Miracle-dz/UniFAR-FTUs huggingface dataset:
Heat Shock Proteins in Lymphoma Immunotherapy

Immunotherapy harnessing the host immune system for tumor destruction revolutionized oncology research and advanced treatment strategies for lymphoma patients. Lymphoma is a heterogeneous group of cancer, where the central roles in pathogenesis play immune evasion and dysregulation of multiple signaling pathways. Immunotherapy-based approaches such as engineered T cells (CAR T), immune checkpoint modulators and NK cell-based therapies are now in the frontline of lymphoma research. Even though emerging immunotherapies showed promising results in treating lymphoma patients, low efficacy and on-target/off-tumor toxicity are of a major concern. To address that issue it is suggested to look into the emerging role of heat shock proteins. Heat shock proteins (HSPs) showed to be highly expressed in lymphoma cells. HSPs are known for their abilities to modulate immune responses and inhibit apoptosis, which made their successful entry into cancer clinical trials. Here, we explore the role of HSPs in Hodgkin and Non-Hodgkin lymphoma and their involvement in CAR T therapy, checkpoint blockade and NK cell- based therapies. Understanding the role of HSPs in lymphoma pathogenesis and the ways how HSPs may enhance anti-tumor responses, may help in the development of more effective, specific and safe immunotherapy.
Targeted Quantification of Detergent-Insoluble RNA-Binding Proteins in Human Brain Reveals Stage and Disease Specific Co-aggregation in Alzheimer’s Disease

Core spliceosome and related RNA-binding proteins aggregate in Alzheimer’s disease (AD) brain even in early asymptomatic stages (AsymAD) of disease. To assess the specificity of RNA-binding protein aggregation in AD, we developed a targeted mass spectrometry approach to quantify broad classes of RNA-binding proteins with other pathological proteins including tau and amyloid beta (Aβ) in detergent insoluble fractions from control, AsymAD, AD and Parkinson’s disease (PD) brain. Relative levels of specific insoluble RNA-binding proteins across different disease groups correlated with accumulation of Aβ and tau aggregates. RNA-binding proteins, including splicing factors with homology to the basic-acidic dipeptide repeats of U1-70K, preferentially aggregated in AsymAD and AD. In contrast, PD brain aggregates were relatively depleted of many RNA-binding proteins compared to AsymAD and AD groups. Correlation network analyses resolved 29 distinct modules of co-aggregating proteins including modules linked to spliceosome assembly, nuclear speckles and RNA splicing. Modules related to spliceosome assembly and nuclear speckles showed stage-specific enrichment of insoluble RBPs from AsymAD and AD brains, whereas the RNA splicing module was reduced specifically in PD. Collectively, this work identifies classes of RNA-binding proteins that distinctly co-aggregate in detergent-insoluble fractions across the specific neurodegenerative diseases we examined.
Vildagliptin Attenuates Myocardial Dysfunction and Restores Autophagy via miR-21/SPRY1/ERK in Diabetic Mice Heart

Aim: Vildagliptin (vild) improves diastolic dysfunction and is associated with a lower relative risk of major adverse cardiovascular events in younger patients. The present study aimed to evaluate whether vild prevents the development of diabetic cardiomyopathy in type 2 diabetic mice and identify its underlying mechanisms. Methods: Type 2 diabetic mouse model was generated using wild-type (WT) (C57BL/6J) and miR-21 knockout mice by treatment with HFD/STZ. Cardiomyocyte-specific miR-21 overexpression was achieved using adeno-associated virus 9. Echocardiography was used to evaluate cardiac function in mice. Morphology, autophagy, and proteins levels in related pathway were analyzed. qRT-PCR was used to detect miR-21. Rat cardiac myoblast cell line (H9c2) cells were transfected with miR-21 mimics and inhibitor to explore the related mechanisms of miR-21 in diabetic cardiomyopathy. Results: Vild restored autophagy and alleviated fibrosis, thereby enhancing cardiac function in DM mice. In addition, miR-21 levels were increased under high glucose conditions. miR-21 knockout DM mice with miR-21 knockout had reduced cardiac hypertrophy and cardiac dysfunction compared to WT DM mice. Overexpression of miR-21 aggravated fibrosis, reduced autophagy, and attenuated the protective effect of vild on cardiac function. In high-glucose-treated H9c2 cells, the downstream effectors of sprouty homolog 1 (SPRY1) including extracellular signal-regulated kinases (ERK) and mammalian target of rapamycin showed significant changes following transfection with miR-21 mimics or inhibitor. Conclusion: The results of our study indicate that vild prevents DCM by restoring autophagy through the miR-21/SPRY1/ERK/mTOR pathway. Therefore, miR-21 is a target in the development of DCM, and vild demonstrates significant potential for clinical application in prevention of DCM.
CD169+ Subcapsular Macrophage Role in Antigen Adjuvant Activity

