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The alternative androgen receptor isoform a mitigates toxicity of polyglutamine-elongated mutant androgen receptor in spinal and bulbar muscular atrophy
No full textIntroduction: Spinal and bulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by a CAG-repeat expansion in the androgen receptor (AR) gene,translated into an elongated polyglutamine (polyQ) tract in the protein. Androgens trigger ARpolyQ toxicity, thus most potential therapeutic approaches involve androgen reduction or AR negative modulation, with severe endocrine side effects. Objective: A start codon (I-AUGs) controls AR translation, while a second one, (II-AUG) downstream to I-AUG and the CAG repeat, drives translation of the shorter AR isoform (AR-A) lacking the polyQ tract, but preserves all relevant AR functional domains. Here, we studied AR-A behaviour and its effect on ARpolyQ toxicity in SBMA. Methods: We took advantage of both cellular and Drosophila melanogaster SBMA models to asses AR-A behaviour and effect on ARpolyQ aggregation and functions. Results: Comparative expression analyses of AR isoforms revealed that AR-A is predominantly located in the mouse brainstem and spinal cord of the central nervous system, but not in muscle. AR-A retains partial androgenic activity, but does not aggregate. Since ARpolyQ and AR-A can heterodimerize, we tested the effect of AR-A on ARpolyQ behaviour, showing that AR-A has a pro-solubilizing effect on ARpolyQ aggregates and that the heterodimers retain the transcriptional activity. Finally, we tested the effect of AR-A in a fly model of SBMA. Flies expressing AR-A alone showed no signs of external eye degeneration, in contrast to those expressing expanded ARpolyQ. Notably, co-expression of AR-A with ARpolyQ significantly reduced ARpolyQ aggregation and eye degeneration, supporting our hypothesis that AR-A enhances ARpolyQ solubility and mitigates its toxicity in vivo. Conclusions: Altogether, our results demonstrate that an increased expression of AR-A may have a role in protecting against ARpolyQ aggregation and toxicity. These findings suggest that AR-A could represent a promising avenue for developing an alternative therapeutic strategy that warrants further investigation
The interpretative arguments from legislator’s intention: Troublesome profiles = Los argumentos interpretativos de la intención del legislador: perfiles problemáticos
No full textThis essay aims to examine the interpretative argument of the legislator’s
intention. We will distinguish six variants of this argument: three variants
referring to historical legislators and three variants referring to an ideal,
rational legislator. For each of them, we will give examples and explain the
values that justify them. Then, we will present the theoretical criticisms
directed against each variant: in support of these criticisms, we will also
present the results of a recent empirical research carried out in the Italian legal
system. We will argue that the theoretical criticisms are justified. The variants
referring to the intention of historical legislators raise conceptual, ontological
and epistemic problems and, in fact, are rarely employed (at least in Italian case
law). The variants referring to the ideal legislator, on the other hand, open up
room for judicial discretion.Este ensayo pretende analizar el argumento interpretativo de la intención del
legislador. Distinguiremos seis variantes de este argumento: tres variantes referidas
a los legisladores históricos y tres variantes referidas a un legislador
ideal y racional. Para cada una de ellas, ofreceremos ejemplos y expondremos
los valores que las justifican. Luego, expondremos las críticas teóricas dirigidas
hacia cada variante. En apoyo de estas críticas, presentaremos también los resultados de una reciente investigación empírica llevada a cabo en el ordenamiento
jurídico italiano. Defenderemos que las críticas teóricas son justificadas.
Las variantes que hacen referencia a la intención de los legisladores históricos
plantean problemas conceptuales, ontológicos y epistémicos y, de hecho, rara
vez se utilizan (al menos en la jurisprudencia italiana). Las variantes referidas
al legislador ideal, en cambio, abren espacio a la discrecionalidad judicial
Molecular Structure of the Monohydrate Hydrochloride Salt of the Antimalarial Drug Chloroquine
No full textWe report the crystallization and single-crystal X-ray analysis of the monohydrate hy
drochloride salt of chloroquine(CQ), abbreviated CQHCl·H2O, an antimalarial drug with
the formula C18H26ClN3. The crystal structure reveals a well-defined supramolecular ar
chitecture stabilized by an extensive hydrogen-bonding network involving CQH+ cations,
chloride anions, and water molecules. Notably, this study provides the first crystallographic
characterization of a monoprotonated chloroquine salt. Additionally, our findings demon
strate the feasibility of isolating pseudo-polymorphic forms of a commercially available
CQsalt via heterogeneous crystallization
Optimization of in vitro fertilization with X-sorted spermatozoa in cattle
No full textIntroduction: Dairy farming has a preferential demand for female calves to sustain milk production. Spermatozoa carrying the X chromosome, selected based on the higher content in DNA, allow to obtain almost exclusively female offspring. However, the separation procedures are stressful to the cells and induce mechanical and chemical modi cations that negatively impact the survival, motility, and ultimately the fertilization potential.
