The bipolar-on-anvil percussion in central Thyrrenian Italy

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Mitochondrial DNA variation of southern Tunisian populations

Due to its complex history of migrations and colonization of African, European and Asian people, the Tunisian territory is an ideal area to study the effects of cultural change on the genetic structure of human populations. We investigated the mtDNA genetic variation of Tunisian populations in order to detect the possible impact of recent historical events on their gene pool. Two Arab and three Berber communities were analysed using a comparison dataset of 45 other populations including African, Arabian, Asian, European and Near Eastern groups. The results obtained were compared with those produced using a large panel of autosomal SNPs. We observed a slight but important difference between the populations that inhabit the southern and central-northern areas of the country. Furthermore, robust signatures of genetic isolation were detected in two Berber populations (Nouvelle Zraoua and Tamezret) and in the seminomadic Arab group of the R’Baya. Our investigation suggests that the genetic structure of investigated southern Tunisian populations retains signatures of historical events which occurred between 7th-17th century, particularly the trans-Saharan slave trade and the emigration of Berbers in remote areas of the south during the Arab conquest

Expression of the Atypical Chemokine Receptor D6 in Human Alveolar Macrophages in COPD

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Berbers and Arabs. Tracing the genetic diversity and history of Southern Tunisia through genome wide analysis

Objectives: Tunisia has been a crossroads for people from Africa, Europe, and the Middle East since prehistoric times. At present, it is inhabited by two main ethnic groups, Arabs and Berbers, and several minorities. This study aims to advance knowledge regarding their genetic structure using new population samplings and a genome-wide approach. Materials and Methods: We investigated genomic variation, estimated ancestry components and dated admixture events in three Berber and two Arab populations from Southern Tunisia, mining a dataset including Middle Eastern, sub-Saharan, and European populations. Results: Differences in the proportion of North African, Arabian, and European ancestries and the varying impact of admixture and isolation determined significant heterogeneity in the genetic structure of Southern Tunisian populations. Admixture time estimates show a multilayer pattern of admixture events, involving both ethnolinguistic groups, which started around the mid XI century and lasted for nearly five centuries. Discussion: Our study provides evidence that the relationships between genetic and cultural diversity of old and new inhabitants of North Africa in southern Tunisia follow different patterns. The Berbers seem to have preserved a significant part of their common genomic heritage despite Islamization, Arab cultural influence, and linguistic diversity. Compared to Morocco and Algeria, southern Tunisian Arabs have retained a higher level of Arabian ancestry. This is more evident in the semi-nomad R'Baya, who have kept their original Bedouin lifestyle, than in the population from Douz, who have undergone multiple events of stratification and admixture

Pharmacological Inhibition of Necroptosis Protects from Dopaminergic Neuronal Cell Death in Parkinson's Disease Models

Dysfunctions in mitochondrial dynamics and metabolism are common pathological processes associated with Parkinson's disease (PD). It was recently shown that an inherited form of PD and dementia is caused by mutations in the OPA1 gene, which encodes for a key player in mitochondrial fusion and structure. iPSC-derived neural cells from these patients exhibited severe mitochondrial fragmentation, respiration impairment, ATP deficits, and heightened oxidative stress. Reconstitution of normal levels of OPA1 in PD-derived neural cells normalized mitochondria morphology and function. OPA1-mutated neuronal cultures showed reduced survival in vitro. Intriguingly, selective inhibition of necroptosis effectively rescued this survival deficit. Additionally, dampening necroptosis in MPTP-treated mice protected from DA neuronal cell loss. This human iPSC-based model captures both early pathological events in OPA1 mutant neural cells and the beneficial effects of blocking necroptosis, highlighting this cell death process as a potential therapeutic target for PD. Iannielli et al. generate iPSCs from Parkinson's disease patients with OPA1 mutations and find that derived NPCs have mitochondria with impaired morphology and bioenergetics. Nec-1s, a pharmacological inhibitor of necroptosis, promotes the survival of human OPA1 mutant neurons and attenuates dopaminergic neuronal loss in MPTP-treated mice

Histological verification of positive positron emission tomography findings in the follow-up of patients with mediastinal lymphoma.

