Dynamical Generation of Elementary Fermion Mass: First Lattice Evidence.

Using lattice simulations we demonstrate from first principles the existence of a nonperturbative mechanism for elementary particle mass generation in models with gauge fields, fermions, and scalars, if an exact invariance forbids power divergent fermion masses and fermionic chiral symmetries broken at UV scale are maximally restored. We show that in the Nambu-Goldstone phase a fermion mass term, unrelated to the Yukawa operator, is dynamically generated. In models with electroweak interactions weak boson masses are also generated, opening new scenarios for beyond the standard model physics.

Tree hole mosquito species composition and relative abundances differ between urban and adjacent forest habitats in northwestern Argentina.

Water-holding tree holes are main larval habitats for many pathogen vectors, especially mosquitoes (Diptera: Culicidae). Along 3 years, the diversity and composition of mosquito species in tree holes of two neighbouring but completely different environments, a city and its adjacent forest, were compared using generalized linear mixed models, PERMANOVA, SIMPER and species association indexes. The city area (Northwest Argentina) is highly relevant epidemiologically due to the presence of Aedes aegypti L. (main dengue vector) and occurrence of dengue outbreaks; the Yungas rainforests are highly biologically diverse. In total seven mosquito species were recorded, in descending order of abundance: Ae. aegypti, Haemagogus spegazzinii Brèthes, Sabethes purpureus (Theobald), Toxorhynchites guadeloupensis Dyar and Knab, Aedes terrens Walker, Haemagogus leucocelaenus Dyar & Shannon and Sabethes petrocchiae (Shannon and Del Ponte). The seven mosquito species were recorded in both city sites and forested areas; however, their mosquito communities significantly diverged because of marked differences in the frequency and relative abundance of some species: Tx. guadeloupensis and Ae. aegypti were significantly more abundant in forest and urban areas, respectively. Positive significant associations were detected between Ae. aegypti, Hg. spegazzinii and Hg. leucocelaenus. The combined presence of Ae. aegypti, Haemagogus and Sabethes in the area also highlight a potential risk of yellow fever epidemics. Overall results show an impoverished tree hole mosquito fauna in urban environments, reflecting negative effects of urbanization on mosquito diversity.

A first-principle calculation of the XANES spectrum of Cu(2+) in water.

The progress in high performance computing we are witnessing today offers the possibility of accurate electron density calculations of systems in realistic physico-chemical conditions. In this paper, we present a strategy aimed at performing a first-principle computation of the low energy part of the X-ray Absorption Spectroscopy (XAS) spectrum based on the density functional theory calculation of the electronic potential. To test its effectiveness, we apply the method to the computation of the X-ray absorption near edge structure part of the XAS spectrum in the paradigmatic, but simple case of Cu(2+) in water. In order to keep into account the effect of the metal site structure fluctuations in determining the experimental signal, the theoretical spectrum is evaluated as the average over the computed spectra of a statistically significant number of simulated metal site configurations. The comparison of experimental data with theoretical calculations suggests that Cu(2+) lives preferentially in a square-pyramidal geometry. The remarkable success of this approach in the interpretation of XAS data makes us optimistic about the possibility of extending the computational strategy we have outlined to the more interesting case of molecules of biological relevance bound to transition metal ions.

On the geometry of surface stress.

We present a fully general derivation of the Laplace-Young formula and discuss the interplay between the intrinsic surface geometry and the extrinsic one ensuing from the immersion of the surface in the ordinary Euclidean three-dimensional space. We prove that the (reversible) work done in a general surface deformation can be expressed in terms of the surface stress tensor and the variation of the intrinsic surface metric.

The role of Zn ions in the interaction between SARS-CoV-2 orf7a protein and BST2/tetherin.

In this paper, we provide evidence that Zn 2 + ions play a role in the SARS-CoV-2 virus strategy to escape the immune response mediated by the BST2-tetherin host protein. This conclusion is based on sequence analysis and molecular dynamics simulations as well as X-ray absorption experiments [1].

The stress tensor in thermodynamics and statistical mechanics.

We prove that the stress tensor, tau(ab), of a molecular system with arbitrary, short-range interactions can be point-wisely expressed as the functional derivative of the partition function with respect to the local deformation tensor. In this approach, the set of components of tau(ab) has a simple interpretation as the set of Lagrangian multipliers which one needs to introduce to enforce the conditions relating point particle displacements to the body local deformation tensor. The question of the possible nonuniqueness of the formula for tau(ab) is discussed.

