred T cells and agents designed to block the CD47-SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a 'don't eat me' signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.

Skeletal Muscle SIRT3 Deficiency Contributes to Pulmonary Vascular Remodeling in Pulmonary Hypertension Due to Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Pulmonary hypertension (PH) is a major complication linked to adverse outcomes in heart failure with preserved ejection fraction (HFpEF), yet no specific therapies exist for PH associated with HFpEF (PH-HFpEF). We have recently reported on the role of skeletal muscle SIRT3 (sirtuin-3) in modulation of PH-HFpEF, suggesting a novel endocrine signaling pathway for skeletal muscle modulation of pulmonary vascular remodeling. In this study, we attempted to define the processes by which skeletal muscle SIRT3 defects affect pulmonary vascular health in PH-HFpEF. METHODS AND RESULTS: Skeletal muscle-specific Sirt3 knockout mice (Sirt3skm-/-) exhibited reduced pulmonary vascular density accompanied by pulmonary vascular proliferative remodeling and elevated pulmonary pressures. Using mass spectrometry-based comparative secretome analysis, we demonstrated elevated secretion of LOXL2 (lysyl oxidase homolog 2) in SIRT3-deficient skeletal muscle cells. Elevated circulation and protein expression levels of LOXL2 were also observed in plasma and skeletal muscle of Sirt3skm-/- mice, a rat model of PH-HFpEF, and humans with PH-HFpEF. In addition, expression levels of CNPY2 (canopy fibroblast growth factor signaling regulator 2), a known proliferative and angiogenic factor, were increased in pulmonary artery endothelial cells and pulmonary artery smooth muscle cells of Sirt3skm-/- mice and animal models of PH-HFpEF. CNPY2 levels were also higher in pulmonary artery smooth muscle cells of subjects with obesity compared with nonobese subjects. Moreover, treatment with recombinant LOXL2 protein promoted pulmonary artery endothelial cell migration/proliferation and pulmonary artery smooth muscle cell proliferation through regulation of CNPY2-p53 signaling. Last, skeletal muscle-specific Loxl2 deletion decreased pulmonary artery endothelial cell and pulmonary artery smooth muscle cell expression of CNPY2 and improved pulmonary pressures in mice with high-fat diet-induced PH-HFpEF. CONCLUSIONS: This study demonstrates a systemic pathogenic impact of skeletal muscle SIRT3 deficiency in remote pulmonary vascular remodeling and PH-HFpEF. This study suggests a new endocrine signaling axis that links skeletal muscle health and SIRT3 deficiency to remote CNPY2 regulation in the pulmonary vasculature through myokine LOXL2. Our data also identify skeletal muscle SIRT3, myokine LOXL2, and CNPY2 as potential targets for the treatment of PH-HFpEF.

Effect of prothymosin α on neuroplasticity following cerebral ischemia­reperfusion injury.

Prothymosin α (ProT), a highly acidic nuclear protein with multiple cellular functions, has shown potential neuroprotective properties attributed to its anti­necrotic and anti­apoptotic activities. The present study aimed to investigate the beneficial effect of ProT on neuroplasticity after ischemia­reperfusion injury and elucidate its underlying mechanism of action. Primary cortical neurons were either treated with ProT or overexpressing ProT by gene transfection and exposed to oxygen­glucose deprivation for 2 h in vitro. Immunofluorescence staining for ProT and MAP­2 was performed to quantify ProT protein expression and assess neuronal arborization. Mice treated with vehicle or ProT (100 µg/kg) and ProT overexpression in transgenic mice received middle cerebral artery occlusion for 50 min to evaluate the effect of ProT on neuroplasticity­associated protein following ischemia­reperfusion injury. The results demonstrated that in cultured neurons ProT significantly increased neurite lengths and the number of branches, accompanied by an upregulation mRNA level of brain­derived neurotrophic factor. Furthermore, ProT administration improved the protein expressions of synaptosomal­associated protein, 25 kDa and postsynaptic density protein 95 after ischemic­reperfusion injury in vivo. These findings suggested that ProT can potentially induce neuroplasticity effects following ischemia­reperfusion injury.

