Miracle-dz/UniFAR-FTUs huggingface dataset:
TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin

Significance Despite exhibiting different phenotypes, the UV-sensitive syndromes trichothiodystrophy (TTD) and xeroderma pigmentosum (XP) result from the same mutated genes encoding specific subunits of the DNA-repair/transcription factor TFIIH. The widely accepted notion is that XP cancer proneness results from mutations interfering with DNA repair, whereas TTD clinical hallmarks (namely, hair anomalies, physical and mental retardation, and premature aging) are because of transcriptional alterations. The present study identifies a TTD-specific overexpression of matrix metalloproteinase 1, leading to collagen I degradation in patient skin. This finding explains the clinical features distinguishing TTD from XP (i.e. bone alterations, pregnancy abnormalities and likely lack of skin cancer despite the accumulation of unrepaired DNA lesions) and the features that TTD shares with osteogenesis imperfecta caused by COL1 mutations. Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH result in distinct clinical entities, including the cancer-prone xeroderma pigmentosum (XP) and the multisystem disorder trichothiodystrophy (TTD), which share only cutaneous photosensitivity. Gene-expression profiles of primary dermal fibroblasts revealed overexpression of matrix metalloproteinase 1 (MMP-1), the gene encoding the metalloproteinase that degrades the interstitial collagens of the extracellular matrix (ECM), in TTD patients mutated in XPD compared with their healthy parents. The defect is observed in TTD and not in XP and is specific for fibroblasts, which are the main producers of dermal ECM. MMP-1 transcriptional up-regulation in TTD is caused by an erroneous signaling mediated by retinoic acid receptors on the MMP-1 promoter and leads to hypersecretion of active MMP-1 enzyme and degradation of collagen type I in the ECM of cell/tissue systems and TTD patient skin. In agreement with the well-known role of ECM in eliciting signaling events controlling cell behavior and tissue homeostasis, ECM alterations in TTD were shown to impact on the migration and wound-healing properties of patient dermal fibroblasts. The presence of a specific inhibitor of MMP activity was sufficient to restore normal cell migration, thus providing a potential approach for therapeutic strategies. This study highlights the relevance of ECM anomalies in TTD pathogenesis and in the phenotypic differences between TTD and XP.
α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation

Significance Physiologically, α-synuclein promotes soluble NSF attachment protein receptor (SNARE) complex assembly during synaptic exocytosis. Pathologically, however, α-synuclein forms neurotoxic aggregates that promote neurodegeneration and represent hallmarks of Parkinson's disease and other synucleinopathies. α-Synuclein exists in a monomeric unfolded state in solution and in an α-helical folded state upon binding to membranes. Yet the relation between these conformational states and their physiological and pathological roles remain unknown. Here, we demonstrate that α-synuclein multimerizes during membrane binding and that the membrane-bound, multimeric form of α-synuclein mediates SNARE complex assembly in presynaptic terminals. Our data delineate a folding pathway for α-synuclein that ranges from a monomeric unfolded form in cytosol to a physiologically functional multimeric form that is membrane bound and chaperones SNARE complex assembly, and that may protect against neurodegeneration. Physiologically, α-synuclein chaperones soluble NSF attachment protein receptor (SNARE) complex assembly and may also perform other functions; pathologically, in contrast, α-synuclein misfolds into neurotoxic aggregates that mediate neurodegeneration and propagate between neurons. In neurons, α-synuclein exists in an equilibrium between cytosolic and membrane-bound states. Cytosolic α-synuclein appears to be natively unfolded, whereas membrane-bound α-synuclein adopts an α-helical conformation. Although the majority of studies showed that cytosolic α-synuclein is monomeric, it is unknown whether membrane-bound α-synuclein is also monomeric, and whether chaperoning of SNARE complex assembly by α-synuclein involves its cytosolic or membrane-bound state. Here, we show using chemical cross-linking and fluorescence resonance energy transfer (FRET) that α-synuclein multimerizes into large homomeric complexes upon membrane binding. The FRET experiments indicated that the multimers of membrane-bound α-synuclein exhibit defined intermolecular contacts, suggesting an ordered array. Moreover, we demonstrate that α-synuclein promotes SNARE complex assembly at the presynaptic plasma membrane in its multimeric membrane-bound state, but not in its monomeric cytosolic state. Our data delineate a folding pathway for α-synuclein that ranges from a monomeric, natively unfolded form in cytosol to a physiologically functional, multimeric form upon membrane binding, and show that only the latter but not the former acts as a SNARE complex chaperone at the presynaptic terminal, and may protect against neurodegeneration.
Neurotensin signaling stimulates glioblastoma cell proliferation by upregulating c-Myc and inhibiting miR-29b-1 and miR-129-3p.