AIM: Considering that overall the X-sorted spermatozoa are characterized by compromised membrane integrity and premature capacitation, a series of experiments was conducted to
test some optimizations of the in vitro fertilization (IVF) procedures to increase
the embryo yield using commercially available X-sorted semen.
Methods: Three series of experiments were conducted that led us to
progressively re ne the IVF procedure with X-sorted spermatozoa. First
different protocols for semen processing were assessed for the yield in motile
spermatozoa. Then the most promising were used in an IVF setting to investigate
the fertilization ability. Finally the most performant protocol was used to
investigate the effect of different IVF co-incubation times on the embryo yield.
Results: By modifying some parameters of the discontinuous density gradient
centrifugation such as the volume of the gradient, the proportion of PVP-coated
colloidal silica solution, the centrifugation speed and the time of processing,
along with the duration of the IVF culture, higher motility and fertilization and
blastocyst rates were obtained (P<0.05).
Discussion: Overall, while studies indicate that different bulls may require speci c
conditions for optimal fertilization and embryo yield, the present report shows
that small adjustments to semen processing can signi cantly improve the
ef ciency of the in vitro embryo production with X-sorted semen
On color differences in context
No full textOver the last century, the study of color differences has attracted considerable attention, with numerous attempts to develop increasingly accurate perceptual metrics that, however, have progressed incrementally but never achieved full adequacy. Although research eventually moved from color spaces to appearance spaces, color was still examined without accounting for its surrounding context, even though visual context has long been known to strongly influence chromatic appearance. This work attempts to address the following question: is it meaningful to pursue marginal improvements in color-difference metrics that treat color in isolation, when embedding color within a visual context can produce appearance changes far greater than the precision gained by the most recent formulas? More broadly, is it still appropriate to measure color differences without accounting for their visual context? The results underscore the necessity for the development of a color metric that takes into account the spatial computations of the scene, thereby aligning more closely with the mechanisms of human vision
Implantation of cancer cells from transoral endoscopic thyroidectomy: a case report
No full textBackground: With the development and new technological knowledge, such as surgical techniques that
accompany the consolidated open surgical procedures, minimally invasive strategies have also emerged for
thyroid surgery. Among these, we can cite the transoral endoscopic vestibular approach known as TOETVA.
Recurrences and metastases of differentiated thyroid cancer frequently manifest in the lymph nodes, lungs,
bones, and liver. Although the primary implantation of cancer cells causing these recurrences and metastases
is considered an uncommon event, it can nonetheless occur in specific instances. This can be a serious
complication for patients, as these recurrences and metastases can be difficult to detect and treat effectively.
Early identification and appropriate management of these cases are crucial for improving patient outcomes.
Case Description: We present a case of a 55-year-old male patient with recurring muscular and
subcutaneous recurrence that developed five years after the initial left thyroidectomy performed via a
TOETVA. The patient therefore required a second surgical procedure of completion thyroidectomy, central
lymph node dissection (level 6 and 7), and removal of nodes in subcutaneous tissue and muscle.
Conclusions: Tumor biology, local environment, technical issues, surgical skills, and the correct
management and handling of neoplastic nodules represent crucial clinical pitfalls and important factors that
can contribute to local recurrence and malignant cellular implantation following a TOETVA for thyroid
surgery
I centri americani di domesticazione delle piante e degli animali
No full textGli studi sull’origine e i processi di domesticazione di piante e animali nascono con Darwin e De Candolle, trovando un punto di svolta nei lavori di Nikolaj Vavilov, ideatore della teoria dei “centri di domesticazione”. Le ricerche moderne, interdisciplinari e supportate da genetica, archeologia e paleoclimatologia, hanno individuato vari centri di domesticazione nel continente americano, in particolare in Mesoamerica e Sudamerica settentrionale già dall’8.000 a.C., con successivi sviluppi nelle Ande, nel Nord America orientale e nell’Amazzonia. Durante l’Epipaleolitico e l’Olocene antico, la gestione delle piante selvatiche e la caccia controllata degli animali portarono progressivamente alla domesticazione, favorita da mutamenti climatici e da pratiche come l’uso del fuoco e la selezione delle specie più utili. Le piante vennero domesticare attraverso differenti meccanismi (gestione ecosistemica, selezione per tuberi, frutti, fibre), mentre gli animali tramite relazioni di commensalismo, predazione o addomesticamento volontario. La diffusione delle specie domestiche fu ampia: mais, zucca e fagioli si espansero dal Messico al Nord America, mentre piante come arachide e pomodoro furono domesticati fuori dal loro areale originario, mostrando casi di “domesticazione alloctona”. Questi processi rientrano nel concetto di “agricoltura predomestica”, basata sulla gestione