Petroleum-contaminated soil bioremediation and microbial community succession induced by application of co-pyrolysis biochar amendment: An investigation of performances and mechanisms.

This study aimed to remediate petroleum-contaminated soil using co-pyrolysis biochar derived from rice husk and cellulose. Rice husk and cellulose were mixed in various weight ratios (0:1, 1:0, 1:1, 1:3 and 3:1) and pyrolyzed under 500 °C. These biochar variants were labeled as R0C1, R1C0, R1C1, R1C3 and R3C1, respectively. Notably, the specific surface area and carbon content of the co- pyrolysis biochar increased, potentially promoting the growth and colonization of soil microorganisms. On the 60th day, the microbial control group achieved a 46.69% removal of pollutants, while the addition of R0C1, R1C0, R1C3, R1C1 and R3C1 resulted in removals of 70.56%, 67.01%, 67.62%, 68.74% and 67.30%, respectively. In contrast, the highest efficiency observed in the abiotic treatment group was only 24.12%. This suggested that the removal of petroleum pollutants was an outcome of the collaborative influence of co-pyrolysis biochar and soil microorganisms. Furthermore, the abundance of Proteobacteria, renowned for its petroleum degradation capability, obviously increased in the treatment group with the addition of co-pyrolysis biochar. This demonstrated that co-pyrolysis biochar could notably stimulate the growth of functionally associated microorganisms. This research confirmed the promising application of co-pyrolysis biochar in the remediation of petroleum-contaminated soil.

Structural Basis of Nucleic Acid Recognition and 6mA Demethylation by Caenorhabditis elegans NMAD-1A.

N6-methyladenine (6mA) of DNA is an emerging epigenetic mark in the genomes of Chlamydomonas, Caenorhabditis elegans, and mammals recently. Levels of 6mA undergo drastic fluctuation and thus affect fertility during meiosis and early embryogenesis. Here, we showed three complex structures of 6mA demethylase C. elegans NMAD-1A, a canonical isoform of NMAD-1 (F09F7.7). Biochemical results revealed that NMAD-1A prefers 6mA Bubble or Bulge DNAs. Structural studies of NMAD-1A revealed an unexpected "stretch-out" conformation of its Flip2 region, a conserved element that is usually bent over the catalytic center to facilitate substrate base flipping in other DNA demethylases. Moreover, the wide channel between the Flip1 and Flip2 of the NMAD-1A explained the observed preference of NMAD-1A for unpairing substrates, of which the flipped 6mA was primed for catalysis. Structural analysis and mutagenesis studies confirmed that key elements such as carboxy-terminal domain (CTD) and hypothetical zinc finger domain (ZFD) critically contributed to structural integrity, catalytic activity, and nucleosome binding. Collectively, our biochemical and structural studies suggest that NMAD-1A prefers to regulate 6mA in the unpairing regions and is thus possibly associated with dynamic chromosome regulation and meiosis regulation.

Genetically Encoded Photocatalysis Enables Spatially Restricted Optochemical Modulation of Neurons in Live Mice.

Light provides high temporal precision for neuronal modulations. Small molecules are advantageous for neuronal modulation due to their structural diversity, allowing them to suit versatile targets. However, current optochemical methods release uncaged small molecules with uniform concentrations in the irradiation area, which lack spatial specificity as counterpart optogenetic methods from genetic encoding for photosensitive proteins. Photocatalysis provides spatial specificity by generating reactive species in the proximity of photocatalysts. However, current photocatalytic methods use antibody-tagged heavy-metal photocatalysts for spatial specificity, which are unsuitable for neuronal applications. Here, we report a genetically encoded metal-free photocatalysis method for the optochemical modulation of neurons via deboronative hydroxylation. The genetically encoded photocatalysts generate doxorubicin, a mitochondrial uncoupler, and baclofen by uncaging stable organoboronate precursors. The mitochondria, nucleus, membrane, cytosol, and ER-targeted drug delivery are achieved by this method. The distinct signaling pathway dissection in a single projection is enabled by the dual optogenetic and optochemical control of synaptic transmission. The itching signaling pathway is investigated by photocatalytic uncaging under live-mice skin for the first time by visible light irradiation. The cell-type-specific release of baclofen reveals the GABABR activation on NaV1.8-expressing nociceptor terminals instead of pan peripheral sensory neurons for itch alleviation in live mice.

