Molecular and clinical studies in five index cases with novel mutations in the GLA gene

Fabry disease is a metabolic and lysosomal storage disorder caused by the functional defect of the α-galactosidase A enzyme; this defect is due to mutations in the GLA gene, that is composed of seven exons and is located on the long arm of the X-chromosome (Xq21–22). The enzymatic deficit is responsible for the accumulation of glycosphingolipids in lysosomes of different cellular types, mainly in those ones of vascular endothelium. It consequently causes a cellular and microvascular dysfunction. In this paper, we described five novel mutations in the GLA gene, related to absent enzymatic activity and typical manifestations of Fabry disease. We identified three mutations (c.846_847delTC, p.E341X and p.C382X) that lead to the introduction of a stop codon in positions 297, 341 and 382. Moreover we found a missense mutation (p.R227P) in the exon 5 of the GLA gene and a single point mutation (c.639 + 5 G > T) occurring five base pairs beyond the end of the exon 4. These mutations have never been found in our group of healthy control subjects > 2300. The studied patients presented some clinical manifestations, such as cornea verticillata, hypo-anhidrosis, left ventricular hypertrophy, cerebrovascular disorders and renal failure, that, considering the null enzymatic activity, suggest that the new mutations reported here are related to the classic form of Fabry disease. The identification of novel mutations in patients with symptomatology referable to FD increases the molecular knowledge of the GLA gene and it gives clinicians an important support for the proper diagnosis of the disease

Non-universal minimal Z' models: present bounds and early LHC reach

We consider non-universal 'minimal' Z' models, whose additional U(1) charge is a non-anomalous linear combination of the weak hypercharge Y, the baryon number B and the partial lepton numbers (L_e, L_mu, L_tau), with no exotic fermions beyond three standard families with right-handed neutrinos. We show that the observed pattern of neutrino masses and mixing can be fully reproduced by a gauge-invariant renormalizable Lagrangian, and flavor-changing neutral currents in the charged lepton sector are suppressed by a GIM mechanism. We then discuss the phenomenology of some benchmark models. The electrophilic B-3L_e model is significantly constrained by electroweak precision tests, but still allows to fit the hint of an excess observed by CDF in dielectrons but not in dimuons. The muonphilic B-3L_mu model is very mildly constrained by electroweak precision tests, so that even the very early phase of the LHC can explore significant areas of parameter space. We also discuss the hadrophobic L_mu-L_tau model, which has recently attracted interest in connection with some puzzling features of cosmic ray spectra.Comment: 29 pages, 13 figure

Multidecadal trend of increasing iron stress in Southern Ocean phytoplankton.

Southern Ocean primary productivity is principally controlled by adjustments in light and iron limitation, but the spatial and temporal determinants of iron availability, accessibility, and demand are poorly constrained, which hinders accurate long-term projections. We present a multidecadal record of phytoplankton photophysiology between 1996 and 2022 from historical in situ datasets collected by Biogeochemical Argo (BGC-Argo) floats and ship-based platforms. We find a significant multidecadal trend in irradiance-normalized nonphotochemical quenching due to increasing iron stress, with concomitant declines in regional net primary production. The observed trend of increasing iron stress results from changing Southern Ocean mixed-layer physics as well as complex biological and chemical feedback that is indicative of important ongoing changes to the Southern Ocean carbon cycle

Theoretical Constraints on the Higgs Effective Couplings

We derive constraints on the sign of couplings in an effective Higgs Lagrangian using prime principles such as the naturalness principle, global symmetries, and unitarity. Specifically, we study four dimension-six operators, O_H, O_y, O_g, and O_gamma, which contribute to the production and decay of the Higgs boson at the Large Hadron Collider (LHC), among other things. Assuming the Higgs is a fundamental scalar, we find: 1) the coefficient of O_H is positive except when there are triplet scalars, resulting in a reduction in the Higgs on-shell coupling from their standard model (SM) expectations if no other operators contribute, 2) the linear combination of O_H and O_y controlling the overall Higgs coupling to fermion is always reduced, 3) the sign of O_g induced by a new colored fermion is such that it interferes destructively with the SM top contribution in the gluon fusion production of the Higgs, if the new fermion cancels the top quadratic divergence in the Higgs mass, and 4) the correlation between naturalness and the sign of O_gamma is similar to that of O_g, when there is a new set of heavy electroweak gauge bosons. Next considering a composite scalar for the Higgs, we find the reduction in the on-shell Higgs couplings persists. If further assuming a collective breaking mechanism as in little Higgs theories, the coefficient of O_H remains positive even in the presence of triplet scalars. In the end, we conclude that the gluon fusion production of the Higgs boson is reduced from the SM rate in all composite Higgs models. Our study suggests a wealth of information could be revealed by precise measurements of the Higgs couplings, providing strong motivations for both improving on measurements at the LHC and building a precision machine such as the linear collider.Comment: 37 pages, one figure; v2: improved discussion on dispersion relation and other minor modifications; version accepted for publication