Designing effective anticancer-radiopeptides. A Molecular Dynamics study of their interaction with model tumor and healthy cell membranes.

One of the greatest merit of the use of radiopeptides in oncology is their selectivity which, however, brings about the drawback that each radiopeptide is specific for a given tumor type. To overcome this problem the direction currently taken in drug design is that of radiolabelling peptide hormones (or their analogues), relying on their intrinsic ability to bind to specific receptors in precise areas of the human body, at the cost, however, of a poor selectivity against healthy cells. We present here an extensive Molecular Dynamics study of a promising alternative inspired by the mechanism through which antimicrobial peptides interact with the negatively charged bacterial membranes. Appropriately modifying the human antimicrobial peptide, LL-37, we designed a functionalized radionuclide carrier capable of binding more strongly to the negatively charged (model) tumor membranes than to the neutral healthy ones. The mechanism behind this behaviour relies on the fact that at the slight acidic pH surrounding tumor tissues the histidines belonging to the peptide get protonated thus making it positively charged. We have investigated by an extended numerical study the way in which this artificial peptide interacts with models of tumor and healthy cell membranes, proving by Potential Mean Force calculations that the affinity of the peptide to model tumor membranes is significantly larger than to healthy ones. These features (high affinity and generic tumor selectivity) recommend antimicrobial derived customized carriers as promising theranostic constructs in cancer diagnostic and therapy.

Long-term safety and efficacy of autologous platelet lysate drops for treatment of ocular GvHD.

Current ocular GvHD (oGvHD) treatments are suboptimal. We investigated the safety and efficacy of long-term continuous treatment with autologous platelet lysate (PL) drops in patients with oGvHD Dry Eye Syndrome (DES) score 2-3 refractory to topical conventional therapy. Ophthalmic evaluation was performed at 6 month intervals. Symptoms were assessed using the Glaucoma Symptom Scale (GSS). Patients were defined 'responders' when showing a reduction at least one grade on National Institutes of Health Eye Score from baseline at the 6 month visit. Thirty-one patients were included, and 16 (51%) completed 36 months of follow-up (range 6.5-72.7). At 6 months all patients were classified as responders: median GSS symptom score decreased from 70 to 41 (33 at 36 months), median GSS function score reduced from 68 to 46 (33 at 36 months) (all P<0.001). Median Tear Break Up Time improved from 3 to 6 s after 6 months and was maintained over time. All signs improved at 6 and 36 months (clinical and statistical significance). No severe adverse events occurred. Long-term treatment with PL drops is secure and effective for oGvHD and can be an efficient therapy option from initial stages of oGvHD to prevent permanent ocular impairment and improving quality of life.

The effect of ß-sheet breaker peptides on metal associated Amyloid-ß peptide aggregation process.

Far-UV Circular Dichroism experiments and Atomic Force Microscopy tomography are employed to assess the impact of ß-sheet breakers on the Aß1-40 peptide aggregation process in the presence of Cu2+ or Zn2+ transition metals. In this work we focus on two specific 5-amino acids long ß-sheet breakers, namely the LPFFD Soto peptide, already known in the literature, and the LPFFN peptide recently designed and studied by our team. We provide evidence that both ß-sheet breakers are effective in reducing the Aß1-40 aggregation propensity, even in the presence of metal ions.

NPY-induced feeding: pharmacological characterization using selective opioid antagonists and antisense probes in rats.

The ability of neuropeptide Y to potently stimulate food intake is dependent in part upon the functioning of mu and kappa opioid receptors. The combined use of selective opioid antagonists directed against mu, delta or kappa receptors and antisense probes directed against specific exons of the MOR-1, DOR-1, KOR-1 and KOR-3/ORL-1 opioid receptor genes has been successful in characterizing the precise receptor subpopulations mediating feeding elicited by opioid peptides and agonists as well as homeostatic challenges. The present study examined the dose-dependent (5-80 nmol) cerebroventricular actions of general and selective mu, delta, and kappa1 opioid receptor antagonists together with antisense probes directed against each of the four exons of the MOR-1 opioid receptor gene and each of the three exons of the DOR-1, KOR-1, and KOR-3/ORL-1 opioid receptor genes upon feeding elicited by cerebroventricular NPY (0.47 nmol, 2 ug). NPY-induced feeding was dose-dependently decreased and sometimes eliminated following pretreatment with general, mu, delta, and kappa1 opioid receptor antagonists. Moreover, NPY-induced feeding was significantly and markedly reduced by antisense probes directed against exons 1, 2, and 3 of the MOR-1 gene, exons 1 and 2 of the DOR-1 gene, exons 1, 2, and 3 of the KOR-1 gene, and exon 3 of the KOR-3/ORL-1 gene. Thus, whereas the opioid peptides, beta-endorphin and dynorphin A(1-17) elicit feeding responses that are respectively more dependent upon mu and kappa opioid receptors and their genes, the opioid mediation of NPY-induced feeding appears to involve all three major opioid receptor subtypes in a manner similar to that observed for feeding responses following glucoprivation or lipoprivation.