Vaccines have played a pivotal role in improving public health, however, many infectious diseases lack an effective vaccine. Controlling the spread of infectious diseases requires continuing studies to develop new and improved vaccines. Our laboratory has been investigating the immune enhancing mechanisms of Toll-like receptor (TLR) ligand-based adjuvants, including the TLR2 ligand Neisseria meningitidis outer membrane protein, PorB. Adjuvant use of PorB increases costimulatory factors on antigen presenting cells (APC), increases antigen specific antibody production, and cytokine producing T cells. We have demonstrated that macrophage expression of MyD88 (required for TLR2 signaling) is an absolute requirement for the improved antibody response induced by PorB. Here-in, we specifically investigated the role of subcapsular CD169+ marginal zone macrophages in antibody production induced by the use of TLR-ligand based adjuvants (PorB and CpG) and non-TLR-ligand adjuvants (aluminum salts). CD169 knockout mice and mice treated with low dose clodronate treated animals (which only remove marginal zone macrophages), were used to investigate the role of these macrophages in adjuvant-dependent antibody production. In both sets of mice, total antigen specific immunoglobulins (IgGs) were diminished regardless of adjuvant used. However, the greatest reduction was seen with the use of TLR ligands as adjuvants. In addition, the effect of the absence of CD169+ macrophages on adjuvant induced antigen and antigen presenting cell trafficking to the lymph nodes was examined using immunofluorescence by determining the relative extent of antigen loading on dendritic cells (DCs) and antigen deposition on follicular dendritic cells (FDC). Interestingly, only vaccine preparations containing PorB had significant decreases in antigen deposition in lymphoid follicles and germinal centers in CD169 knockout mice or mice treated with low dose clodronate as compared to wildtype controls. Mice immunized with CpG containing preparations demonstrated decreased FDC networks in the mice treated with low dose clodronate. Conversely, alum containing preparations only demonstrated significant decreases in IgG in CD169 knockout mice. These studies stress that importance of subcapsular macrophages and their unique role in adjuvant-mediated antibody production, potentially due to an effect of these adjuvants on antigen trafficking to the lymph node and deposition on follicular dendritic cells.
Individual Differences Facing the COVID-19 Pandemic: The Role of Age, Gender, Personality, and Positive Psychology

Research on individual differences in facing the COVID-19 pandemic seems to be crucial in order to design diverse and highly effective intervention strategies. This study uses a sample of 302 North American participants who were recruited through the crowdsourcing platform ProA; different profiles were established, profiling variables of interest in facing the COVID-19 outbreak. Socio-demographic and psychological (personality traits, gratitude, life purpose, and religiosity) variables were explored. These results are of interest if we want to deepen the study of individual differences at both a theoretical and applied level.
TMAO Aggregates Neurological Damage Following Ischemic Stroke by Promoting Reactive Astrocytosis and Glial Scar Formation via the Smurf2/ALK5 Axis

Ischemic stroke has been reported to cause significant changes to memory, thinking, and behavior. Intriguingly, recently reported studies have indicated the association of Trimethylamine N-oxide (TMAO) with the acute phase of ischemic stroke. However, the comprehensive underlying mechanism remained unknown. The objective of the present study was to investigate the association between TMAO and recovery of neurological function after ischemic stroke. For this purpose, a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model was established and treated with TMAO or/and sh-ALK5, followed by the neurological function evaluation. Behaviors of rats were observed through staircase and cylinder tests. Moreover, the expression of Smurf2 and ALK5 was detected by immunohistochemistry while expression of GFAP, Neurocan, and Phosphacan in brain tissues was determined by immunofluorescence. Thereafter, gain- and loss-of-function assays in astrocytes, the proliferation, viability, and migration were evaluated by the EdU, CCK-8, and Transwell assays. Besides, Smurf2 mRNA expression was determined by the RT-qPCR, whereas, Smurf2, ALK5, GFAP, Neurocan, and Phosphacan expression was evaluated by the Western blotting. Finally, the interaction of Smurf2 with ALK5 and ALK5 ubiquitination was assessed by the co-immunoprecipitation. Notably, our results showed that TMAO promoted the proliferation of reactive astrocyte and formation of glial scar in MCAO/R rats. However, this effect was abolished by the Smurf2 overexpression or ALK5 silencing. We further found that TMAO upregulated the ALK5 expression by inhibiting the ubiquitination role of Smurf2. Overexpression of ALK5 reversed the inhibitory effect of Smurf2 on astrocyte proliferation, migration, and viability. Collectively, our work identifies the evolutionarily TMAO/Smurf2/ALK5 signaling as a major genetic factor in the control of reactive astrocyte proliferation and glial scar formation in ischemic stroke, thus laying a theoretical foundation for the identification of ischemic stroke.
Greater Reduction in Contralesional Hand Use After Frontoparietal Than Frontal Motor Cortex Lesions in Macaca mulatta