Inosine induces stemness features in CAR-T cells and enhances potency.

Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR-T cells express CD39 and CD73, which mediate proximal steps in Ado generation. Here, we sought to enhance CAR-T cell potency by knocking out CD39, CD73, or adenosine receptor 2a (A2aR) but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness and enhanced CAR-T functionality. Similarly, CAR-T cell exposure to INO augmented function and induced features of stemness. INO induced profound metabolic reprogramming, diminishing glycolysis, increasing mitochondrial and glycolytic capacity, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of CAR-T cell metabolism and epigenetic stemness programming and deliver an enhanced potency platform for cell manufacturing.

Metal-Free 1,3-Boronate Rearrangement to Ketones Driven by Visible Light.

Boronate rearrangements, such as the Matteson and Petasis reactions, are valuable metal-free reactions for the transfer of the carbo group on boron to intramolecular electrophilic sites. However, only highly reactive electrophiles are suitable, and ketones are too inactive for those boronate rearrangements due to the high energy barriers. We disclose here the 1,3-boronate rearrangement to ketones, for which a high energy barrier (44.9 kcal/mol) is prohibitory for thermal reactions in the ground state. The reaction is enabled by the key keto-enol-boronate bidentate complex formation in situ, which absorbs visible light to reach the excited state for the chemoselective 1,3-boronate rearrangement to ketones. Experimental and computational investigations exclude free radical intermediates from organoboronates. The aryl, alkenyl, and alkyl boronic acids react with various 1,3-diketones driven by visible light irradiation to construct structurally diverse ß-keto tertiary alcohols under metal-free conditions. The reaction demonstrates substrate diversity with 58 examples, yields up to 98 %, and it is suitable for gram-scale synthesis.

Noncoding mutations cause super-enhancer retargeting resulting in protein synthesis dysregulation during B cell lymphoma progression.

Whole-genome sequencing of longitudinal tumor pairs representing transformation of follicular lymphoma to high-grade B cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma) identified coding and noncoding genomic alterations acquired during lymphoma progression. Many of these transformation-associated alterations recurrently and focally occur at topologically associating domain resident regulatory DNA elements, including H3K4me3 promoter marks located within H3K27ac super-enhancer clusters in B cell non-Hodgkin lymphoma. One region found to undergo recurrent alteration upon transformation overlaps a super-enhancer affecting the expression of the PAX5/ZCCHC7 gene pair. ZCCHC7 encodes a subunit of the Trf4/5-Air1/2-Mtr4 polyadenylation-like complex and demonstrated copy number gain, chromosomal translocation and enhancer retargeting-mediated transcriptional upregulation upon lymphoma transformation. Consequently, lymphoma cells demonstrate nucleolar dysregulation via altered noncoding 5.8S ribosomal RNA processing. We find that a noncoding mutation acquired during lymphoma progression affects noncoding rRNA processing, thereby rewiring protein synthesis leading to oncogenic changes in the lymphoma proteome.

Creating a Box-Cavity Defect Model in the Cortical Bone of Rat Femora.