A cross-sectional study on vision-related quality of life in patients with ocular GvHD.

Ocular GvHD affects about 40-60% of patients receiving bone marrow transplantation. Ocular complaints worsen quality of life (QoL), which, besides survival time, is a primary end point in a patient's follow-up. The aim of our study was to assess the ocular surface status and vision-related QoL (VRQoL) and explore the potential determinants in VRQoL in patients with chronic GvHD with ocular involvement. In this cross-sectional study, we investigated 40 patients with ocular GvHD after allogeneic hematopoietic stem cell transplantation assessing ocular symptoms and signs, VRQoL and ophthalmologic parameters. The median age was 52.1 years; 32.5% were females. Most of them presented a multiple organ involvement. Ophthalmological parameter examinations were on average abnormal. Corneal staining was severe/very severe in 25%; conjunctival staining in 10% of subjects. The worse QoL scores were on 'general vision', 'ocular pain', 'vision-specific mental health' and 'vision-specific role difficulties'. Both symptoms and sign scores indicate poor VRQoL. A lower VRQoL was related to schooling level, job position, underlying disease and extracorporeal photopheresis. Corneal staining, Schirmer and tear film breakup time were negatively associated to visual function-related subscales. An accurate ophthalmological and VRQoL assessment should be mandatory for a long time to promptly recognize early signs of ocular suffering, and to prevent irreversible ocular complications.

Antisense mapping the MOR-1 opioid receptor: evidence for alternative splicing and a novel morphine-6 beta-glucuronide receptor.

Although MOR-1 encodes a mu opioid receptor, its relationship to the pharmacologically defined mu receptor subtypes has been unclear. Antisense mapping now suggests that these subtypes result from alternative splicing of MOR-1. Three oligodeoxynucleotide probes targeting exon 1 and another oligodeoxynucleotide directed against the coding region of exon 4 block supraspinal morphine analgesia, a mu1 action, while five of six oligodeoxynucleotides directed against exons 2 and 3 are inactive. Inhibition of gastrointestinal transit and spinal morphine analgesia, two mu2 actions, are blocked only by the probe against exon 4 and not by those directed against exon 1. In contrast, the analgesic actions of the extraordinarily potent mu drug morphine-6 beta-glucuronide are blocked by six different antisense oligodeoxynucleotides targeting exons 2 and 3, but not by those acting on exons 1 or 4. These results suggest that the mu1 and mu2 receptor subtypes originally defined in binding and pharmacological studies result from alternative splicing of MOR-1 while morphine-6 beta-glucuronide acts through a novel, previously unidentified receptor which is yet another MOR-1 splice variant.

3-Methoxynaltrexone, a selective heroin/morphine-6beta-glucuronide antagonist.

Recent work has suggested that heroin and morphine-6beta-glucuronide (M6G) both act through a novel mu opioid receptor subtype distinct from those mediating morphine's actions. This very high affinity 3H-M6G site is selectively competed by 3-methoxynaltrexone. In vivo, 3-methoxynaltrexone (2.5 ng, i.c.v.) selectively antagonizes the analgesic actions of heroin and M6G without interfering with mu (morphine and [D-Ala2,MePhe4,Gly(ol)5]enkephalin), delta ([D-Pen2,D-Pen5]enkephalin), kappa1 (U50,488H) or kappa3 (naloxone benzoylhydrazone) analgesia. In dose-response studies, 3-methoxynaltrexone (2.5 ng, i.c.v.) significantly shifted the ED50 values for heroin and its active metabolite, 6-acetylmorphine, without affecting the morphine curve. These results indicate that 3-methoxynaltrexone selectively blocks a novel 3H-M6G binding site which is responsible for the analgesic actions of heroin and M6G. This ability to selectively antagonize heroin actions opens new possibilities in the development of therapeutics for the treatment of opioid abuse.

Autoradiographic localization of (125)I[Tyr(14)]orphanin FQ/nociceptin and (125)I[Tyr(10)]orphanin FQ/nociceptin(1-11) binding sites in rat brain.