BACKGROUND Neurotensin (NTS) and its primary receptor NTSR1 are implicated in cancer progression. Aberrant expression of NTS/NTSR1 contributes to the proliferation of glioblastoma cells; however, the mechanism is not fully understood. METHODS Microarray and real-time PCR were performed to identify the NTS-regulated micro (mi)RNAs. The targets of the miRNAs were identified by luciferase assays and immunoblot analysis. The c-Myc binding sites in the miR-29b-1 and cyclin-dependent kinase (CDK)4 promoters were identified through chromatin immunoprecipitation assay. Cell proliferation was evaluated by Cell Counting Kit-8 assay and flow cytometry analysis. An orthotopic xenograft model demonstrated the role of NTS/NTSR1 and miRNAs in glioblastoma growth in vivo. RESULTS Pharmacological inhibition or small interfering NTSR1 treatment blocked glioblastoma cell cycle progression in the G1 phase with a concomitantly decreased expression of CDK6, CDK4, and c-Myc. Knockdown of NTSR1 increased the expression of miR-29b-1 and miR-129-3p, which were responsible for the decreased CDK6 expression. NTS/NTSR1 signaling activated the transcription factor c-Myc in U87 cells, leading to increased CDK4 expression and repressed miR-29b-1 expression. Knockdown of NTSR1 decreased the glioblastoma growth in vivo and significantly prolonged the survival time of the tumor-bearing mice, an effect that can be largely reversed by antagomir. CONCLUSIONS Our study showed a novel regulatory mechanism of NTS/NTSR1, an upstream signaling of miRNAs and c-Myc, in glioblastoma progression. The inhibition of the NTSR1 function or the upregulation of miR-29b-1 and miR-129-3p expression impaired glioma cell proliferation. These results suggested that the NTS/NTSR1/c-Myc/miRNA axis may be a potential therapeutic target for glioblastoma therapy.
Cord blood‐circulating endothelial progenitors for treatment of vascular diseases

Adult peripheral blood (PB) endothelial progenitor cells (EPC) are produced in the bone marrow and are able to integrate vascular structures in sites of neoangiogenesis. EPCs thus represent a potential therapeutic tool for ischaemic diseases. However, use of autologous EPCs in cell therapy is limited by their rarity in adult PB. Cord blood (CB) contains more EPCs than PB, and they are functional after expansion. They form primary colonies that give rise to secondary colonies, each yielding more than 107 cells after few passages. The number of endothelial cells obtained from one unit of CB is compatible with potential clinical application. EPC colonies can be securely produced, expanded and cryopreserved in close culture devices and endothelial cells produced in these conditions are functional as shown in different in vitro and in vivo assays. As CB EPC‐derived endothelial cells would be allogeneic to patients, it would be of interest to prepare them from ready‐existing CB banks. We show that not all frozen CB units from a CB bank are able to generate EPC colonies in culture, and when they do so, number of colonies is lower than that obtained with fresh CB units. However, endothelial cells derived from frozen CB have the same phenotypical and functional properties than those derived from fresh CB. This indicates that CB cryopreservation should be improved to preserve integrity of stem cells other than haematopoietic ones. Feasibility of using CB for clinical applications will be validated in porcine models of ischaemia.
CD47 regulates the phagocytic clearance and replication of the Plasmodium yoelii malaria parasite

