Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of secreted proteins that reflect autophagy dynamics within tumor cells

Macroautophagy, a catabolic process of cellular self-digestion, is an important tumor cell survival mechanism and a potential target in antineoplastic therapies. Recent discoveries have implicated autophagy in the cellular secretory process, but potential roles of autophagy-mediated secretion in modifying the tumor microenvironment are poorly understood. Furthermore, efforts to inhibit autophagy in clinical trials have been hampered by suboptimal methods to quantitatively measure tumor autophagy levels. Here, we leveraged the autophagy-based involvement in cellular secretion to identify shed proteins associated with autophagy levels in melanoma. The secretome of low-autophagy WM793 melanoma cells was compared to its highly autophagic metastatic derivative, 1205Lu in physiological 3-dimensional cell culture using quantitative proteomics. These comparisons identified candidate autophagy biomarkers IL1B (interleukin 1, β), CXCL8 (chemokine (C-X-C motif) ligand 8), LIF (leukemia inhibitory factor), FAM3C (family with sequence similarity 3, member C), and DKK3 (dickkopf WNT signaling pathway inhibitor 3) with known roles in inflammation and tumorigenesis, and these proteins were subsequently shown to be elevated in supernatants of an independent panel of high-autophagy melanoma cell lines. Secretion levels of these proteins increased when low-autophagy melanoma cells were treated with the autophagy-inducing tat-BECN1 (Beclin 1) peptide and decreased when ATG7 (autophagy-related 7) was silenced in high-autophagy cells, thereby supporting a mechanistic link between these secreted proteins and autophagy. In addition, serum from metastatic melanoma patients with high tumor autophagy levels exhibited higher levels of these proteins than serum from patients with low-autophagy tumors. These results suggest that autophagy-related secretion affects the tumor microenvironment and measurement of autophagy-associated secreted proteins in plasma and possibly in tumors can serve as surrogates for intracellular autophagy dynamics in tumor cells.
Suppression of premature termination codons as a therapeutic approach

In this review, we describe our current understanding of translation termination and pharmacological agents that influence the accuracy of this process. A number of drugs have been identified that induce suppression of translation termination at in-frame premature termination codons (PTCs; also known as nonsense mutations) in mammalian cells. We discuss efforts to utilize these drugs to suppress disease-causing PTCs that result in the loss of protein expression and function. In-frame PTCs represent a genotypic subset of mutations that make up ~11% of all known mutations that cause genetic diseases, and millions of patients have diseases attributable to PTCs. Current approaches aimed at reducing the efficiency of translation termination at PTCs (referred to as PTC suppression therapy) have the goal of alleviating the phenotypic consequences of a wide range of genetic diseases. Suppression therapy is currently in clinical trials for treatment of several genetic diseases caused by PTCs, and preliminary results suggest that some patients have shown clinical improvements. While current progress is promising, we discuss various approaches that may further enhance the efficiency of this novel therapeutic approach.
Phototropin 1 and dim-blue light modulate the red light de-etiolation response

Light signals regulate seedling morphological changes during de-etiolation through the coordinated actions of multiple light-sensing pathways. Previously we have shown that red-light-induced hypocotyl growth inhibition can be reversed by addition of dim blue light through the action of phototropin 1 (phot1). Here we further examine the fluence-rate relationships of this blue light effect in short-term (hours) and long-term (days) hypocotyl growth assays. The red stem-growth inhibition and blue promotion is a low-fluence rate response, and blue light delays or attenuates both the red light and far-red light responses. These de-etiolation responses include blue light reversal of red or far-red induced apical hook opening. This response also requires phot1. Cryptochromes (cry1 and cry2) are activated by higher blue light fluence-rates and override phot1's influence on hypocotyl growth promotion. Exogenous application of auxin transport inhibitor naphthylphthalamic acid abolished the blue light stem growth promotion in both hypocotyl growth and hook opening. Results from the genetic tests of this blue light effect in auxin transporter mutants, as well as phytochrome kinase substrate mutants indicated that aux1 may play a role in blue light reversal of red light response. Together, the phot1-mediated adjustment of phytochrome-regulated photomorphogenic events is most robust in dim blue light conditions and is likely modulated by auxin transport through its transporters.
Proteins affecting thylakoid morphology – the key to understanding vesicle transport in chloroplasts?