The endogenous ligand for the orphan opioid receptor, orphanin FQ/nociceptin (OFQ), has recently been characterized. The OFQ peptide sequence contains paired basic amino acids, suggesting the possibility of posttranslational processing to a peptide containing the first 11 amino acids of the OFQ peptide. This peptide has been reported in the brain and it has a unique pharmacology. In the present study, we compared the autoradiographic distribution of (125)I[Tyr(14)]OFQ and (125)I[Tyr(10)]OFQ(1-11) in coronal rat brain sections. Nonspecific binding was defined with unlabeled OFQ or OFQ(1-11), respectively. Both radioligands demonstrated high levels of specific binding (>95% of total binding), with no appreciable binding in white matter areas with either ligand. (125)I[Tyr(14)]OFQ binding was widely distributed throughout the rat brain. In contrast, (125)I[Tyr(10)]OFQ(1-11) binding was more restricted. The highest (125)I[Tyr(14)]OFQ binding levels measured in this study were found in the locus coeruleus, an area which contained very low (125)I[Tyr(10)]OFQ(1-11) binding. Both ligands labeled the cortex, hippocampus and amygdala. In the thalamus, (125)I[Tyr(14)]OFQ binding was prominent in most nuclei, whereas (125)I[Tyr(10)]OFQ(1-11) binding was restricted to the midline thalamus. (125)I[Tyr(14)]OFQ binding was heavy in the suprachiasmatic hypothalamus, and moderate in other hypothalamic nuclei. (125)I[Tyr(10)]OFQ(1-11) binding in the hypothalamus, however, was present mainly in the ventromedial hypothalamic nucleus. Lower binding levels of both ligands were found in the caudate putamen. The distinct autoradiographic patterns of these two ligands are consistent with different binding sites, which might help explain their different functional activities.

Analgesic activity of orphanin FQ2, murine prepro-orphanin FQ141-157 in mice.

Orphanin FQ/nociceptin (OFQ/N) is generated from a larger precursor peptide, prepro-orphanin FQ (ppOFQ). Within the sequence of murine ppOFQ is another putative heptadecapeptide, orphanin FQ2 (OFQ2), corresponding to murine ppOFQ141-157. OFQ2 was a potent analgesic given either supraspinally (ED50 0.5 microgram, i.c.v.) or spinally (ED50 0.7 microgram, i.t.). As with opioids and OFQ/N, OFQ2 analgesia was enhanced by blockade of sigma receptors with haloperidol, which increased the potency of the peptide over 10-fold. Supraspinal OFQ2 analgesia was readily reversed by naloxone, implying that it activated opioid systems. Spinal OFQ2 analgesia was insensitive to naloxone. OFQ2 also inhibited gastrointestinal transit. Together, these studies suggest that OFQ2 may be a relevant neuropeptide with important physiological actions.

Medullary mu and delta opioid receptors modulate mesencephalic morphine analgesia in rats.

Supraspinal opioid analgesia is mediated in part by connections between the midbrain periaqueductal gray (PAG) and rostral ventral medulla (RVM) which includes the nuclei raphe magnus and reticularis gigantocellularis. Serotonergic 5HT2 and 5HT3 receptor subtypes appear to participate in this pathway since general and selective serotonergic antagonists microinjected into the RVM significantly reduced morphine analgesia elicited from the PAG. Since both an enkephalinergic pathway between the PAG and RVM and intrinsic enkephalinergic cells in the RVM exist, the present study evaluated the abilities of general (naltrexone), mu-selective (beta-funaltrexamine: B-FNA) and delta 2-selective (naltrindole) opioid receptor subtype antagonists microinjected into the RVM to alter morphine (2.5 micrograms) analgesia elicited from the PAG as measured by the tail-flick and jump tests. Mesencephalic morphine analgesia was significantly reduced after pretreatment in the RVM with naltrexone (1-10 micrograms), B-FNA (0.5-5 micrograms) or naltrindole (0.5-5 micrograms). Naltrexone in the RVM failed to alter basal nociceptive thresholds and none of the opioid antagonists were effective in reducing mesencephalic morphine analgesia when they were microinjected into placements lateral or dorsal to the RVM. These data indicate that mu and delta 2 opioid receptors in the RVM modulate the transmission of opioid pain-inhibitory signals from the PAG.

Synergistic brainstem interactions for morphine analgesia.

