Incomplete Neutralization in Articulatory Phonology

Previous studies have found small but significant phonetic traces of underlying distinctions for phonologically “neutralized” contrasts. This phenomenon, often called incomplete neutralization, has been found for final devoicing in many languages, (e.g., German; Port, Robert F. & O’Dell, 1985), but has also been reported for other neutralizing phenomena, including flapping in American English (Herd et al., 2010), monomoraic lengthening in Japanese (Braver & Kawahara, 2016), vowel deletion in French (Fougeron & Steriade, 1997), vowel epenthesis in Levantine Arabic (Gouskova & Hall, 2009), among others. In my dissertation, I explore the (in)completeness of Russian palatalization in the Articulatory Phonology framework, implementing gestural coordination of complex segments and segment sequences. In Russian, the contrast between a palatalized consonant (e.g., /lj/) and a plain consonant (e.g., /l/) is reported to be neutralized to the palatal counterpart when a plain consonant is followed by a glide. That is, the palatalization of the plain stop in the environment preceding palatal glides results in neutralization: e.g., /lʲut/ [lʲut] ‘fierce’ (underlyingly palatalization) vs. /ljut/ [lʲjut] ‘pour (3p pl)’(coarticulatory palatalization). However, given that “plain” consonants possibly feature a secondary articulation involving the retraction of the tongue dorsum (velarization/uvularization, see Litvin, 2014; Roon & Whalen, 2019; Skalozub, 1963), this dissertation tests the hypothesis that the gestural blending of two secondary articulation gestures (palatalization and velarization/uvularization) leads to the incomplete neutralization of underlying and coarticulatory palatalization in Russian. To this end, this dissertation will explore how complete the neutralization is between underlyingly palatalized consonants and coarticulatorily palatalized consonants (underlyingly plain). In so doing, I will first quantify the extent of palatalization by investigating temporal coordination in both complex segments and segment sequences in Russian and English. I will then present Electromagnetic Articulography (EMA) experiments that examine temporal coordination and spatial positions of articulators involving both underlyingly and coarticulatorily palatalized consonants in Russian. I will also present simulations from computational modeling that can be tested against EMA recordings. In the first experiment, evidence from articulatory kinematic data collected with EMA on Russian palatalized consonants and English consonant-glide sequences revealed that gestural coordination for complex segments (Russian) differs from segment sequences (English). Specifically, the Russian data is consistent with the hypothesis that the constituent gestures of complex segments are coordinated according to their gesture onsets, showing no correlation between G1 duration and onset lag. In contrast, the English data exhibits a positive correlation between G1 duration and onset lag, suggesting that G2 is timed to some gestural landmark later in the unfolding of G1. Results from a second EMA experiment regarding incomplete neutralization of Russian palatalization also reveal that the palatal-plain contrast is neutralized, but more importantly, this neutralization is phonetically incomplete. In particular, both types of palatalizations exhibit the temporal coordination of complex segments, suggesting that plain consonants in the coarticulatory palatalization context are also palatalized. However, I also find residual evidence of an underlying tongue dorsum retraction for the coarticulatory palatalization. This is in line with previous findings of Russian plain consonants having secondary velarization. The computational simulations show that gestural blending of palatalization and velarization as well as their eccentric timing in coarticulatory palatalization results in incomplete neutralization of underlying and coarticulatory palatalization in Russian. This dissertation provides new insights for interpreting incomplete neutralization in the AP framework by showing that at least some cases of incomplete neutralization can be accounted for by gestural overlap. The results present substantial potential for the gestural overlap account to be generalized across a wide range of incomplete neutralization, including final devoicing. This dissertation is important both for the analysis of Russian palatalization and for discussion on incomplete neutralization, as well as articulatory phonology more generally