We recently showed that a Rab protein, CPRabA5e (CP = chloroplast localized), is located in chloroplasts of Arabidopsis thaliana where it is involved in various processes, such as thylakoid biogenesis and vesicle transport. Using a yeast two-hybrid method, CPRabA5e was shown to interact with a number of chloroplast proteins, including the CURVATURE THYLAKOID 1A (CURT1A) protein and the light-harvesting chlorophyll a/b binding protein (LHCB1.5). CURT1A has recently been shown to modify thylakoid architecture by inducing membrane curvature in grana, whereas LHCB1.5 is a protein of PSII (Photosystem II) facilitating light capture. LHCB1.5 is imported to chloroplasts and transported to thylakoid membranes using the post-translational Signal Recognition Particle (SRP) pathway. With this information as starting point, we here discuss their subsequent protein-protein interactions, given by the literature and Interactome 3D. CURT1A itself and several of the proteins interacting with CURT1A and LHCB1.5 have relations to vesicle transport and thylakoid morphology, which are also characteristics of cprabA5e mutants. This highlights the previous hypothesis of an alternative thylakoid targeting pathway for LHC proteins using vesicles, in addition to the SRP pathway.
Human RECQL5: Guarding the crossroads of DNA replication and transcription and providing backup capability

Abstract DNA helicases are ubiquitous enzymes that catalyze unwinding of duplex DNA and function in all metabolic processes in which access to single-stranded DNA is required, including DNA replication, repair, recombination and RNA transcription. RecQ helicases are a conserved family of DNA helicases that display highly specialized and vital roles in the maintenance of genome stability. Mutations in three of the five human RecQ helicases, BLM, WRN and RECQL4 are associated with the genetic disorders Bloom syndrome, Werner syndrome and Rothmund-Thomson syndrome that are characterized by chromosomal instability, premature aging and predisposition to cancer. The biological role of human RECQL5 is only partially understood and RECQL5 has not yet been associated with any human disease. Illegitimate recombination and replication stress are hallmarks of human cancers and common instigators for genomic instability and cell death. Recql5 knockout mice are cancer prone and show increased chromosomal instability. Recql5-deficient mouse embryonic fibroblasts are sensitive to camptothecin and display elevated levels of sister chromatid exchanges. Unlike other human RecQ helicases, RECQL5 is recruited to single-stranded DNA breaks and is also proposed to play an essential role in RNA transcription. Here, we review the established roles of RECQL5 at the cross roads of DNA replication, recombination and transcription, and propose that human RECQL5 provides important backup functions in the absence of other DNA helicases.
Structure and Initial Validation of a Short Form of the Therapeutic Factors Inventory

Abstract This study examined the factor structure and validity of the Therapeutic Factors Inventory-Short Form (TFI-S), a measure originally developed to assess Yalom’s eleven conceptually derived therapeutic factors. Patients in a group-oriented day treatment program (n = 174) completed the TFI-S and other measures to assess concurrent and predictive validity. Four broad therapeutic factors were identified: Instillation of Hope, Secure Emotional Expression, Awareness of Interpersonal Impact, and Social Learning. Alpha coefficients ranged from . 71 to . 91. Significant correlations between the TFI-S factors and Group Climate Questionnaire subscales provided preliminary evidence for the concurrent validity of the TFI S. Significant relationships were also identified between the TFI-S factors and improvement in symptoms, quality of life, and interpersonal distress at the end of treatment, suggesting that the TFI-S may have predictive validity.
Long‐term effect of motor cortical repetitive transcranial magnetic stimulation induces