Morphine is a potent analgesic when microinjected into the periaqueductal gray (PAG), the rostral ventral medulla (RVM) which contains the nuclei raphe magnus and reticularis gigantocellularis and the dorsolateral pons (DLP) which includes the locus coeruleus. Coadministration of low morphine doses which are inactive alone into combinations of these three regions elicits dramatic analgesic responses, implying the existence of synergy. The most effective combination is the PAG/RVM, whereas the PAG/DLP and RVM/DLP combinations are much less efficacious. In addition to fixed combinations, inclusion of a low morphine dose in one region shifts the analgesic dose-response curves in the others. The marked synergy between the PAG and the RVM is sensitive to naloxonazine, implying a role for mu 1 receptors. Thus, these studies indicate the presence of intrinsic brainstem mu 1 receptor systems with synergistic interactions which can be pharmacologically distinguished from the brainstem mu 2 receptors mediating supraspinal/spinal synergy.

Mu and delta opioid synergy between the periaqueductal gray and the rostro-ventral medulla.

Microinjection of [D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAMGO) into either the periaqueductal gray (PAG) or the rostral ventral medulla (RVM) elicits analgesia in the tailflick assay in the rat. Co-administration of DAMGO into both regions together results in a profound synergistic interaction similar to that we previously reported with morphine. U50,488H and DPDPE are inactive when given into either region. [D-Ala2,Glu4]Deltorphin (deltorphin), on the other hand, elicits an analgesic response, although the maximal response is less than than mu agonists. Co-administration of DAMGO into one region with deltorphin in the other also results in a significant synergy. However, co-administration of DAMGO and deltorphin together in the same region gives only additive effects. These results confirm the existence of mu/mu synergy between the PAG and RVM. kappa 1 and delta 1 agents are inactive, but the delta 2 agonist deltorphin is active in both regions. Our results indicate the presence of mu/delta 2 synergy between the PAG and RVM which appears to involve interactions of pathways rather than receptor interactions at the cellular level.

Antisense mapping KOR-1: evidence for multiple kappa analgesic mechanisms.

In binding assays, both dynorphin B and alpha-neoendorphin are relatively selective for the kappa1b site, unlike U50,488H which has high affinity for both kappa1a and kappa1b sites. In vivo, U50,488H, dynorphin B and alpha-neoendorphin analgesia are reversed by the kappa1-selective antagonist, nor-binaltorphimine (norBNI). Antisense mapping the three exons of KOR-1 revealed that probes targeting all three exons blocked U50,488H analgesia, as expected. However, the selectivity profile of dynorphin B and alpha-neoendorphin analgesia towards the various antisense oligodeoxynucleotides differed markedly from U50,488H, implying a different receptor mechanism of action.

Mercaptoacetate induces feeding through central opioid-mediated mechanisms in rats.

The endogenous opioid system has been implicated in the mediation of food intake elicited by such regulatory challenges as glucoprivation induced by 2-deoxy-D-glucose (2DG) or food deprivation in rodents. Administration of the free fatty acid oxidation inhibitor, mercaptoacetate (MA), produces a potent short-term increase in feeding in rats, the mechanisms of which have been dissociated from that elicited by 2DG. The present study evaluated whether MA-induced feeding in rats was mediated by the endogenous opioid system through systemic administration of the general opioid antagonist, naltrexone, through central administration of either general, mu, mu(1), kappa(1) or delta opioid antagonists, and through central administration of antisense oligodeoxynucleotide (AS ODN) probes directed against specific exons of either the mu (MOR-1), kappa (KOR-1), kappa(3) (KOR-3/ORL-1) or delta (DOR-1) opioid receptor clones. MA-induced feeding was significantly and dose-dependently reduced by systemic naltrexone (0.005-5 mg/kg); these ingestive effects were quite selective since neither total, ambulatory nor stereotypic activity was affected by either MA itself or MA paired with naltrexone. MA-induced feeding was significantly reduced by central pretreatment with either naltrexone (0.1-20 microgram) or mu-selective (beta-funaltrexamine, 0.1-20 microgram), mu(1)-selective (naloxonazine, 1-20 microgram), kappa(1)-selective (nor-binaltorphamine, 0.1-20 microgram), or delta-selective (naltrindole, 1-20 microgram) opioid receptor antagonists. MA-induced feeding was significantly reduced by AS ODN probes directed against either exons 1, 2 or 3, but not exon 4 of the MOR-1 clone, exon 3, but not exons 1 or 2 of the KOR-1 clone, exons 1 or 2, but not exon 3 of the KOR-3/ORL-1 clone, and exon 1, but not exons 2 or 3 of the DOR-1 clone. These data are discussed in terms of opioid mediation of ingestive responses related to fat, and in terms of potential central sites of action at which lipoprivic ingestive responses might act.