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Immune checkpoint blockade therapies targeting the PD-L1/PD-1 axis have demonstrated clear clinical benefits. Improved understanding of the underlying regulatory mechanisms might contribute new insights into immunotherapy. Here, we identify transmembrane and ubiquitin-like domain-containing protein 1 (TMUB1) as a modulator of PD-L1 post-translational modifications in tumor cells. Mechanistically, TMUB1 competes with HECT, UBA and WWE domain-containing protein 1 (HUWE1), a E3 ubiquitin ligase, to interact with PD-L1 and inhibit its polyubiquitination at K281 in the endoplasmic reticulum. Moreover, TMUB1 enhances PD-L1 N-glycosylation and stability by recruiting STT3A, thereby promoting PD-L1 maturation and tumor immune evasion. TMUB1 protein levels correlate with PD-L1 expression in human tumor tissue, with high expression being associated with poor patient survival rates. A synthetic peptide engineered to compete with TMUB1 significantly promotes antitumor immunity and suppresses tumor growth in mice. These findings identify TMUB1 as a promising immunotherapeutic target. Cancer cells exploit immune checkpoint pathways, such as PD-1/PD-L1, to evade elimination by the immune system. Here, the authors demonstrate that TMUB1 regulates post-translational modifications of PD-L1 and that targeting the TMUB1/PD-L1 interaction promotes anti-tumour T cells responses

•WMH is not as important predictor of PiB SUVR as sex, age, and education.•Permuted feature importance is robust for interpreting artificial neural networks.•We develop a novel feature relevance metric that is robust.•Feature relevance identifies a sex-specific risk architecture for predicting PiB. In older adults without dementia, White Matter Hyperintensities (WMH) in MRI have been shown to be highly associated with cerebral amyloid deposition, measured by the Pittsburgh compound B (PiB) PET. However, the relation to age, sex, and education in explaining this association is not well understood. We use the voxel counts of regional WMH, age, one-hot encoded sex, and education to predict the regional PiB using a multilayer perceptron with only rectilinear activations using mean squared error. We then develop a novel, robust metric to understand the relevance of each input variable for prediction. Our observations indicate that sex is the most relevant predictor of PiB and that WMH is not relevant for prediction. These results indicate that there is a sex-specific risk architecture for Aβ deposition.

As avionics advance, heat dissipation becomes more challenging. Microencapsulated phase change material slurry (MPCMS), with its latent heat transfer properties, offers a potential solution. However, the low thermal conductivity of microencapsulated phase change material (MPCM) limits heat transfer rates, and most studies focus on improving conductivity, with little attention given to convective enhancement. This study prepared MPCMS with an MPCM mass fraction (Wm) of 10% and 20%, investigating melting heat transfer under mechanical stirring at 0–800 RPM and heat fluxes of 8.5–17.0 kW/m2. Stirring significantly alters MPCMS heat transfer behavior. As rotational speed increases, both wall-to-slurry and internal temperature differences decrease. Stirring extends the time at which the heating wall temperature (Tw) stays below a threshold. For example, at Wm = 10% MPCM and 8.50 kW/m2, increasing speed from 0 to 800 RPM raises the holding time below 70 °C by 169.6%. The effect of MPCM mass fraction on heat transfer under stirring is complex: at 0 RPM, 0% > 10% > 20%; at 400 RPM, 10% > 0% > 20%; and at 800 RPM, 10% > 20% > 0%. This is because as Wm increases, the latent heat and volume expansion coefficients of MPCMS rise, promoting heat transfer, while viscosity and thermal conductivity decrease, hindering it. At 0 RPM, the net effect is negative even at Wm = 10%. Stirring enhances internal convection and significantly improves heat transfer. At 400 RPM, heat transfer is positive at Wm = 10% but still negative at Wm = 20%. At 800 RPM, both Wm levels show positive effects, with slightly better performance at Wm = 10%. In addition, at the same heat flux, higher speeds maintain Tw below a threshold longer. Overall, stirring improves MPCMS cooling performance, offering an effective means of convective enhancement for avionics thermal management.

PD-L1(CD274) is a well-known immunosuppressive molecule, which confers immunoescape features to cancer cells and has become one of the major targets in cancer immunotherapies. Understanding the regulatory mechanisms that control PD-L1 protein expression is important for guiding immune checkpoint blockade therapy. Here, we showed that ubiquitin specific peptidase 5 (USP5) was a novel PD-L1 deubiquitinase in non-small cell lung cancer (NSCLC) cells. USP5 directly interacted with PD-L1 and deubiquitinated PD-L1, therefore enhances PD-L1 protein stability. Meanwhile, USP5 protein levels were highly elevated and positively correlated to PD-L1 levels in NSCLC tissues, and were closely correlated with poor prognosis of these patients. In addition, knockdown of USP5 retarded tumor growth in the Lewis lung carcinoma mouse model. Thus, we identified that USP5 was a new regulator of PD-L1 and targeting USP5 is a promising strategy for cancer therapy.

