Timely N-Acetyl-Cysteine and Environmental Enrichment Rescue Oxidative Stress-Induced Parvalbumin Interneuron Impairments via MMP9/RAGE Pathway: A Translational Approach for Early Intervention in Psychosis.

Research in schizophrenia (SZ) emphasizes the need for new therapeutic approaches based on antioxidant/anti-inflammatory compounds and psycho-social therapy. A hallmark of SZ is a dysfunction of parvalbumin-expressing fast-spiking interneurons (PVI), which are essential for neuronal synchrony during sensory/cognitive processing. Oxidative stress and inflammation during early brain development, as observed in SZ, affect PVI maturation. We compared the efficacy of N-acetyl-cysteine (NAC) and/or environmental enrichment (EE) provided during juvenile and/or adolescent periods in rescuing PVI impairments induced by an additional oxidative insult during childhood in a transgenic mouse model with gluthation deficit (Gclm KO), relevant for SZ. We tested whether this rescue was promoted by the inhibition of MMP9/RAGE mechanism, both in the mouse model and in early psychosis (EP) patients, enrolled in a double-blind, randomized, placebo-controlled clinical trial of NAC supplementation for 6 months. We show that a sequential combination of NAC+EE applied after an early-life oxidative insult recovers integrity and function of PVI network in adult Gclm KO, via the inhibition of MMP9/RAGE. Six-month NAC treatment in EP patients reduces plasma sRAGE in association with increased prefrontal GABA, improvement of cognition and clinical symptoms, suggesting similar neuroprotective mechanisms. The sequential combination of NAC+EE reverses long-lasting effects of an early oxidative insult on PVI/perineuronal net (PNN) through the inhibition of MMP9/RAGE mechanism. In analogy, patients vulnerable to early-life insults could benefit from a combined pharmacological and psycho-social therapy

Cell migration leads to spatially distinct but clonally related airway cancer precursors

Background Squamous cell carcinoma of the lung is a common cancer with 95% mortality at 5 years. These cancers arise from preinvasive lesions, which have a natural history of development progressing through increasing severity of dysplasia to carcinoma in situ (CIS), and in some cases, ending in transformation to invasive carcinoma. Synchronous preinvasive lesions identified at autopsy have been previously shown to be clonally related. Methods Using autofluorescence bronchoscopy that allows visual observation of preinvasive lesions within the upper airways, together with molecular profiling of biopsies using gene sequencing and loss-of-heterozygosity analysis from both preinvasive lesions and from intervening normal tissue, we have monitored individual lesions longitudinally and documented their visual, histological and molecular relationship. Results We demonstrate that rather than forming a contiguous field of abnormal tissue, clonal CIS lesions can develop at multiple anatomically discrete sites over time. Further, we demonstrate that patients with CIS in the trachea have invariably had previous lesions that have migrated proximally, and in one case, into the other lung over a period of 12 years. Conclusions Molecular information from these unique biopsies provides for the first time evidence that field cancerisation of the upper airways can occur through cell migration rather than via local contiguous cellular expansion as previously thought. Our findings urge a clinical strategy of ablating high-grade premalignant airway lesions with subsequent attentive surveillance for recurrence in the bronchial tree

The dual string sigma-model of the SU_q(3) sector

In four-dimensional N=4 super Yang-Mills (SYM) the SU(3) sub-sector spanned by purely holomorphic fields is isomorphic to the corresponding mixed one spanned by both holomorphic and antiholomorphic fields. This is no longer the case when one considers the marginally deformed N=4 SYM. The mixed SU(3) sector marginally deformed by a complex parameter beta, i.e. SU_q(3) with q=e^{2 i\pi\beta}, has been shown to be integrable at one-loop hep-th/0703150, while it is not the case for the corresponding purely holomorphic one. Moreover, the marginally deformed N=4 SYM also has a gravity dual constructed by Lunin and Maldacena in hep-th/0502086. However, the mixed SU_q(3) sector has not been studied from the supergravity point of view. Hence in this note, for the case of purely imaginary marginal $\beta$-deformations, we compute the superstring SU_q(3) \sigma-model in the fast spinning string limit and show that, for rational spinning strings, it reproduces the energy computed via Bethe equations.Comment: 20 page