Alveolar adenoma of the lung: unusual diagnosis of a lesion positive on PET scan. A case report

The authors report a clinical case of alveolar adenoma presenting as a solitary pulmonary nodule which was positive to PET and deeply located in the lung. Few cases of alveolar adenomas have been reported in literature; these lesions are considered pulmonary neoplasms with benign behaviour, usually presenting as a peripheral or subpleural coin lesion; the PET activities of such neoplasms were unknown

The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients

Background: Preoperative chemoradiotherapy (CRT) followed by surgery is the standard care for locally advanced rectal cancer, but tumour response to CRT and disease outcome are variable. The current study aimed to investigate the effectiveness of plasma telomerase reverse transcriptase (TERT) levels in predicting tumour response and clinical outcome. Methods: 176 rectal cancer patients were included. Plasma samples were collected at baseline (before CRT\ubcT0), 2 weeks after CRT was initiated (T1), post-CRT and before surgery (T2), and 4\u20138 months after surgery (T3) time points. Plasma TERT mRNA levels and total cell-free RNA were determined using real-time PCR. Results: Plasma levels of TERT were significantly lower at T2 (Po0.0001) in responders than in non-responders. Post-CRT TERT levels and the differences between pre- and post-CRT TERT levels independently predicted tumour response, and the prediction model had an area under curve of 0.80 (95% confidence interval (CI) 0.73\u20130.87). Multiple analysis demonstrated that patients with detectable TERT levels at T2 and T3 time points had a risk of disease progression 2.13 (95% CI 1.10\u20134.11)-fold and 4.55 (95% CI 1.48\u201313.95)-fold higher, respectively, than those with undetectable plasma TERT levels. Conclusions: Plasma TERT levels are independent markers of tumour response and are prognostic of disease progression in rectal cancer patients who undergo neoadjuvant therapy

T-parity, its problems and their solution

We point out a basic difficulty in the construction of little-Higgs models with T-parity which is overlooked by large part of the present literature. Almost all models proposed so far fail to achieve their goal: they either suffer from sizable electroweak corrections or from a breakdown of collective breaking. We provide a model building recipe to bypass the above problem and apply it to build the simplest T-invariant extension of the Littlest Higgs. Our model predicts additional T-odd pseudo-Goldstone bosons with weak scale masses.Comment: 25 pages, 2 appendice

Estrogen-dependent dynamic profile of eNOS-DNA associations in prostate cancer

In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERβ) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with ≈ 55% of them in extragenic DNA regions and an intriguing involvement of the 5′ domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine-tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa

Neuroimaging Evidence of Major Morpho-Anatomical and Functional Abnormalities in the BTBR T+TF/J Mouse Model of Autism

BTBR T+tf/J (BTBR) mice display prominent behavioural deficits analogous to the defining symptoms of autism, a feature that has prompted a widespread use of the model in preclinical autism research. Because neuro-behavioural traits are described with respect to reference populations, multiple investigators have examined and described the behaviour of BTBR mice against that exhibited by C57BL/6J (B6), a mouse line characterised by high sociability and low self-grooming. In an attempt to probe the translational relevance of this comparison for autism research, we used Magnetic Resonance Imaging (MRI) to map in both strain multiple morpho-anatomical and functional neuroimaging readouts that have been extensively used in patient populations. Diffusion tensor tractography confirmed previous reports of callosal agenesis and lack of hippocampal commissure in BTBR mice, and revealed a concomitant rostro-caudal reorganisation of major cortical white matter bundles. Intact inter-hemispheric tracts were found in the anterior commissure, ventro-medial thalamus, and in a strain-specific white matter formation located above the third ventricle. BTBR also exhibited decreased fronto-cortical, occipital and thalamic gray matter volume and widespread reductions in cortical thickness with respect to control B6 mice. Foci of increased gray matter volume and thickness were observed in the medial prefrontal and insular cortex. Mapping of resting-state brain activity using cerebral blood volume weighted fMRI revealed reduced cortico-thalamic function together with foci of increased activity in the hypothalamus and dorsal hippocampus of BTBR mice. Collectively, our results show pronounced functional and structural abnormalities in the brain of BTBR mice with respect to control B6 mice. The large and widespread white and gray matter abnormalities observed do not appear to be representative of the neuroanatomical alterations typically observed in autistic patients. The presence of reduced fronto-cortical metabolism is of potential translational relevance, as this feature recapitulates previously-reported clinical observations