Classification of first-episode psychosis using cortical thickness: A large multicenter MRI study.

Machine learning classifications of first-episode psychosis (FEP) using neuroimaging have predominantly analyzed brain volumes. Some studies examined cortical thickness, but most of them have used parcellation approaches with data from single sites, which limits claims of generalizability. To address these limitations, we conducted a large-scale, multi-site analysis of cortical thickness comparing parcellations and vertex-wise approaches. By leveraging the multi-site nature of the study, we further investigated how different demographical and site-dependent variables affected predictions. Finally, we assessed relationships between predictions and clinical variables. 428 subjects (147 females, mean age 27.14) with FEP and 448 (230 females, mean age 27.06) healthy controls were enrolled in 8 centers by the ClassiFEP group. All subjects underwent a structural MRI and were clinically assessed. Cortical thickness parcellation (68 areas) and full cortical maps (20,484 vertices) were extracted. Linear Support Vector Machine was used for classification within a repeated nested cross-validation framework. Vertex-wise thickness maps outperformed parcellation-based methods with a balanced accuracy of 66.2% and an Area Under the Curve of 72%. By stratifying our sample for MRI scanner, we increased generalizability across sites. Temporal brain areas resulted as the most influential in the classification. The predictive decision scores significantly correlated with age at onset, duration of treatment, and positive symptoms. In conclusion, although far from the threshold of clinical relevance, temporal cortical thickness proved to classify between FEP subjects and healthy individuals. The assessment of site-dependent variables permitted an increase in the across-site generalizability, thus attempting to address an important machine learning limitation.

Mechanism and dynamics of fatty acid photodecarboxylase.

Fatty acid photodecarboxylase (FAP) is a photoenzyme with potential green chemistry applications. By combining static, time-resolved, and cryotrapping spectroscopy and crystallography as well as computation, we characterized Chlorella variabilis FAP reaction intermediates on time scales from subpicoseconds to milliseconds. High-resolution crystal structures from synchrotron and free electron laser x-ray sources highlighted an unusual bent shape of the oxidized flavin chromophore. We demonstrate that decarboxylation occurs directly upon reduction of the excited flavin by the fatty acid substrate. Along with flavin reoxidation by the alkyl radical intermediate, a major fraction of the cleaved carbon dioxide unexpectedly transformed in 100 nanoseconds, most likely into bicarbonate. This reaction is orders of magnitude faster than in solution. Two strictly conserved residues, R451 and C432, are essential for substrate stabilization and functional charge transfer.

Interaction between DRD2 variation and sound environment on mood and emotion-related brain activity.

Sounds, like music and noise, are capable of reliably affecting individuals' mood and emotions. However, these effects are highly variable across individuals. A putative source of variability is genetic background. Here we explored the interaction between a functional polymorphism of the dopamine D2 receptor gene (DRD2 rs1076560, G>T, previously associated with the relative expression of D2S/L isoforms) and sound environment on mood and emotion-related brain activity. Thirty-eight healthy subjects were genotyped for DRD2 rs1076560 (G/G=26; G/T=12) and underwent functional magnetic resonance imaging (fMRI) during performance of an implicit emotion-processing task while listening to music or noise. Individual variation in mood induction was assessed before and after the task. Results showed mood improvement after music exposure in DRD2GG subjects and mood deterioration after noise exposure in GT subjects. Moreover, the music, as opposed to noise environment, decreased the striatal activity of GT subjects as well as the prefrontal activity of GG subjects while processing emotional faces. These findings suggest that genetic variability of dopamine receptors affects sound environment modulations of mood and emotion processing.

PCAF ubiquitin ligase activity inhibits Hedgehog/Gli1 signaling in p53-dependent response to genotoxic stress.

The Hedgehog (Hh) signaling regulates tissue development, and its aberrant activation is a leading cause of malignancies, including medulloblastoma (Mb). Hh-dependent tumorigenesis often occurs in synergy with other mechanisms, such as loss of p53, the master regulator of the DNA damage response. To date, little is known about mechanisms connecting DNA-damaging events to morphogen-dependent processes. Here, we show that genotoxic stress triggers a cascade of signals, culminating with inhibition of the activity of Gli1, the final transcriptional effector of Hh signaling. This inhibition is dependent on the p53-mediated elevation of the acetyltransferase p300/CBP-associated factor (PCAF). Notably, we identify PCAF as a novel E3 ubiquitin ligase of Gli1. Indeed PCAF, but not a mutant with a deletion of its ubiquitination domain, represses Hh signaling in response to DNA damage by promoting Gli1 ubiquitination and its proteasome-dependent degradation. Restoring Gli1 levels rescues the growth arrest and apoptosis effect triggered by genotoxic drugs. Consistently, DNA-damaging agents fail to inhibit Gli1 activity in the absence of either p53 or PCAF. Finally, Mb samples from p53-null mice display low levels of PCAF and upregulation of Gli1 in vivo, suggesting PCAF as potential therapeutic target in Hh-dependent tumors. Together, our data define a mechanism of inactivation of a morphogenic signaling in response to genotoxic stress and unveil a p53/PCAF/Gli1 circuitry centered on PCAF that limits Gli1-enhanced mitogenic and prosurvival response.

Temporal superresolution of ultrashort laser pulses.

