Control of cross-presentation during dendritic cell maturation

The initiation of most cytotoxic immune responses requires MHC class I-restricted presentation of internalized antigens to CD8(+) T lymphocytes, a process called cross-presentation. In dendritic cells (DC), the only antigen-presenting cells that activate naive T cells, cross-presentation is particularly efficient after internalization of opsonized antigens or immune complexes, which are cross-presented through a proteasome- and transporter associated with antigen processing (TAP)-dependent MHC class I antigen presentation pathway. We now show that FcgammaR-mediated cross-presentation is tightly regulated during DC maturation. Cross-presentation increases soon after activation by lipopolysaccharides, and it is then inhibited in fully mature cells. The initial induction of cross-presentation results from an increase of both antigen internalization and delivery to the cytosol, and from a slight rise in the activity of the proteasome and TAP. The subsequent block of cross-presentation in mature DC is a consequence of the selective down-modulation of antigen internalization and cytosolic delivery, while proteasome and TAP activities continue to rise. Therefore, FcgammaR-mediated cross-presentation is regulated during DC maturation by the selective control of antigen internalization and transport to the cytosol.     

Association study of dysbindin gene with clinical and outcome measures in a representative cohort of Italian schizophrenic patients.

There is evidence suggesting that Dysbindin (DTNBP1) is a susceptibility gene for schizophrenia in Caucasian, Chinese, and Japanese populations. We sought to determine if dysbindin was associated with schizophrenia and its symptoms in a representative group of schizophrenic patients from a Community-Based Mental Health Service (CMHS) in Verona, Italy. A prevalence cohort of schizophrenic patients (n = 141) was assessed at baseline and then 3 and 6 years later. Eighty patients and 106 healthy controls were genotyped for polymorphisms in dysbindin. We tested if diagnosis, clinical symptoms as measured by the Brief Psychiatric Rating Scale (BPRS), and functioning as measured by the Global Assessment of Functioning Scale (GAF), were associated with the presence of certain dysbindin polymorphisms. Finally, using the longitudinal clinical data, we tested if patients carrying dysbindin high-risk haplotypes had a more unfavorable longitudinal clinical outcome. A trend towards statistical association (P = 0.058) between schizophrenia and rs2619538 was found. Using GENECOUNTING software, we found that rs2619538-P1583 (P = 0.048), P1320-P1757 (P = 0.034), and rs2619538-P1583-P1578 (P = 0.040) haplotypes occurred more often in cases compared to controls before correction for multiple testing. The rs2619538-P1583 haplotype was more likely to be transmitted to subjects with more severe and persistent psychopathology. These preliminary results are compatible with the view that DTNBP1 is a susceptibility factor for schizophrenia, and is associated with worse psychopathology.     

Genetically driven CD39 expression shapes human tumor-infiltrating CD8+ T-cell functions

In our study, we investigated the role of CD39 on tumor-infiltrating CD8⁺ T lymphocytes (CD8⁺ TILs) in colorectal, head and neck and pancreatic cancers. Partially confirming recent observations correlating the CD39 expression with T-cell exhaustion, we demonstrated a divergent functional activity in CD39⁺CD8⁺ TILs. On the one hand, CD39⁺CD8⁺ TILs (as compared to their CD39⁻ counterparts) produced significantly lower IFN-γ and IL-2 amounts, expressed higher PD-1, and inversely correlated with perforin and granzyme B expression. On the other, they displayed a significantly higher proliferative capacity ex vivo that was inversely correlated with the PD-1 expression. Therefore, CD39⁺CD8⁺ TILs, including those co-expressing the CD103 (a marker of T resident memory [TRM] cells), were defined as partially dysfunctional T cells that correlate with tumor patients with initial progression stages. Interestingly, our results identified for the first time a single nucleotide polymorphism (SNP rs10748643 A>G), as a genetic factor associated with CD39 expression in CD8⁺ TILs. Finally, we demonstrated that compounds inhibiting CD39-related ATPases improved CD39⁺CD8⁺ T-cell effector function ex vivo, and that CD39⁺CD8⁺ TILs displayed effective suppression function in vitro. Overall these data suggest that the SNP analysis may represent a suitable predictor of CD39⁺CD8⁺ T-cell expression in cancer patients, and propose the modulation of CD39 as a new strategy to restore partially exhausted CD8⁺ TILs.     

Pathways to care,DUP, and types of interventions over 5 years following psychosis onset: findings from a naturalistic study conducted in routine generalist mental health services

Social Psychiatry and Psychiatric Epidemiology - To describe pathways to care, duration of untreated psychosis (DUP), and types of interventions provided to first-episode psychosis (FEP) patients...     

Refinement of macaque synteny arrangement with respect to the official rheMac2 macaque sequence assembly

We have compared the synteny block organization of the official macaque genome sequence assembly (Jan. 2006; rheMac2) with an independent assembly that used a molecular cytogenetic approach. The mapping of four synteny segments, ranging in size from 4 Mb to 24 Mb, was found to be inconsistent between the two datasets. We specifically investigated these discrepancies by appropriate co-hybridization FISH experiments with validated reference probes located outside the area under study. We found that in the macaque rheMac2 release three synteny segments were wrongly mapped and one segment was incorrectly oriented.     