Significance Several Plasmodium species exhibit age-based preference for the red blood cells (RBC) they invade, with implications for virulence and disease severity. CD47, a marker of self, prevents the early clearance of cells by phagocytosis. We report here that in the absence of CD47, growth of a Plasmodium species that preferentially infects CD47hi young RBC is highly attenuated, and the macrophages from CD47−/− mice are more effective in phagocytizing the malaria-parasitized RBC than wild-type mice. We suggest that preferential invasion of young RBC is an evolutionary adaptation that shields the malaria parasite from phagocytic clearance and controls parasitemia, as fewer RBC are available for invasion. Modulation of CD47 levels by antibody treatment may have therapeutic value in patients with severe malaria. Several Plasmodium species exhibit a strong age-based preference for the red blood cells (RBC) they infect, which in turn is a major determinant of disease severity and pathogenesis. The molecular basis underlying this age constraint on the use of RBC and its influence on parasite burden is poorly understood. CD47 is a marker of self on most cells, including RBC, which, in conjunction with signal regulatory protein alpha (expressed on macrophages), prevents the clearance of cells by the immune system. In this report, we have investigated the role of CD47 on the growth and survival of nonlethal Plasmodium yoelii 17XNL (PyNL) malaria in C57BL/6 mice. By using a quantitative biotin-labeling procedure and a GFP-expressing parasite, we demonstrate that PyNL parasites preferentially infect high levels of CD47 (CD47hi)-expressing young RBC. Importantly, C57BL/6 CD47−/− mice were highly resistant to PyNL infection and developed a 9.3-fold lower peak parasitemia than their wild-type (WT) counterparts. The enhanced resistance to malaria observed in CD47−/− mice was associated with a higher percentage of splenic F4/80+ cells, and these cells had a higher percentage of phagocytized parasitized RBC than infected WT mice during the acute phase of infection, when parasitemia was rapidly rising. Furthermore, injection of CD47-neutralizing antibody caused a significant reduction in parasite burden in WT C57BL/6 mice. Together, these results strongly suggest that CD47hi young RBC may provide a shield to the malaria parasite from clearance by the phagocytic cells, which may be an immune escape mechanism used by Plasmodium parasites that preferentially infect young RBC.
Lethal coalitionary aggression and long-term alliance formation among Yanomamö men

Significance Humans, like chimpanzees, engage in coalitionary violence: Members of both species coordinate lethal activity against conspecifics. The origin and adaptive functions of this behavior are poorly understood, and data from tribal populations are rare. We examine the composition of lethal coalitions from the Yanomamö, a tribal society in Amazonia. In contrast to chimpanzees, Yanomamö coalitions are composed of individuals from different lineages and natal communities. Many coalition partners are ideal marriage exchange partners. Men who kill together more often are more likely to live together in the same village later in life and to engage in marriage exchange. Our results highlight connections between coalitionary aggression and alliance formation and illuminate differences in social structure distinguishing humans from other primates. Some cross-cultural evidence suggests lethal coalitionary aggression in humans is the product of residence and descent rules that promote fraternal interest groups, i.e., power groups of coresident males bonded by kinship. As such, human lethal coalitions are hypothesized to be homologous to chimpanzee (Pan troglodytes) border patrols. However, humans demonstrate a unique metagroup social structure in which strategic alliances allow individuals to form coalitions transcending local community boundaries. We test predictions derived from the fraternal interest group and strategic alliance models using lethal coalition data from a lowland South American population, the Yanomamö. Yanomamö men who kill an enemy acquire a special status, termed unokai. We examine the social characteristics of co-unokais or men who jointly kill others. Analyses indicate co-unokais generally are (i) from the same population but from different villages and patrilines, (ii) close age mates, and (iii) maternal half-first cousins. Furthermore, the incident rate for co-unokai killings increases if men are similar in age, from the same population, and from different natal communities. Co-unokais who have killed more times in the past and who are more genetically related to each other have a higher probability of coresidence in adulthood. Last, a relationship exists between lethal coalition formation and marriage exchange. In this population, internal warfare unites multiple communities, and co-unokais strategically form new residential groups and marriage alliances. These results support the strategic alliance model of coalitionary aggression, demonstrate the complexities of human alliance formation, and illuminate key differences in social structure distinguishing humans from other primates.
A new patient-derived orthotopic malignant meningioma model treated with oncolytic herpes simplex virus.