We introduce the notion of temporal superresolution for ultrashort laser pulses, by analogy with the well-known method of optical superresolution in imaging systems. Simple linear spectral masks are presented, that shapes a laser pulse into a central peak of very short duration, well below the Fourier limited width of Gaussian pulses, but accompanied by low intensity satellite pulses. A proof-of-principle experiment is presented, using a short pulse, high intensity laser system. Such lasers may induce very strongly non linear phenomena in laser-matter interactions, suppressing the effect of the satellite pulses and therefore fully mimicking shorter light pulses. As an example, we show theoretically that the field ionization asymmetry induced by cosine few cycle pulses is strongly enhanced using temporally superresolved laser pulses.

Feasibility of photopheresis to reduce the occurrence of restenosis after percutaneous transluminal coronary angioplasty: a clinical pilot study.

BACKGROUND: Photopheresis was evaluated as a means of preventing restenosis on the basis of immune modulation. METHODS: This was a prospective, randomized, controlled clinical trial analyzing clinical restenosis at 6 months after percutaneous transluminal coronary angioplasty (PTCA). Seventy-eight patients with single-vessel angioplasty were randomly assigned to a control group of 41 patients and a treatment group of 37 patients. At 6 months, there were 72 evaluable patients: 39 control patients and 33 treated. Twenty-nine control patients received balloon PTCA only and 10 patients received stents. Twenty treated patients received PTCA only and 13 patients received stents. Baseline clinical characteristics of both groups were similar. The treatment group received photopheresis for a total of 5 treatments. Primary end points were death from any cause, myocardial infarction, ischemia, and repeat revascularization procedures. RESULTS: By intention-to-treat analysis, clinical restenosis occurred in 27% of control patients versus 8% of treated patients (P =.040, relative risk = 0.30). CONCLUSIONS: Photopheresis therapy in patients undergoing balloon PTCA with and without stent deployment has been shown to be effective in reducing restenosis. The use of photopheresis in such patients merits further investigation.

Living-unrelated kidney donation: a single-center experience.

For 140 consecutive renal transplants performed from January 1995 to October 1997, 25 (18%) were from living-unrelated donors (15 women, 10 men, aged 25-63, mean 43 yr). All donors had pre-transplant imaging evaluation of renal anatomy following renal function assessment (minimal creatinine clearance 75 cm3/min). Admission to the hospital on the day of donation preceded nephrectomy under general anesthesia using an anterior flank, extra-retroperitoneal approach (no rib resection). Post-operative epidural pain control was used for all but 1 donor. The 25 kidney donors were hospitalized for 2 (n = 1), 3 (n = 12), 4 (n = 7), or 5-8 d (n = 5) (average 3.9 d) and had a mean hospitalization charge of $15,501 (range $10,808-$29,579). One intra-operative hemorrhage required transfusion; 1 late neural-related pain syndrome required outpatient wound exploration. Two kidneys were lost: a husband recipient from repetitive acute rejections at 3 months; a friend recipient from chronic rejection at 2.5 yr; both await cadaver transplant. The other 23 kidneys are functioning with a mean serum creatinine of 1.8 (range 1.0-3.3) at 3-36 months (patient survival 100%; graft survival 92%). While most donors were spouses (8 husbands and 10 wives), friends, distant cousins, in-laws, and adoptive relatives did well as donors and recipients. Transplantation may increase by 20% or more at centers which encourage broad application of living donor nephrectomy.

Current issues in living donor nephrectomy.

Of 96 consecutive renal transplants in 2 years, 50 (52%) were living donor grafts. Donor demographics, treatment plans, length of stay (LOS), charges, and complications were reviewed. Donors included 27 women and 23 men aged 22 to 61 (mean 42.2) years; 33 were living related and 17 living unrelated donors. Racial distribution included 1 Hispanic, 2 Asian, 8 black, and 39 white donors. Pretransplant evaluation defined renal anatomy and function (minimal creatinine clearance 75 cc/min). Hospital admission occurred the morning of donation. Nephrectomy under general anesthesia entailed an anterior flank, extra-retroperitoneal approach (no rib resection); and postoperative epidural pain control was standard. Progressive early ambulation and pulmonary self-care optimized recovery. The 50 donors were hospitalized for 2 (n = 7), 3 (n = 18), 4 (n = 15), 5 (n = 6), and 6-8 (n = 4) days (mean LOS: 3.74 +/- 0.17, range 2-8 days). The mean charge for donor hospitalization was $15,415 +/- $397 (range $10,808-$29,579). One major intraoperative hemorrhage required transfusion; 1 patient was readmitted for wound drainage and pneumonia treated medically. While 40 of 50 patients (80%) were hospitalized for 4 days or less, there was no readmission because of short hospital stay. One early graft loss (3 days) occurred from technical problems; all others gained excellent life sustaining function. Three additional kidneys failed from rejection, noncompliance, and systemic coagulopathy. One recipient died at 8 months (CVA) with normal renal function. Current strategies for successful living kidney donation are thorough patient and family education, ambulatory preoperative testing, morning of surgery admission, and discharge planning beginning before hospitalization. Excellent outcomes may be accompanied by a brief LOS, epidural pain management, and liberal use of willing and healthy related and unrelated living donors.