On String S-matrix, Bound States and TBA

The study of finite J effects for the light-cone AdS superstring by means of the Thermodynamic Bethe Ansatz requires an understanding of a companion 2d theory which we call the mirror model. It is obtained from the original string model by the double Wick rotation. The S-matrices describing the scattering of physical excitations in the string and mirror models are related to each other by an analytic continuation. We show that the unitarity requirement for the mirror S-matrix fixes the S-matrices of both theories essentially uniquely. The resulting string S-matrix S(z_1,z_2) satisfies the generalized unitarity condition and, up to a scalar factor, is a meromorphic function on the elliptic curve associated to each variable z. The double Wick rotation is then accomplished by shifting the variables z by quarter of the imaginary period of the torus. We discuss the apparent bound states of the string and mirror models, and show that depending on a choice of the physical region there are one, two or 2^{M-1} solutions of the M-particle bound state equations sharing the same conserved charges. For very large but finite values of J, most of these solutions, however, exhibit various signs of pathological behavior. In particular, they might receive a finite J correction to their energy which is complex, or the energy correction might exceed corrections arising due to finite J modifications of the Bethe equations thus making the asymptotic Bethe ansatz inapplicable.Comment: 77 pages, 6 figures, v2: the statement about the periodicity condition for mirror fermions corrected; typos corrected; references added, v3: misprints correcte

CADM1 inhibits squamous cell carcinoma progression by reducing STAT3 activity.

Although squamous cell carcinomas (SqCCs) of the lungs, head and neck, oesophagus, and cervix account for up to 30% of cancer deaths, the mechanisms that regulate disease progression remain incompletely understood. Here, we use gene transduction and human tumor xenograft assays to establish that the tumour suppressor Cell adhesion molecule 1 (CADM1) inhibits SqCC proliferation and invasion, processes fundamental to disease progression. We determine that the extracellular domain of CADM1 mediates these effects by forming a complex with HER2 and integrin α6β4 at the cell surface that disrupts downstream STAT3 activity. We subsequently show that treating CADM1 null tumours with the JAK/STAT inhibitor ruxolitinib mimics CADM1 gene restoration in preventing SqCC growth and metastases. Overall, this study identifies a novel mechanism by which CADM1 prevents SqCC progression and suggests that screening tumours for loss of CADM1 expression will help identify those patients most likely to benefit from JAK/STAT targeted chemotherapies

One-loop spectroscopy of semiclassically quantized strings: bosonic sector

We make a further step in the analytically exact quantization of spinning string states in semiclassical approximation, by evaluating the exact one-loop partition function for a class of two-spin string solutions for which quadratic fluctuations form a non-trivial system of coupled modes. This is the case of a folded string in the SU(2) sector, in the limit described by a quantum Landau–Lifshitz model. The same applies to the full bosonic sector of fluctuations over the folded spinning string in AdS5 with an angular momentum J in S5. Fluctuations are governed by a special class of fourth-order differential operators, with coefficients being meromorphic functions on the torus, which we are able to solve exactly

Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects.

Cone-rod degeneration (CRD) belongs to the disease spectrum of retinal degenerations, a group of hereditary disorders characterized by an extreme clinical and genetic heterogeneity. It mainly differentiates from other retinal dystrophies, and in particular from the more frequent disease retinitis pigmentosa, because cone photoreceptors degenerate at a higher rate than rod photoreceptors, causing severe deficiency of central vision. After exome analysis of a cohort of individuals with CRD, we identified biallelic mutations in the orphan gene CEP78 in three subjects from two families: one from Greece and another from Sweden. The Greek subject, from the island of Crete, was homozygous for the c.499+1G>T (IVS3+1G>T) mutation in intron 3. The Swedish subjects, two siblings, were compound heterozygotes for the nearby mutation c.499+5G>A (IVS3+5G>A) and for the frameshift-causing variant c.633delC (p.Trp212Glyfs(∗)18). In addition to CRD, these three individuals had hearing loss or hearing deficit. Immunostaining highlighted the presence of CEP78 in the inner segments of retinal photoreceptors, predominantly of cones, and at the base of the primary cilium of fibroblasts. Interaction studies also showed that CEP78 binds to FAM161A, another ciliary protein associated with retinal degeneration. Finally, analysis of skin fibroblasts derived from affected individuals revealed abnormal ciliary morphology, as compared to that of control cells. Altogether, our data strongly suggest that mutations in CEP78 cause a previously undescribed clinical entity of a ciliary nature characterized by blindness and deafness but clearly distinct from Usher syndrome, a condition for which visual impairment is due to retinitis pigmentosa