We previously reported that rhesus monkeys recover spontaneous use of the more impaired (contralesional) hand following neurosurgical lesions to the arm/hand representations of primary motor cortex (M1) and lateral premotor cortex (LPMC) (F2 lesion) when tested for reduced use (RU) in a fine motor task allowing use of either hand. Recovery occurred without constraint of the less impaired hand and with occasional forced use of the more impaired hand, which was the preferred hand for use in fine motor tasks before the lesion. Here, we compared recovery of five F2 lesion cases in the same RU test to recovery after unilateral lesions of M1, LPMC, S1 and anterior portion of parietal cortex (F2P2 lesion – four cases). Average and highest %use of the contralesional hand in the RU task in F2 cases were twice that in F2P2 cases (p < 0.05). Recovery in the RU task was closely associated with volume and percentage of lesion to caudal (new) M1 (M1c) in both F2 and F2P2 lesion cases. One F2P2 case, with the largest M1c lesion and a large rostral somatosensory cortex (S1r) lesion developed severe contralesional hand non-use despite exhibiting some recovery of fine motor function initially. We conclude that the degree of reduced use of the contralesional hand is primarily related to the volume of M1c injury and that severe non-use requires extensive injury to M1c and S1r. Thus, assessing peri-Rolandic injury extent in stroke patients may have prognostic value for predicting susceptibility to RU and non-use in rehabilitation.
SOCS3 Expression by Thymic Stromal Cells Is Required for Normal T Cell Development

The suppressor of cytokine signaling 3 (SOCS3) is a major regulator of immune responses and inflammation as it negatively regulates cytokine signaling. Here, the role of SOCS3 in thymic T cell formation was studied in Socs3fl/fl Actin-creER mice (Δsocs3) with a tamoxifen inducible and ubiquitous Socs3 deficiency. Δsocs3 thymi showed a 90% loss of cellularity and altered cortico-medullary organization. Thymocyte differentiation and proliferation was impaired at the early double negative (CD4-CD8-) cell stage and apoptosis was increased during the double positive (CD4+CD8+) cell stage, resulting in the reduction of recent thymic emigrants in peripheral organs. Using bone marrow chimeras, transplanting thymic organoids and using mice deficient of SOCS3 in thymocytes we found that expression in thymic stromal cells rather than in thymocytes was critical for T cell development. We found that SOCS3 in thymic epithelial cells (TECs) binds to the E3 ubiquitin ligase TRIM 21 and that Trim21−/− mice showed increased thymic cellularity. Δsocs3 TECs showed alterations in the expression of genes involved in positive and negative selection and lympho-stromal interactions. SOCS3-dependent signal inhibition of the common gp130 subunit of the IL-6 receptor family was redundant for T cell formation. Together, SOCS3 expression in thymic stroma cells is critical for T cell development and for maintenance of thymus architecture.
Virtual Terroir and the Premium Coffee Experience