Plants are continuously challenged by various abiotic and biotic stresses. To tide over these adversities, plants evolved intricate regulatory networks to adapt these unfavorable environments. So far, many researchers have clarified the molecular and genetic pathways involved in regulation of stress responses. However, the mechanism through which these regulatory networks operate is largely unknown. In this study, we cloned a C2H2-type zinc finger protein gene ZFP3 from Arabidopsis thaliana and investigated its function in salt and osmotic stress response. Our results showed that the expression level of ZFP3 was highly suppressed by NaCl, mannitol and sucrose. Constitutive expression of ZFP3 enhanced tolerance of plants to salt and osmotic stress while the zfp3 mutant plants displays reduced tolerance in Arabidopsis. Gain- and Loss-of-function studies of ZFP3 showed that ZFP3 significantly changes proline accumulation and chlorophyll content. Furthermore, over-expression of ZFP3 induced the expressions of stress-related gene KIN1, RD22, RD29B and AtP5CS1. These results suggest that ZFP3 is involved in salt and osmotic stress response.

Deregulation of alternative splicing is implicated as a relevant source of molecular heterogeneity in cancer. However, the targets and intrinsic mechanisms of splicing in hepatocarcinogenesis are largely unknown. Here, we report a functional impact of a Splicing Regulatory Glutamine/Lysine-Rich Protein 1 (SREK1) variant and its regulator, Serine/arginine-rich splicing factor 10 (SRSF10). HCC patients with poor prognosis express higher levels of exon 10-inclusive SREK1 (SREK1 L ). SREK1 L can sustain BLOC1S5-TXNDC5 (B-T) expression, a targeted gene of nonsense-mediated mRNA decay through inhibiting exon-exon junction complex binding with B-T to exert its oncogenic role. B-T plays its competing endogenous RNA role by inhibiting miR-30c-5p and miR-30e-5p, and further promoting the expression of downstream oncogenic targets SRSF10 and TXNDC5. Interestingly, SRSF10 can act as a splicing regulator for SREK1 L to promote hepatocarcinogenesis via the formation of a SRSF10-associated complex. In summary, we demonstrate a SRSF10/SREK1 L /B-T signalling loop to accelerate the hepatocarcinogenesis. Alternative splicing is dysregulated in hepatocellular carcinoma. Here, the authors investigate the role of the splice variant of Splicing Regulatory Glutamic Acid and Lysine Rich Protein 1 (SREK1) and its upstream regulator, Serine/arginine-rich splicing factor 10 (SRSF10) in sustaining the oncogenic signal.

Vascular cambium is the continuation of meristem activity at the top of plants, which promotes lateral growth of plants. The vascular cambium evolved as an adaptation for secondary growth, initially in early seed plants, and became more refined in the evolution of gymnosperms and angiosperms. In angiosperms, it is crucial for plant growth and wood formation. The vascular cambium is regulated by a complex interplay of phytohormones, which are chemical messengers that coordinate various aspects of plant growth and development. This paper synthesizes the current knowledge on the regulatory effects of primary plant hormones and peptide signals on the development of the cambium in forest trees, and it outlines the current research status and future directions in this field. Understanding these regulatory mechanisms holds significant potential for enhancing our ability to manage and cultivate forest tree species in changing environmental conditions.

To characterize the functional neuroanatomy of late-life depression (LLD) by probing for both episodic and persistent alterations in the executive-control circuit of elderly adults. Event-related functional magnetic resonance imaging (fMRI) data were collected while participants performed an executive-control task. Participants were recruited through a depression-treatment study within the Pittsburgh, PA, Intervention Research Center for Late-Life Mood Disorders. Thirteen nondepressed elderly comparison participants and 13 LLD patients. The depressed patients underwent imaging before initiating and after completing 12 weeks of paroxetine. Regional fMRI activity was assessed in the dorsolateral prefrontal cortex (dLPFC: BA9 and BA46 bilaterally) and the dorsal anterior cingulate cortex (dACC). Functional connectivity was assessed by correlating the fMRI time-series in the dLPFC and dACC. Both depressed and comparison participants performed the task as expected, with greater response latency during high versus low-load trials. The response-latency load-effect did not differ between groups. In contrast to the null findings for behavioral data, pretreatment, depressed patients showed diminished activity in the dLPFC (BA46 left, t(25) = 1.9, p = 0.035) and diminished functional connectivity between the dLPFC and dACC. Moreover, right dLPFC (BA46 right, t(25) = 2.17, p <0.02) showed increased activity after treatment. These results support a model of both episodic and persistent neurobiologic components of LLD. The altered functional connectivity, perhaps due to vascular damage to frontal white matter, appears to be persistent. Further, at least some of the prefrontal hypoactivity (in the right dLPFC) seems to be an episodic characteristic of acute depression amenable to treatment.