BACKGROUND Higher-grade meningiomas (HGMs; World Health Organization grades II and III) pose a clinical problem due to high recurrence rates and the absence of effective therapy. Preclinical development of novel therapeutics requires a disease model that recapitulates the genotype and phenotype of patient HGM. Oncolytic herpes simplex virus (oHSV) has shown efficacy and safety in cancers in preclinical and clinical studies, but its utility for HGM has not been well characterized. METHODS Tumorsphere cultures and serial orthotopic xenografting in immunodeficient mice were used to establish a patient-derived HGM model. The model was pathologically and molecularly characterized by immunohistochemistry, western blot, and genomic DNA sequencing and compared with the patient tumor. Anti-HGM effects of oHSV G47Δ were assessed using cell viability and virus replication assays in vitro and animal survival analysis following intralesional injections of G47Δ. RESULTS We established a serially transplantable orthotopic malignant meningioma model, MN3, which was lethal within 3 months after tumorsphere implantation. MN3 xenografts exhibited the pathological hallmarks of malignant meningioma such as high Ki67 and vimentin expression. Both the patient tumor and xenografts were negative for neurofibromin 2 (merlin) and had the identical NF2 mutation. Oncolytic HSV G47Δ efficiently spread and killed MN3 cells, as well as other patient-derived HGM lines in vitro. Treatment with G47Δ significantly extended the survival of mice bearing subdural MN3 tumors. CONCLUSIONS We established a new patient-derived meningioma model that will enable the study of targeted therapeutic approaches for HGM. Based on these studies, it is reasonable to consider a clinical trial of G47Δ for HGM.
A ketogenic diet increases transport and oxidation of ketone bodies in RG2 and 9L gliomas without affecting tumor growth.

BACKGROUND The dependence of tumor cells, particularly those originating in the brain, on glucose is the target of the ketogenic diet, which creates a plasma nutrient profile similar to fasting: increased levels of ketone bodies and reduced plasma glucose concentrations. The use of ketogenic diets has been of particular interest for therapy in brain tumors, which reportedly lack the ability to oxidize ketone bodies and therefore would be starved during ketosis. Because studies assessing the tumors' ability to oxidize ketone bodies are lacking, we investigated in vivo the extent of ketone body oxidation in 2 rodent glioma models. METHODS Ketone body oxidation was studied using (13)C MR spectroscopy in combination with infusion of a (13)C-labeled ketone body (beta-hydroxybutyrate) in RG2 and 9L glioma models. The level of ketone body oxidation was compared with nontumorous cortical brain tissue. RESULTS The level of (13)C-beta-hydroxybutyrate oxidation in 2 rat glioma models was similar to that of contralateral brain. In addition, when glioma-bearing animals were fed a ketogenic diet, the ketone body monocarboxylate transporter was upregulated, facilitating uptake and oxidation of ketone bodies in the gliomas. CONCLUSIONS These results demonstrate that rat gliomas can oxidize ketone bodies and indicate upregulation of ketone body transport when fed a ketogenic diet. Our findings contradict the hypothesis that brain tumors are metabolically inflexible and show the need for additional research on the use of ketogenic diets as therapy targeting brain tumor metabolism.
The effect of different intervention programmes on the self-concept and motor proficiency of 7- to 9-year-old children with DCD.