Repetitive transcranial magnetic stimulation (rTMS) recently has been assessed as a noninvasive treatment modality for movement and psychiatric disorders, whereas the mechanism underlying the therapeutic effects is not fully understood. Studies in rodents showed lasting functional changes in some selected regions, such as limbic‐associated structures, but unfocused brain stimulation did not clarify the regional effects. To address the topographical and temporal profiles of the effects on glucose metabolism in primate brain, we performed rTMS and repeated 18F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) before, during, and up to 16 days after rTMS in anesthetized cynomologous monkeys. We delivered a total of 2,000 pulses of 5Hz‐rTMS over the right precentral gyrus using a small‐sized eight‐figured coil that induced a localized electrical field. Voxel‐based analysis in a standard space of the macaque brain showed statistically robust changes in FDG uptake: a decrease in the motor/premotor cortices and an increase in the limbic‐associated areas involving the anterior/posterior cingulate, and orbitofrontal cortices. Interestingly, these uptake changes continued for at least 8 days and the magnitude of the lasting effects in the limbic‐related areas was negatively correlated across subjects with those in the motor/premotor cortices. The results demonstrate that motor rTMS has a long‐term lasting effect on motor‐related regions and distant limbic‐related areas via functional connections.
Group Process as a Mechanism of Change in the Group Treatment of Anger and Aggression

Abstract Angry reactions can present unique challenges to the process of conducting group therapy, especially when providing group treatment to participants who have histories of angry or aggressive behavior. This article briefly reviews relevant literature and describes a group-based violence reduction training program (VRTP). The VRTP conceptualizes anger and aggression from a frustration-aggression framework and employs treatment derived from research in the area of social problem-solving. An emphasis is placed on how fostering group experiences consistent with Irving Yalom’s classic work on the theory and practice of group therapy can reinforce skill acquisition and general treatment responsiveness. Management of the group process is a plausible mechanism of change in group treatment of anger. We highlight the challenges and benefits of dealing with anger-infused communication while ensuring the integrity of the overall group process. Case examples are provided for illustration of VRTP. Future research can answer important questions about group process and mechanisms of change in group-based treatments for anger and aggression.
THE ELECTROCARDIOGRAM IN LATER LIFE

The increasing number of persons who are attaining the age of 70 and the frequency with which they suffer attacks of acute coronary occlusion make it expedient that certain standards of normalcy be established electeocardiographically for this age group. The series of records presented here was assembled in an attempt to determine what constitutes a normal electrocardiogram for an elderly person without symptoms of cardiovascular disease. MATERIAL One hundred persons over 70 years of age were selected for this study. Accurate and painstaking histories were obtained in order to eliminate any one who had manifestations of impaired cardiac function other than that which could be properly ascribed to aging alone. All persons without physical signs of cardiovascular disease except mild hypertension (pressure not exceeding 150 mm. of mercury systolic and 90 mm. diastolic) and moderate ventricular enlargement with an apical impulse palpable less than 12 cm. to the left of
Hemicellulosic ethanol production by immobilized cells of Scheffersomyces stipitis: Effect of cell concentration and stirring

Bioconversion of hemicellulosic hydrolysate into ethanol plays a pivotal role in the overall success of biorefineries. For the efficient fermentative conversion of hemicellulosic hydrolysates into ethanol, the use of immobilized cells system could provide the enhanced ethanol productivities with significant time savings. Here, we investigated the effect of 2 important factors (e.g., cell concentration and stirring) on ethanol production from sugarcane bagasse hydrolysate using the yeast Scheffersomyces stipitis immobilized in calcium alginate matrix. A 22 full factorial design of experiment was performed considering the process variables- immobilized cell concentration (3.0, 6.5 and 10.0 g/L) and stirring (100, 200 and 300 rpm). Statistical analysis showed that stirring has the major influence on ethanol production. Maximum ethanol production (8.90 g/l) with ethanol yield (Yp/s) of 0.33 g/g and ethanol productivity (Qp) of 0.185 g/l/h was obtained under the optimized process conditions (10.0 g/L of cells and 100 rpm).
Gene expression profiling in adipose tissue from growing broiler chickens