With its origin-centric value proposition, the specialty coffee industry seeks to educate consumers about the value of the origin of coffee and how the relationship with farmers ensures quality and makes coffee a premium product. While the industry has widely used stories and visual cues to communicate this added value, research studying whether and how these efforts influence consumers' experiences is scarce. Through three experiments, we explored the effect of images that evoke the terroir of coffee on the perception of premiumness. Our results revealed that online images that resembled the broad origin of coffee (i.e., a farm) could influence premiumness expectations of coffee (Experiment 1). Similarly, a virtual reality environment that depicted this broad origin (vs. a control but not a city atmosphere) could enhance the perception of coffee premiumness for non-expert consumers (Experiment 2) and the enjoyment of the experience for coffee professionals (Experiment 3). Importantly, we found that congruence between the coffee and the virtual reality (VR) atmospheres mediated how much non-experts enjoyed the experience (Experiment 2). VR atmospheres also influenced expectations of sweetness and acidity for non-experts (Experiment 2). These findings serve as a steppingstone for further exploration of the effects of congruence between visual cues and product/brand attributes on premiumness expectations and perception, and more generally on consumer experience. From a practical standpoint, this study provides insights into key aspects for the development of immersive virtual product experiences.
Positive Youth Development Attributes and Parenting as Protective Factors Against Adolescent Social Networking Addiction in Hong Kong

This study examined the predictive effects of 15 positive youth development (PYD) attributes and parenting behavior on adolescent social networking addiction (SNA) in a representative sample of Hong Kong students. In total, 1,896 Hong Kong Secondary 1 students from 20 randomly selected schools (age = 13.19 ± 0.52 years) completed the Bergen Social Media Addiction Scale (BSMAS), the Chinese Positive Youth Development Scale, and the Chinese Parenting Behavior Scale. Of the participants, 11.4% could be classified as being addicted to Social Networking Sites (SNSs). Regression analyses showed that students' emotional competence (β = −0.09; p < 0.01), behavioral competence (β = −0.12; p < 0.001), beliefs in the future (β = −0.10; p < 0.01), and spirituality (β = −0.08; p < 0.01) were negatively associated with SNA, while social competence (β = 0.07; p < 0.05) and positive identity (β = 0.13; p < 0.001) were positively related to SNA. Paternal and maternal responsiveness showed indirect effects on students' SNA through the full mediation of PYD attributes. Specific PYD attributes and positive parenting behavior may serve as important protective factors against the development of SNA among Hong Kong adolescents.
Circadian Rhythm Gene PER3 Negatively Regulates Stemness of Prostate Cancer Stem Cells via WNT/β-Catenin Signaling in Tumor Microenvironment

Prostate cancer (PCa) cells are heterogeneous, containing a variety of cancer cells with phenotypical and functional discrepancies in the tumor microenvironment, where prostate cancer stem cells (PCSCs) play a vital role in PCa development. Our earlier studies have shown that ALDHhiCD44+ (DP) PCa cells and the corresponding ALDHloCD44– (DN) PCa cells manifest as PCSCs and non-PCSCs, respectively, but the underlying mechanisms regulating stemness of the PCSCs are not completely understood. To tackle this issue, we have performed RNA-Sequencing and bioinformatic analysis in DP (versus DN) cells in this study. We discovered that, PER3 (period circadian regulator 3), a circadian rhythm gene, is significantly downregulated in DP cells. Overexpression of PER3 in DP cells significantly suppressed their sphere- and colony-forming abilities as well as tumorigenicity in immunodeficient hosts. In contrast, knockdown of PER3 in DN cells dramatically promoted their colony-forming and tumor-initiating capacities. Clinically, PER3 is downregulated in human prostate cancer specimens and PER3 expression levels are highly correlated with the prognosis of the PCa patient. Mechanistically, we observed that low levels of PER3 stimulates the expression of BMAL1, leading to the phosphorylation of β-catenin and the activation of the WNT/β-catenin pathway. Together, our results indicate that PER3 negatively regulates stemness of PCSCs via WNT/β-catenin signaling in the tumor microenvironment, providing a novel strategy to treat PCa patients.
Estimating Market Potential for Solar Photovoltaic Systems in Uganda

With only 28% of the population having access to electricity, Uganda presents a huge market potential for alternative technologies to provide electricity such as solar PV systems. Using a simple statistical method (neighbourhood approach), this study estimates the market potential for solar PV in households based on a 2018 National Electrification Survey dataset collected by Uganda Bureau of Statistics (UBOS). Results show that approximately 5.3 million households lack access to electricity, thus the total market potential. Over 60% of households lack access to electricity due to supply-side gaps (also known as absence of coverage) while the rest of the households have coverage but lack access due to demand side limitations (also known as no uptake). On the contrary, our results suggest that supply-side gaps constitute the biggest proportion of electricity access deficit in Uganda’s households. Implying that these households may be willing and have the ability to pay but lack supply, thus these households constitute an immediate market potential for solar PV systems. To address the electricity access deficit, private solar companies should target unserved households with appropriate systems/products and innovative business models to suit their needs. Government on the other hand should subsidize households with affordability challenges or enhance their income.
Red Cell Distribution Width Upon Hospital Admission Predicts Short-Term Mortality in Hospitalized Patients With COVID-19: A Single-Center Experience