Severe bone defects or complex fractures can result in serious complications such as nonunion or insufficient bone healing. Tissue engineering, which involves the application of cells, scaffolds, and cytokines, is considered a promising solution for bone regeneration. Consequently, various animal models that simulate bone defects play a crucial role in exploring the therapeutic potential of tissue engineering for bone healing. In this study, we established a box-shaped cortical bone defect model in the mid-femur of rats, which could serve as an ideal model for assessing the function of biomaterials in promoting bone healing. This box-shaped cortical bone defect was drilled using an oral low-speed handpiece and shaped by a lathe needle. Post-operative micro-CT analysis was immediately conducted to confirm the successful establishment of the box-cavity cortical bone defect. The femurs on the operated side of the rats were then harvested at multiple time points post-surgery (0 days, 2 weeks, 4 weeks, and 6 weeks). The healing process of each sample's defect area was evaluated using micro-CT, hematoxylin and eosin (H&E) staining, and Masson trichrome staining. These results demonstrated a healing pattern consistent with intramembranous ossification, with healing essentially complete by 6 weeks. The categorization of this animal model's healing process provides an effective in vivo method for investigating novel biomaterials and drugs that target intramembranous ossification during bone tissue defect healing.

Confounding clinical picture in the diagnosis of left ventricular and valvular masses: a case report.

Background: Masses in the heart and valves have a broad differential diagnosis including infective and rheumatic causes as well as primary or metastatic tumours. Diagnosis involves delineating the location, shape, and origin of the mass/masses and considering the clinical context. This case outlines the work-up and approach to diagnosing a cardiac mass along with imaging findings of a unique secondary metastatic mass in the left ventricle (LV). Case summary: A 69-year-old female with past medical history of metastatic lung cancer treated with radiotherapy and breast cancer treated with mastectomy presented with dyspnoea and fever. Due to concern for infective endocarditis, transthoracic echocardiogram (TTE) was performed revealing 2 cm × 0.72 cm finger-like, echo-lucent, mobile mass, appearing to originate from LV lateral wall, protruding into the LV cavity, along with valvular masses on mitral and tricuspid valves. Initial differential diagnosis included benign pathologies, but due to the clinical suspicion of malignancy, cardiac MRI was performed which revealed a broad-based mass with invasion into the LV lateral wall and delayed gadolinium enhancement, suggestive of metastatic tumour. The patient was given Aspirin to prevent embolization and eventually underwent hospice care. Discussion: Atypical appearing cardiac masses can be seen on TTE. Cardiac magnetic resonance imaging (MRI) should be used for definite diagnosis in cases where clinical features do not match the echocardiographic findings.

Endovascular therapy versus medical management for acute ischemic stroke with large infarct core: Systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To compare the efficacy and safety of endovascular therapy (EVT) versus best medical management (BMM) in patients with acute ischemic stroke (AIS) with large infarct core. METHODS: We searched Pubmed, Embase and Cochrane Central Register of Controlled Trials for published randomized clinical trials (RCTs) from inception to February 18, 2023. We defined patients with large core infarcts as having an Alberta Stroke Program early computed tomography score (ASPECTS) of 3-5. The primary outcome was functional independence, defined as a score of 0-2 on the modified Rankin scale (mRS) at 90 days. Secondary outcome was independent ambulation defined as mRS 0-3 at 90 days. Safety outcomes were mortality at 90 days, symptomatic intracranial hemorrhage (sICH) and any intracranial hemorrhage (ICH). RESULTS: The overall treatment effect was more favourable to EVT group. EVT was significantly correlated with improvement of functional independence at 90 days (mRS 0-2) (RR = 2.40; 95 % CI, 1.82-3.16; P < 0.01; I2 = 0 %) and independent ambulation (mRS 0-3) (RR = 1,78; 95 % CI, 1.28-2.48; P < 0.01; I2 = 58 %) at 90 days. 90-day mortality was not significantly different between the two groups(RR = 0.95; 95 % CI, 0.78-1.16; P > 0.05; I2 = 0 %). The risk of sICH and any ICH was higher in EVT group than in BMM group. CONCLUSION: Compared with BMM, EVT may improve functional outcomes in patients with ASPECTS 3-5, despite being associated with an increased risk of sICH and any ICH.

Identifying cadmium and lead co-accumulation from living rice blade spectrum.