avanzata di risorse naturali anche senza piena domesticazione. Oggi molte specie americane — tra cui mais, patata, manioca, cacao e pomodoro — sono fondamentali per l’economia e l’alimentazione globali, mentre solo pochi animali domestici americani, come tacchino e anatra muta, si sono diffusi su scala mondiale.Studies of the origin and processes of plant and animal domestication began with Darwin and De Candolle, reaching a turning point with the work of Nikolaj Vavilov, founder of the theory of “centers of domestication.” Modern interdisciplinary research, supported by genetics, archaeology, and paleoclimatology, has identified several domestication centers in the Americas—particularly in Mesoamerica and northern South America as early as 8,000 B.C., with later developments in the Andes, eastern North America, and the Amazon. During the Epipaleolithic and early Holocene, the management of wild plants and controlled hunting of animals gradually led to domestication, driven by climatic changes and practices such as the use of fire and the selection of the most useful species. Plants were domesticated through different mechanisms (ecosystem management, selection for tubers, fruits, and fibers), while animals were domesticated through relationships of commensalism, predation, or voluntary taming. The spread of domesticated species was extensive: maize, squash, and beans expanded from Mexico to North America, while crops such as peanuts and tomatoes were domesticated outside their original range, representing cases of “alloctonous domestication.” These processes fall under the concept of “predomestication agriculture,” based on advanced management of natural resources even without full domestication. Today, many American species—including maize, potato, cassava, cacao, and tomato—are fundamental to global economies and food systems, while only a few American domestic animals, such as the turkey and the Muscovy duck, have spread worldwide
Prenormal Categories
No full textIn this paper we introduce the notion of (pointed) prenormal category, modelled after regular categories, but with the key notions of coequaliser and kernel pair replaced by those of cokernel and kernel. This framework provides a natural setting for extending certain classical results in algebra. We study the fundamental properties of prenormal categories, including a characterisation in terms of a factorisation system involving normal epimorphisms, and a categorical version of Noether’s so-called ‘third isomorphism theorem’. We also present a range of examples, with the category of commutative monoids constituting a central one. In the second part of the paper we extend prenormality and its related properties to the non-pointed context, using kernels and cokernels defined relative to a distinguished class of trivial objects
ULTRA-LOW LEVEL SOLUBLE P24 IS ASSOCIATED WITH INFLAMMATION IN PEOPLE WITH HIV ON LONG-TERM VIROLOGICALLY SUPPRESSIVE ANTIRETROVIRAL THERAPY
No full textIntroduction: Despite virologically suppressive antiretroviral therapy (ART), residual inflammation persists in people with HIV (PWH), thus driving higher risk of serious non-AIDS events (SNAEs) and mortality. Circulating HIV proteins have been detected in some suppressed PWH, as an expression of the persistence of the translation-competent reservoir. We therefore seek to investigate whether peripheral inflammation and mortality risk are associated with p24 production in this population.
Methods: PWH on suppressive ART and age/sex-matched healthy controls without HIV were enrolled. Ultra-low level serum p24 was cross-sectionally (baseline) and longitudinally (6 and 12 months) quantified by Simoa following immune complexes dissociation. In addition, the following were cross-sectionally measured at baseline: plasma biomarkers of inflammaging (Luminex/ELISA), CD38+CD8+ T-cells (flow cytometry), cell-associated total/unintegrated/integrated HIV DNA (qPCR). Mortality risk was estimated by VACS Index 2.0. In vitro experiments tested whether p24 modulates IP-10 secretion by PBMCs.
Results: 120 PWH and 20 controls were recruited. PWH exhibited a distinct inflammaging profile characterised by elevated IP-10, TNF-α, IL-17A, IL-8, sCD14, sCD163, TIMP-1, and GDF-15 compared to controls. Several biomarkers were associated with the VACS Index 2.0 in univariable analyses, but only IP-10 and GDF-15 remained independently associated in multivariable modelling. Soluble p24 was detectable in 25/120 (20.8%) PWH at baseline (median: 0.0516 pg/mL; range: 0.0264–0.8280 pg/mL), and its detectability was associated with male sex yet not with immunological parameters or HIV DNA. Among inflammaging biomarkers, p24 was associated exclusively with higher plasma IP-10, both as categorical and continuous variable, even after adjustment for sex, age, CD4 T-cell count, and ART duration. Longitudinal analyses in a subset of 30 PWH revealed dynamic p24 patterns, with persistently p24-positive PWH exhibiting the highest baseline IP-10 levels. In vitro, p24 alone did not induce IP-10 secretion, but in the presence of IFN-γ and TNF-α, it produced a modest yet significant increase, supporting a context-dependent proinflammatory effect.
Conclusions: These findings demonstrate that a subset (~21%) of virologically suppressed PWH produce detectable levels of soluble p24, and that this residual HIV protein expression is selectively associated with heightened IP-10–mediated inflammation. Given the positive association between IP-10 and VACS Index 2.0, a measure of physiologic frailty and risk of death, these data suggest that p24-driven inflammation may contribute to SNAEs and mortality in virologically suppressed PWH