Background and Objectives Follow-ups of patients with mediastinal lymphoma are not accurate if they rely on computed tomography (CT). Positron emission tomography (PET) has been suggested to be useful in several lymphoma settings, such as initial staging, evaluation of residual masses after therapy, and assessment of response early in the course of treatment. The aim of this retrospective study was to verify the reliability of positive PET scans of the mediastinum in following up patients wirh mediastinal lymphoma, using histological findings as a comparison. Design and Methods From January 2002 to July 2005, 151 patients with mediastinal lymphoma (57 with Hodgkin's disease [HD] and 94 with aggressive non-Hodgkin's lymphoma [NHL]) were followed-up after the end of front-line treatment. Patients with a positive PET scan of the mediastinum underwent CT scanning and surgical biopsy. Results In 30 (21 HD and 9 NHL) out of 151 patients (20%) a suspicion of lymphoma relapse was raised based on positive mediastinal PET scanning. Histology confirmed this suspicion in 17 (10 HD and 7 NHL) out of 30 patients (57%), whereas either benign (9 fibrosis, 3 sarcoid-like granulomatosis) or unrelated neoplastic conditions (1 thymoma) were demonstrated in the remaining 13 patients (43%). SUVmax was significantly higher among patients who had signs of relapse (17 true positive cases) than among those who stayed in remission (13 false positive cases), the median values being 5.95 (range, 3.5–26.9) and 2.90 (range, 1.4–3.3), respectively ( p =0.01). Interpretation and Conclusions We suggest that a positive PET scan of the mediastinum of a patient being followed-up for a mediastinal lymphoma should not be considered sufficient for diagnostic purposes in view of its lack of discrimination. Histological confirmation can safely be carried out with various biopsy techniques, the choice of which should be made on the basis of the findings of the clinical and imaging studies of the individual case

Identification of novel 2-(1H-Indol-1-yl)benzohydrazides CXCR4 ligands impairing breast cancer growth and motility

Stromal-derived-factor-1 (SDF-1) and the G-protein-coupled receptor CXCR4 are involved in several physiological and pathological processes including breast cancer spread and progression. Several CXCR4 antagonists have currently reached advanced development stages as potential therapeutic agents for different diseases. Results: A small series of novel CXCR4 ligands, based on a 2-(1H-indol-1-yl)-benzohydrazide scaffold, has been designed and synthesized. The interaction with CXCR4-active site was predicted by molecular docking and confirmed by whole cell-based [125I]-SDF-1 ligand competition binding assays. One of the synthesized compounds was particularly active in blocking SDF-1-induced breast cancer cell motility, proliferation and downstream signaling activation in different breast cancer cell models and coculture systems. Conclusion: The newly synthesized compounds represent suitable leads for the development of innovative therapeutic agents targeting CXCR

Control of Cytoskeletal Dynamics by β-Arrestin1/Myosin Vb Signaling Regulates Endosomal Sorting and Scavenging Activity of the Atypical Chemokine Receptor ACKR2

The atypical chemokine receptor ACKR2, formerly named D6, is a scavenger chemokine receptor with a non-redundant role in the control of inflammation and immunity. The scavenging activity of ACKR2 depends on its trafficking properties, which require actin cytoskeleton rearrangements downstream of a β-arrestin1-Rac1-PAK1-LIMK1-cofilin-dependent signaling pathway. We here demonstrate that in basal conditions, ACKR2 trafficking properties require intact actin and microtubules networks. The dynamic turnover of actin filaments is required to sustain ACKR2 constitutive endocytosis, while both actin and microtubule networks are involved in processes regulating ACKR2 constitutive sorting to rapid, Rab4-dependent and slow, Rab11-dependent recycling pathways, respectively. After chemokine engagement, ACKR2 requires myosin Vb activity to promote its trafficking from Rab11-positive recycling endosomes to the plasma membrane, which sustains its scavenging activity. Other than cofilin phosphorylation, induction of the β-arrestin1-dependent signaling pathway by ACKR2 agonists also leads to the rearrangement of microtubules, which is required to support the myosin Vb-dependent ACKR2 upregulation and its scavenging properties. Disruption of the actin-based cytoskeleton by the apoptosis-inducing agent staurosporine results in impaired ACKR2 internalization and chemokine degradation that is consistent with the emerging scavenging-independent activity of the receptor in apoptotic neutrophils instrumental for promoting efficient efferocytosis during the resolution of inflammation. In conclusion, we provide evidence that ACKR2 activates a β-arrestin1-dependent signaling pathway, triggering both the actin and the microtubule cytoskeletal networks, which control its trafficking and scavenger properties

β-Arrestin-Dependent Activation of the Cofilin Pathway Is Required for the Scavenging Activity of the Atypical Chemokine Receptor D6.

International audienceChemokines promote the recruitment of leukocytes to sites of infection and inflammation by activating conventional heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). Chemokines are also recognized by a set of atypical chemokine receptors (ACRs), which cannot induce directional cell migration but are required for the generation of chemokine gradients in tissues. ACRs are presently considered "silent receptors" because no G protein-dependent signaling activity is observed after their engagement by cognate ligands. We report that engagement of the ACR D6 by its ligands activates a β-arrestin1-dependent, G protein-independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin through the Rac1-p21-activated kinase 1 (PAK1)-LIM kinase 1 (LIMK1) cascade. This signaling pathway is required for the increased abundance of D6 protein at the cell surface and for its chemokine-scavenging activity. We conclude that D6 is a signaling receptor that exerts its regulatory function on chemokine-mediated responses in inflammation and immunity through a distinct signaling pathway