Beyond the proteasome: trimming,degradation and generation of MHC class I ligands by auxiliary proteases

The proteasome is now recognized to be implicated in the generation of the vast majority of MHC class I ligands. Moreover, it is probably the only cytosolic protease generating their carboxyterminals. However, solid evidence documents a role of additional and only partly identified proteases in MHC class I antigen processing. Cytosolic tripeptidyl peptidase (TTP II) may be able to carry out some functions normally ascribed to the proteasome, including that of generating antigenic peptides. Several cytosolic enzymes, including bleomycin hydrolase (BH) and puromycin-sensitive aminopeptidase (PSA), but especially the IFNgamma-inducible leucyl aminopeptidase (LAP), can trim the aminoterminal ends of class I ligands. The vast majority of cytosolic peptides is degraded, a process likely to limit antigen presentation, in which thimet oligopeptidase (TOP) may play an important role. Proteolytic activity in the secretory pathway, though much more limited than in the cytosol, also contributes to class I antigen presentation. Signal peptide fragments and peptides at the carboxyterminal end of various proteins targeted to the endoplasmic reticulum can be highly efficient TAP-independent class I ligands. However, an as yet unidentified luminal trimming aminopeptidase may eventually turn out to play the most important role for class I ligand generation in the secretory pathway. Defining the extent of the involvement of cytosolic and luminal peptidases in class I antigen processing will be a challenging task for the future.     

Access to and Use of Psychiatric Services by Migrants Resettled in Northern Italy

The present study was conducted to describe access to and use of psychiatric services by migrants resettled in a large and well-defined catchment area. The study was conducted in a catchment area of 459,536 inhabitants in Verona, a city located in the Northeast of Italy. Using a psychiatric case register, all native and migrant individuals with a first ever psychiatric contact from 2000 to 2015 were identified. Service use data during the 12 months following first contact were collected. During the study period a total of 2610 migrants and 28,860 natives had at least one psychiatric contact. A progressive rise in the proportion of migrants seeking psychiatric care was observed, from 2.5% in 2000 to more than 14% in 2015. During the 12 months following first contact, the proportion of patients with a single consultation did not differ between resettled migrants and natives. However, migrants were more often marked users or heavy users of psychiatric services. Multivariate linear regression analyses showed that younger male individuals with psychotic disorders experienced higher psychiatric services use regardless their native or migrant condition. In a large catchment area with a well-developed community-based system of mental health care a progressive rise in the number of migrants seeking psychiatric care was observed. The pattern of service use during the 12 months after first contact was not related to nationality, suggesting the capacity of community psychiatric services to retain people in care. These findings call for the development of culturally and linguistically appropriate community psychiatric services.     

A balanced de novo inv(7)(p14.3q22.3) disrupting PDE1C and ATXN7L1 in a 14-year old developmentally delayed boy

We report a 14 year old male patient ascertained for developmental delay, carrying a de novo pericentric inversion on chr(7)(p14.3q22.3). Sequencing revealed that the breakpoints overlap a LTR sequence on 7q22.3 and a LINE on 7p14.3. A TTTAAA motif was found in proximity of the breakpoints on both arms. In addition the sequencing detected several small micro-rearrangements, deletion, duplication, insertion, at the breakpoints. No significant sequence identity exists between the 7p14.3 and 7q22.3 breakpoints. These features at the breakpoint junctions suggest that the inversion was triggered by the TTTAAA motif, LTR and LINE and healed by a Non Homologous End Joining (NHEJ) mechanism. The genes ATXN7L1 and PDE1C are disrupted by the inversion. PDE1C is responsible for the hydrolysis of the second messenger molecules cAMP and cGMP and is highly expressed in the human heart and certain brain regions. In mice, Pde1c is expressed in migrating neuronal cells within the central nervous system during early embryo development. Although neuronal migration disorder was not seen in our patient, this is the first patient described with haploinsufficiency of PDE1C possibly causing developmental delay.     

Cumulative radiation dose from medical imaging in kidney transplant patients

Background Although many patients undergoing kidney transplant are exposed to multiple examinations that increase cumulative effective doses (CEDs) of ionizing radiation, no data are available characterizing their total longitudinal radiation burden and relating radiation burden with risk factors for more exposure. Methods We did a retrospective cohort study of 92 patients (mean age 52 years; range: 20-75 years) who underwent kidney transplant at University Hospital, Novara, Italy, that evaluated all following medical imaging procedures involving ionizing radiation undergone beginning June 2007, and all subsequent procedures through August 2011, at the centre. Results The mean and median annual CED were 17.2 and 4.9 millisieverts (mSv) per patient-year. The mean and median total CED per patient over the study period were 46.1 and 17.3 mSv, respectively. Twenty-eight and 12% of patients had total CED >50 and 100 mSv, values which are associated with a good or strong evidence of an increased cancer mortality risk, respectively. Computed tomography scanning accounted for 73% of the total CED. The annual CED was significantly higher in incident patients and in patients with ischaemic heart disease and cancer. Conclusion In this institution, multiple testing of kidney transplant patients was common in many patients associated with high cumulative estimated doses of ionizing radiation.