Neither cadmium (Cd) nor lead (Pb) is necessary for crop growth, but they both can accumulate in soil and crop tissues, resulting in land degradation and crop reduction. Few researchers have explored how to detect Cd-Pb co-accumulation in leaves using proximal sensing techniques, especially by low-cost, easy-to-use leaf clips that capture hyperspectral reflections at suitable foliar positions. In this study, a hyperspectral imager was employed to collect images of the rice canopy from a designed greenhouse experiment that included 16 pretreatments of Cd-Pb co-accumulation, followed by spectral extractions from 3 foliar positions: the blade root, the middle of the leaf, and the leaf apex. A support vector machine with leave-one-out cross-validation was performed to diagnose the contaminative levels based on the feature wavelengths selected by an improved successive projection algorithm. Partial least squares regression was used to predict Cd-Pb concentrations in rice blades. The results indicated that diagnostic accuracies were varied using spectra of different foliar positions. The blade root and leaf apex of rice blades were the optimal foliar position for detecting Cd and Pb contamination, respectively. At the optimal foliar positions, diagnostic accuracies exceeded 0.80 for distinguishing whether the rice is subject to Cd-Pb contamination. The Cd prediction performed 'very good' with a residual prediction deviation (RPD) of 2.21, a R2 of 0.79, and a root mean square error (RMSE)of 6.14, while that of Pb was 1.62, 0.61, and 186.54. Important wavelengths were identified at 659-694 nm and 667-694 nm to detect Cd and Pb contamination. In summary, our results verified the feasibility and clarified the optimal foliar positions of rice blades to detect Cd-Pb contamination. The wavelengths selecting have the great potential in the design of future leaf clips, and the optimal foliar position can provide suggestions to improve diagnostic performances in field applications.

Nicotinamide Deteriorates Post-Stroke Immunodepression Following Cerebral Ischemia-Reperfusion Injury in Mice.

(1) Background: Inducing experimental stroke leads to biphasic immune responses, where the early activation of immune functions is followed by severe immunosuppression accompanied by spleen and thymus atrophy. Nicotinamide, a water-soluble B-group vitamin, is a known neuroprotectant against brain ischemia in animal models. We examined the effect of nicotinamide on the central and peripheral immune response in experimental stroke models. (2) Methods: Nicotinamide (500 mg/kg) or saline was intravenously administered to C57BL/6 mice during reperfusion after transiently occluding the middle cerebral artery or after LPS injection. On day 3, the animals were examined for behavioral performance and were then sacrificed to assess brain infarction, blood-brain barrier (BBB) integrity, and the composition of immune cells in the brain, thymus, spleen, and blood using flow cytometry. (3) Results: Nicotinamide reduced brain infarction and microglia/macrophage activation following MCAo (p < 0.05). Similarly, in LPS-injected mice, microglia/macrophage activation was decreased upon treatment with nicotinamide (p < 0.05), suggesting a direct inhibitory effect of nicotinamide on microglia/macrophage activation. Nicotinamide decreased the infiltration of neutrophils into the brain parenchyma and ameliorated Evans blue leakage (p < 0.05), suggesting that a decreased infiltration of neutrophils could, at least partially, be the result of a more integrated BBB structure following nicotinamide treatment. Our studies also revealed that administering nicotinamide led to retarded B-cell maturation in the spleen and subsequently decreased circulating B cells in the thymus and bloodstream (p < 0.05). (4) Conclusions: Cumulatively, nicotinamide decreased brain inflammation caused by ischemia-reperfusion injury, which was mediated by a direct anti-inflammatory effect of nicotinamide and an indirect protective effect on BBB integrity. Administering nicotinamide following brain ischemia resulted in a decrease in circulating B cells. This warrants attention with respect to future clinical applications.

Tumor-associated monocytes promote mesenchymal transformation through EGFR signaling in glioma.