BACKGROUND The self-concept of children is influenced by developmental co-ordination disorder (DCD). The aim was to determine the most effective method in enhancing motor proficiency and self-concept of 7- to 9-year-old children with DCD. METHODS Teachers at nine different schools identified 201 possible DCD candidates. The Movement Assessment Battery for Children identified 58 with DCD (36 boys and 22 girls). Self-concept and anxiety were determined by the Tennessee Self-Concept Scale (Child Form) and Child Anxiety Scale respectively. The children were randomly grouped into four experimental groups [motor intervention (MI), self-concept (SC) enhancing intervention, psycho-motor intervention (P-MI) and a control group (CG)]. A two-way analysis of variance (anova) with a group factor and a repeated measures over time followed by a Bonferroni post hoc analysis and separate one-way anovas followed by a Tukey post hoc analysis were conducted to determine between-group and within-group differences at the pre-, post- and re-tests. Effect sizes (d) were calculated to determine the practical significance of statistical differences (P < 0.05). RESULTS After completion of the intervention programmes, no significant improvement in motor proficiency was found in the SC group, while the MI, P-MI and CG groups improved significantly (P < 0.01). No further improvements were found after the retention period in all the groups. From the pre-test to retest 2, the MI, P-MI and CG improved (P < 0.01), while the SC showed lower (P > 0.05) motor proficiency. A tendency of lower anxiety (P > 0.05) was found in the SC, while the total self-concept of the P-MI showed the biggest improvement (P < 0.05). CONCLUSION Motor proficiency and self-concept of children with DCD benefit from intervention, but both should be addressed for optimal benefits.
Transcription factor interaction with COMPASS-like complex regulates histone H3K4 trimethylation for specific gene expression in plants

Significance In metazoans, pausing of Pol II during early elongation is a widespread regulatory mechanism for transcription regulation. However, preinitiation complex (PIC) assembly is more important for transcription in plants. Chromatin remodeling and histone modifications are considered important for access of protein factors to the underlying DNA sequences. However, how histone modifications are specifically and timely generated at active promoters is less understood. COMPASS-like complex plays a critical role in PIC assembly and histone H3K4 trimethylation. We found that Arabidopsis transcription factors bZIP28/bZIP60 interact with COMPASS-like components both in vitro and in vivo. We present a general model on how histone H3K4 trimethylation is specifically formed during inducible gene expression by using the endoplasmic reticulum (ER) stress response system in Arabidopsis plants. Accumulation of unfolded or misfolded proteins causes endoplasmic reticulum (ER) stress, which activates a set of ER membrane-associated transcription factors for protein homeostasis regulation. Previous genome-wide chromatin immunoprecipitation analysis shows a strong correlation between histone H3K4 trimethylation (H3K4me3) and active gene expression. However, how the histone modification complex is specifically and timely recruited to the active promoters remains unknown. Using ER stress responsive gene expression as a model system, we demonstrate that sequence-specific transcription factors interact with COMPASS-like components and affect H3K4me3 formation at specific target sites in Arabidopsis. Gene profiling analysis reveals that membrane-associated basic leucine zipper (bZIP) transcription factors bZIP28 and bZIP60 regulate most of the ER stress responsive genes. Loss-of-functions of bZIP28 and bZIP60 impair the occupancy of H3K4me3 on promoter regions of ER stress responsive genes. Further, in vitro pull-down assays and in vivo bimolecular fluorescence complementation (BiFC) experiments show that bZIP28 and bZIP60 interact with Ash2 and WDR5a, both of which are core COMPASS-like components. Knockdown expression of either Ash2 or WDR5a decreased the expression of several ER stress responsive genes. The COMPASS-like complex is known to interact with histone methyltransferase to facilitate preinitiation complex (PIC) assembly and generate H3K4me3 during transcription elongation. Thus, our data shows that the ER stress stimulus causes the formation of PIC and deposition of H3K4me3 mark at specific promoters through the interaction between transcription factor and COMPASS-like components.