Background: Coronavirus disease (COVID-19) was first described at the end of 2019 in China and has since spread across the globe. Red cell distribution width (RDW) is a potent prognostic marker in several medical conditions and has recently been suggested to be of prognostic value in COVID-19. Methods: This retrospective, observational study of consecutive patients with COVID-19 was conducted from March 12, 2020 to December 4, 2020 in the Wilhelminenhospital, Vienna, Austria. RDWlevels on admission were collected and tested for their predictive value of 28-day mortality. Results: A total of 423 eligible patients with COVID-19 were included in the final analyses and 15.4% died within 28 days (n = 65). Median levels of RDWwere significantly higher in non-survivors compared to survivors [14.6% (IQR, 13.7–16.3) vs. 13.4% (IQR, 12.7– 14.4), P < 0.001]. Increased RDW was a significant predictor of 28-day mortality [crude odds ratio (OR) 1.717, 95% confidence interval (CI) 1.462–2.017; P = < 0.001], independent of clinical confounders, comorbidities and established prognostic markers of COVID-19 (adjusted OR of the final model 1.368, 95% CI 1.126–1.662; P = 0.002). This association remained consistent upon sub-group analysis. Our study data also demonstrate that RDW levels upon admission for COVID-19 were similar to previously recorded, non-COVID-19 associated RDW levels [14.2% (IQR, 13.3–15.7) vs. 14.0% [IQR, 13.2–15.1]; P = 0.187]. Conclusions: In this population, RDWwas a significant, independent prognostic marker of short-term mortality in patients with COVID-19.
Transcription Factors Associated With IL-15 Cytokine Signaling During NK Cell Development

Natural killer (NK) cells are lymphocytes primarily involved in innate immunity and possess important functional properties in anti-viral and anti-tumor responses; thus, these cells have broad potential for clinical utilization. NK cells originate from hematopoietic stem cells (HSCs) through the following two independent and continuous processes: early commitment from HSCs to IL-15-responsive NK cell progenitors (NKPs) and subsequent differentiation into mature NK cells in response to IL-15. IL-15 is the most important cytokine for NK cell development, is produced by both hematopoietic and nonhematopoietic cells, and functions through a distinct delivery process termed transpresentation. Upon being transpresented to NK cells, IL-15 contributes to NK cell development via the activation of several downstream signaling pathways, including the Ras–MEK–MAPK, JAK–STAT5, and PI3K–ATK–mTOR pathways. Nonetheless, the exact role of IL-15 in NK cell development has not been discussed in a consecutive and comprehensive manner. Here, we review current knowledge about the indispensable role of IL-15 in NK cell development and address which cells produce IL-15 to support NK cell development and when IL-15 exerts its function during multiple developmental stages. Specifically, we highlight how IL-15 supports NK cell development by elucidating the distinct transpresentation of IL-15 to NK cells and revealing the downstream target of IL-15 signaling during NK cell development.
Personalization in Modern Radiation Oncology: Methods, Results and Pitfalls. Personalized Interventions and Breast Cancer

Breast cancer, the most frequent malignancy in women worldwide, is a heterogeneous group of diseases, characterized by distinct molecular aberrations. In precision medicine, radiation oncology for breast cancer aims at tailoring treatment according to tumor biology and each patient’s clinical features and genetics. Although systemic therapies are personalized according to molecular sub-type [i.e. endocrine therapy for receptor-positive disease and anti-human epidermal growth factor receptor 2 (HER2) therapy for HER2-positive disease] and multi-gene assays, personalized radiation therapy has yet to be adopted in the clinical setting. Currently, attempts are being made to identify prognostic and/or predictive factors, biomarkers, signatures that could lead to personalized treatment in order to select appropriate patients who might, or might not, benefit from radiation therapy or whose radiation therapy might be escalated or de-escalated in dosages and volumes. This overview focuses on what has been achieved to date in personalized post-operative radiation therapy and individual patient radiosensitivity assessments by means of tumor sub-types and genetics.