The role of brain immune compartments in glioma evolution remains elusive. We profile immune cells in glioma microenvironment and the matched peripheral blood from 11 patients. Glioblastoma exhibits specific infiltration of blood-originated monocytes expressing epidermal growth factor receptor (EGFR) ligands EREG and AREG, coined as tumor-associated monocytes (TAMo). TAMo infiltration is mutually exclusive with EGFR alterations (p = 0.019), while co-occurring with mesenchymal subtype (p = 4.7 × 10-7) and marking worse prognosis (p = 0.004 and 0.032 in two cohorts). Evolutionary analysis of initial-recurrent glioma pairs and single-cell study of a multi-centric glioblastoma reveal association between elevated TAMo and glioma mesenchymal transformation. Further analyses identify FOSL2 as a TAMo master regulator and demonstrates that FOSL2-EREG/AREG-EGFR signaling axis promotes glioma invasion in vitro. Collectively, we identify TAMo in tumor microenvironment and reveal its driving role in activating EGFR signaling to shape glioma evolution.

Flagella of Tumor-Targeting Bacteria Trigger Local Hemorrhage to Reprogram Tumor-Associated Macrophages for Improved Antitumor Therapy.

Tumor-associated macrophages (TAMs) exhibit an immunosuppressive M2 phenotype and lead to failure of antitumor therapy. Infiltrated erythrocytes during hemorrhage are recognized as a promising strategy for polarizing TAMs. However, novel materials that precisely induce tumor hemorrhage without affecting normal coagulation still face challenges. Here, tumor-targeting bacteria (flhDC VNP) are genetically constructed to realize precise tumor hemorrhage. FlhDC VNP colonizes the tumor and overexpresses flagella during proliferation. The flagella promote the expression of tumor necrosis factor α, which induces local tumor hemorrhage. Infiltrated erythrocytes during the hemorrhage temporarily polarize macrophages to the M1 subtype. In the presence of artesunate, this short-lived polarization is transformed into a sustained polarization because artesunate and heme form a complex that continuously produces reactive oxygen species. Therefore, the flagella of active tumor-targeting bacteria may open up new strategies for reprogramming TAMs and improving antitumor therapy.

Emerging triple-reassortant influenza C virus with household-associated infection during an influenza A(H3N2) outbreak, China, 2022.

Recent research have shown that influenza C virus (ICV) has a possible higher clinical impact than previously thought. But knowledge about ICV is limited compared with influenza A and B viruses, due to poor systematic surveillance and inability to propagate. Herein, a case infected with triple reassortant ICV was identified during an influenza A(H3N2) outbreak, which was the first report of ICV infection in mainland China. Phylogenetic analysis showed that this ICV was triple reassortant. Serological evidence revealed that the index case might be related to family-clustering infection. Therefore, it is essential to heighten surveillance for the prevalence and variation of ICV in China, during the COVID-19 pandemic.

Application of hybrid biophysical-biochemical methods to unravel the molecular basis for auto-inhibition and activation of protein tyrosine phosphatase TCPTP/PTPN2.

Since the discovery of protein tyrosine phosphorylation as one of the critical post-translational modifications, it has been well known that the activity of protein tyrosine kinases (PTKs) is tightly regulated. On the other hand, protein tyrosine phosphatases (PTPs) are often regarded to act constitutively active, but recently we and others have shown that many PTPs are expressed in an inactive form due to allosteric inhibition by their unique structural features. Furthermore, their cellular activity is highly regulated in a spatiotemporal manner. In general, PTPs share a conserved catalytic domain comprising about 280 residues that is flanked by either an N-terminal or a C-terminal non-catalytic segment, which differs significantly in size and structure from each other and is known to regulate specific PTP's catalytic activity. The well-characterized non-catalytic segments can be globular or intrinsically disordered. In this work, we have focused on the T-Cell Protein Tyrosine Phosphatase (TCPTP/PTPN2) and demonstrated how the hybrid biophysical-biochemical methods can be applied to unravel the underlying mechanism through which TCPTP's catalytic activity is regulated by the non-catalytic C-terminal segment. Our analysis showed that TCPTP is auto-inhibited by its intrinsically disordered tail and trans-activated by Integrin alpha-1's cytosolic region.