Generalized cusp in AdS_4 x CP^3 and more one-loop results from semiclassical strings

We evaluate the exact one-loop partition function for fundamental strings whose world-surface ends on a cusp at the boundary of AdS_4 and has a "jump" in CP^3. This allows us to extract the stringy prediction for the ABJM generalized cusp anomalous dimension Gamma_{cusp}^{ABJM} (phi,theta) up to NLO in sigma-model perturbation theory. With a similar analysis, we present the exact partition functions for folded closed string solutions moving in the AdS_3 parts of AdS_4 x CP^3 and AdS_3 x S^3 x S^3 x S^1 backgrounds. Results are obtained applying to the string solutions relevant for the AdS_4/CFT_3 and AdS_3/CFT_2 correspondence the tools previously developed for their AdS_5 x S^5 counterparts.Comment: 48 pages, 2 figures, version 3, corrected misprints in formulas 2.12, B.86, C.33, added comment on verification of the light-like limi

Lung adenocarcinoma originates from retrovirus infection of proliferating type 2 pneumocytes during pulmonary post-natal development or tissue repair

Jaagsiekte sheep retrovirus (JSRV) is a unique oncogenic virus with distinctive biological properties. JSRV is the only virus causing a naturally occurring lung cancer (ovine pulmonary adenocarcinoma, OPA) and possessing a major structural protein that functions as a dominant oncoprotein. Lung cancer is the major cause of death among cancer patients. OPA can be an extremely useful animal model in order to identify the cells originating lung adenocarcinoma and to study the early events of pulmonary carcinogenesis. In this study, we demonstrated that lung adenocarcinoma in sheep originates from infection and transformation of proliferating type 2 pneumocytes (termed here lung alveolar proliferating cells, LAPCs). We excluded that OPA originates from a bronchioalveolar stem cell, or from mature post-mitotic type 2 pneumocytes or from either proliferating or non-proliferating Clara cells. We show that young animals possess abundant LAPCs and are highly susceptible to JSRV infection and transformation. On the contrary, healthy adult sheep, which are normally resistant to experimental OPA induction, exhibit a relatively low number of LAPCs and are resistant to JSRV infection of the respiratory epithelium. Importantly, induction of lung injury increased dramatically the number of LAPCs in adult sheep and rendered these animals fully susceptible to JSRV infection and transformation. Furthermore, we show that JSRV preferentially infects actively dividing cell in vitro. Overall, our study provides unique insights into pulmonary biology and carcinogenesis and suggests that JSRV and its host have reached an evolutionary equilibrium in which productive infection (and transformation) can occur only in cells that are scarce for most of the lifespan of the sheep. Our data also indicate that, at least in this model, inflammation can predispose to retroviral infection and cancer

Insights into the Complex Formed by Matrix Metalloproteinase-2 and Alloxan Inhibitors: Molecular Dynamics Simulations and Free Energy Calculations

Matrix metalloproteinases (MMP) are well-known biological targets implicated in tumour progression, homeostatic regulation, innate immunity, impaired delivery of pro-apoptotic ligands, and the release and cleavage of cell-surface receptors. Hence, the development of potent and selective inhibitors targeting these enzymes continues to be eagerly sought. In this paper, a number of alloxan-based compounds, initially conceived to bias other therapeutically relevant enzymes, were rationally modified and successfully repurposed to inhibit MMP-2 (also named gelatinase A) in the nanomolar range. Importantly, the alloxan core makes its debut as zinc binding group since it ensures a stable tetrahedral coordination of the catalytic zinc ion in concert with the three histidines of the HExxHxxGxxH metzincin signature motif, further stabilized by a hydrogen bond with the glutamate residue belonging to the same motif. The molecular decoration of the alloxan core with a biphenyl privileged structure allowed to sample the deep S1′ specificity pocket of MMP-2 and to relate the high affinity towards this enzyme with the chance of forming a hydrogen bond network with the backbone of Leu116 and Asn147 and the side chains of Tyr144, Thr145 and Arg149 at the bottom of the pocket. The effect of even slight structural changes in determining the interaction at the S1′ subsite of MMP-2 as well as the nature and strength of the binding is elucidated via molecular dynamics simulations and free energy calculations. Among the herein presented compounds, the highest affinity (pIC50 = 7.06) is found for BAM, a compound exhibiting also selectivity (>20) towards MMP-2, as compared to MMP-9, the other member of the gelatinases