In this study, total RNA was collected from abdominal adipose tissue samples obtained from ten broiler chickens at 3, 4, 5, and 6 weeks of age and prepared for gene microarray analysis with Affymetrix GeneChip Chicken Genome Arrays (Affymetrix) and quantitative real-time PCR analysis. Studies of global gene expression in chicken adipose tissue were initiated since such studies in many animal species show that adipose tissue expresses and secretes many factors that can influence growth and physiology. Microarray results indicated 333 differentially expressed adipose tissue genes between 3 and 6 wk, 265 differentially expressed genes between 4 and 6 wk and 42 differentially expressed genes between 3 and 4 wk. Enrichment scores of Gene Ontology Biological Process categories indicated strong age upregulation of genes involved in the immune system response. In addition to microarray analysis, quantitative real-time PCR analysis was used to confirm the influence of age on the expression of adipose tissue CC chemokine ligands (CCL), toll-like receptor (TLR)-2, lipopolysaccharide-induced TNF factor (LITAF), chemokine (C-C motif) receptor 8 (CCR8), and several other genes. Between 3 and 6 wk of age CCL5, CCL1, and CCR8 expression increased (P = 0.0001) with age. Furthermore, TLR2, CCL19, and LITAF expression increased between 4 and 6 wk of age (P = 0.001). This is the first demonstration of age related changes in CCL, LITAF, and TLR2 gene expression in chicken adipose tissue. Future studies are needed to elucidate the role of these adipose tissue genes in growth and the immune system.
Prospective predictors of suicide attempts in borderline personality disorder at one, two, and two-to-five year follow-up.

Efforts to identify reliable predictors of suicidal behavior in Borderline Personality Disorder have been confounded by the marked dimensional heterogeneity of the disorder, frequent comorbidity with other high risk disorders, debilitating social and vocational consequences of BPD over time. Using survival analyses, we assessed the predictive association between risk factors in each of these symptom domains and suicide attempts in BPD subjects followed for 12 months, 18-24 months and 2-5 years. The suicide attempt rate was 19% in the first year, 24.8% through the second year. The risk of suicidal behavior among 137 BPD subjects completing the first 12 months was increased by comorbid MDD and poor social adjustment. Outpatient treatment decreased short-term risk. Among 133 subjects completing 18-24 months in the study, the relative risk of a suicide attempt was increased by hospitalization (prior to any attempt), and poor social adjustment. Among 122 subjects followed for 2-5 years, increased risk was associated with hospitalization and medication visits (prior to any attempt), an attempt in the first year, and a low GAS score at baseline. Long term risk was decreased by "any outpatient treatment. " Predictors of suicidal behavior in BPD change over time. MDD has a short-term effect on suicide risk, while poor social adjustment may increase risk throughout each follow-up interval. Assessing and supporting family, work, and social relationships may decrease suicidal behavior in BPD, and should be a principal focus of long-term treatment.
Polymorphisms and haplotypes in multidrug resistance 1 gene are not associated with chronic lymphocytic leukemia susceptibility and prognostic parameters of chronic lymphocytic leukemia in Chinese population

The human multidrug resistance (MDR1, ABCB1) gene encodes P-glycoprotein (P-gp), which affects the pharmacokinetics of many drugs. Here, we investigated whether common MDR1 single nucleotide polymorphisms (SNPs) (C1236T, C3435T, and G2677T/A) affect predisposition to chronic lymphocytic leukemia (CLL). Genotyping was performed in 150 patients with CLL and 117 controls using polymerase chain reaction (PCR)-based assays. Haplotypes were inferred using the PHASE algorithm. We found comparable allele and genotype frequencies among patients with CLL and controls. Moreover, patient and control groups did not differ regarding MDR1 haplotype distribution (p = 0.97). Furthermore, no correlation was shown between the MDR1 1236, 3435, or 2677 genotypes and Binet stage, unmutated immunoglobulin heavy-chain variable region (IGHV) status, CD38 expression, ZAP-70 expression, and p53 deletion. In conclusion, our results do not support a major influence of MDR1 variants on the risk of CLL, and these genomic polymorphisms are not associated with clinical prognostic factors in Chinese patients with CLL.
Autophagy plays a protective role in endoplasmic reticulum stress-mediated pancreatic β cell death

There is a growing evidence of the role of autophagy in pancreatic β cell homeostasis. During development of type 2 diabetes, β cells are required to supply the increased demand of insulin. In such a stage, β cells have to address high ER stress conditions that could lead to abnormal insulin secretion, and ultimately, β cell death and overt diabetes. In this study, we used insulin secretion-deficient β cells derived from fetal mice. These cells present an increased accumulation of polyubiquitinated protein aggregates and LC3B-positive puncta, when compared with insulinoma-derived β cell lines. We found that insulin secretion deficiency renders these cells hypersensitive to endoplasmic reticulum (ER) stress-mediated cell death. Chemical or shRNA-mediated inhibition of autophagy increased β cell death under ER stress. On the other hand, rapamycin treatment increased both autophagy and cell survival under ER stress. Insulin secretion-deficient β cells showed a marked reduction of the antiapoptotic protein BCL2, together with increased BAX expression and ERN1 hyperactivation upon ER stress induction. These results showed how insulin secretion deficiency in β cells may be contributing to ER stress-mediated cell death, and in this regard, we showed how the autophagic response plays a prosurvival role.
Allogeneic hematopoietic cell transplant for peripheral T-cell non-Hodgkin lymphoma results in long-term disease control

The study analyzed outcomes of a consecutive case series of 37 patients with peripheral T-cell non-Hodgkin lymphoma, from related and unrelated donors, using allogeneic hematopoietic cell transplant (allo-HCT), between the years 2000 and 2007. All patients were pretreated; the majority had either relapsed or progressive disease (n = 25, 68%), 13 had cutaneous histologies (CTCL), and all were ineligible for autologous transplant. Fully ablative conditioning regimens were used in 13 patients while 24 patients underwent reduced intensity conditioning (RIC). At 5 years the overall survival (OS) and progression-free survival (PFS) probabilities were 52.2% and 46.5%, respectively. At the time of analysis, nine (24.3%) patients had either relapsed (n = 6) or progressed (n = 3) post allo-HCT. The cumulative incidences of relapse/progression and non-relapse mortality at 5 years were 24.3% and 28.9%. No statistically significant variables for survival or relapse were discovered by univariate Cox regression analysis of disease and patient characteristics; differences between CTCL and other histologies were not significant. The median follow-up of 64.0 months (range: 16.4–100.4) indicates a mature data-set with probable cure in the survivors. The relapse/progression curves reached and maintained plateaus after 1 year post-transplant, demonstrating that long-term disease control is possible after allo-HCT in patients with peripheral T-cell lymphoma with advanced disease.
Proximal phalangeal fracture and repair following digit amputation in a calf

Fracture and repair of the proximal (first) phalanx of the remaining digit following amputation of the paired digit has not been previously reported. Here, we describe a case of proximal phalangeal fracture in the medial digit following lateral digit amputation through the distal portion of the proximal phalanx (P1) in a young Aberdeen Angus crossbred calf. Successful repair was achieved through external coaptation using a fibreglass cast.
Evaluation of methylation modification in E-cadherin gene and its application in the improvement of breast cancer

CDH1 (E-cadherin), which mediates cell-cell interaction and polarity, is known as glycoprotein in cytoskeleton. The objective of this study was to evaluate CDH1 expression loss as the metastatic marker by defining the methylation pattern in the promoter region and determining whether or not the methylation pattern changes in correlation with a kind of tumor, grade and metastatic status. Fifty patients with breast carcinoma were enrolled in this study and fifty normal breast tissues were obtained from an adjacent tumor area as control from the same patients’ breast. All of these patients had different grades, metastasis status and tumor kind. Fresh tissue sections of breast cancers were obtained and their DNA was isolated, bisulfite treated, PCR amplified and analyzed for sequencing. The loss of CDH1 was assessed as percentage of methylation (full, partial and non-methylated) in the promoter region, and the number of CpG sites involved in methylation was assessed as the methylation pattern. The percentage of CDH1 gene promoter methylation in the tumor samples was 44% for full methylation, 50% for partial methylation and 6% for non-methylated. There was significant difference between normal and tumor tissues in methylated CpG sites and also between different grades and kinds of tumor. More so, there was no significant variation in the recurrence state of tumor. Even though loss of CDH1 expression in breast cancer has been established before, its critical role in cell-cell contact can reflect the metastatic effect of the lost expression during the metastatic phase of cancer. However, methylation pattern significantly differs in high grade tumor samples (p<0.00). Key words: E-cadherin, promoter, methylation, breast cancer, prognosis.