Development of mucus permeating nanoparticles-based drug delivery systems

Existeix un interès creixent, tant en el món acadèmic com en la recerca industrial en el desenvolupament de sistemes d’alliberament de fàrmacs macromoleculars (proteïnes, pèptids, oligonucleotids) capaços de travessar la mucosa. En aquest sentit, la utilització de vectors sintètics per a l’alliberament de les esmentades macromolècules, permet disposar d’una plataforma versàtil i altament eficient. Tanmateix, la capa de mucosa amb propietats adhesives i altament viscoelàstica, té una elevada capacitat d’atrapar i eliminar qualsevol substància estranya que quedi adherida sobre la seva superfície, limitant, de forma evident, la eficàcia de qualsevol tractament Aquesta Tesi es centra en el desenvolupament de sistemes d’alliberament de DNA, dissenyats a mida, que presenten una elevada estabilitat i eficàcia de transfecció amb un nivell molt baix de toxicitat i molt important en el context de la tesi, una capacitat de permeació a través de la mucosa. A més la tesi també es centra en el disseny i el desenvolupament de mètodes i tècniques in vitro que ajudin a una millor selecció de sistemes eficients d’alliberament a través de la mucosa. Així s’ha desenvolupat un mètode simple i eficient, basat en la utilització de una microbalança de quartz amb dissipació (QCM-D). Aquest mètode ha permès avaluar la interacció de polímers i nanopartícules amb una capa de mucina. Els resultats obtinguts amb el mètode desenvolupat han permés dissenyar sistemes de nanopartícules amb un potencial més gran de permeació a través de la mucosa. Aquesta tècnica d’alta sensibilitat també ha ofert la possibilitat d’avaluar las dos propietats oposades, el coneixement de les quals és necessari per un correcte disseny de sistemes cpaços de creuar la mucosa: mucoadhesió vs mucopenetració. Los Poly(β-amino ester)s (PBAEs) s’han proposat com a sistemes biodegradables capaços de formar nanopartícules, per complexació amb DNA, que presenten una elevada capacitat de transfecció. Tanmateix, mostren problemes d’estabilitat en condicions fisiològiques i són incapaços de travessar la capa de mucosa. En aquesta tesi es descriu una nova solució en la preparació de les formulacions dels nanocomplejos basada en la utilització de recobriments que estabilitzen les nanopartícules i augmenten la seva permeabilitat. Els recubrimeintos proposats inclutyen: i) sucres (sucroses, trhalosa i manitol), ii) quitosà sense modificar de 22 KDa i amb 60-120 kDa, iii) quitosan modificat amb àcid tioglicolidoi i iv) acid poliacrílic-bromelaina. Totes les noves formulacions s’han avaluat amb diferents quantitat de recobriment. S’han determinat les seves propietats fisicoquímiques i la seva eficàcia de transfecció i citotoxicitat en front de cèl.lules COS-7. S’ha estudiat La difusió de las partícules a través de la mucosa gàstrica de porc utilitzant diferents tècniques com el tub rotatori de silicona o el multiple particle tracking (MPT). Els resultats obtinguts han mostrat la superior estabilitat, eficàcia de transfecció i permeabilitat sobre la mucosa de las noves formulacions dissenyades.Existe un interés creciente, tanto en el mundo académico como en la investigación industrial en el desarrollo de sistemas de liberación de fármacos macromoleculares (proteínas, péptidos, oligonucleótidos) capaces de atravesar la mucosa. En este sentido, la utilización de vectores sintéticos para la liberación de dichas macromoléculas, permite disponer de una plataforma versátil y altamente eficiente. Sin embargo, la capa de mucosa con propiedades adhesivas y altamente viscoelástica, tiene una elevada capacidad de atrapar y eliminar cualquier sustancia extraña que quede adherida sobre su superficie, limitando, de forma evidente, la eficacia de cualquier tratamiento Esta Tesis se centra en el desarrollo de sistemas de liberación de ADN, diseñados a medida, que presentan una elevada estabilidad y eficacia de transfección con un nivel muy bajo de toxicidad y muy importante en el contexto de la tesis, una capacidad de permeación a través de la mucosa. Además la tesis también se centra en el diseño y el desarrollo de métodos y técnicas in vitro que ayuden a una mejor selección de sistemas eficientes de liberación a través de la mucosa. Así se ha desarrollado un método simple y eficiente, basado en la utilización de una microbalanza de cuarzo con disipación (QCM-D). Este método ha permitido evaluar la interacción de polímeros y nanopartículas con una capa de mucina. Los resultados obtenidos con el método desarrollado han permitido diseñar sistemas de nanopartículas con un mayor potencial de permeación a través de la mucosa. Esta técnica de alta sensibilidad también ha ofrecido la posibilidad de evaluar las dos propiedades opuestas, el conocimiento de las cuales es necesario para un correcto diseño de sistemas cpaços de cruzar la mucosa: mucoadhesió vs mucopenetració. Los Poly (β-amino ester)s (PBAEs) se han propuesto como sistemas biodegradables capaces de formar nanopartículas, por complejación con ADN, que presentan una elevada capacidad de transfección. Sin embargo, muestran problemas de estabilidad en condiciones fisiológicas y son incapaces de atravesar la capa de mucosa. En esta tesis se describe una nueva solución en la preparación de las formulaciones de los nanocomplejos basada en la utilización de recubrimientos que estabilizan las nanopartículas y aumentan su permeabilidad. Los recubrimeintos propuestos inclutyen: i) azúcares (sucrosa, trhalosa y manitol), ii) quitosano sin modificar de 22 KDa y con 60-120 kDa, iii) quitosano modificado con ácido tioglicólico y iv) ácido poliacrílico-bromelaina. Todas las nuevas formulaciones se han evaluado con diferentes cantidades de recubrimiento. Se han determinado sus propiedades fisicoquímicas y su eficacia de transfección y citotoxicidad frente a células COS-7. Se ha estudiado La difusión de las partículas a través de la mucosa gástrica de cerdo utilizando diferentes técnicas como el tubo rotatorio de silicona o el múltiple particle tracking (MPT). Los resultados obtenidos han mostrado superior estabilidad, eficacia de transfección y permeabilidad sobre la mucosa de las nuevas formulaciones diseñadas.Mucus penetrating nanoparticle-based delivery systems of macromolecular drugs are currently receiving increasing attention in both academic and industrial research. Synthetic delivery systems provide highly suitable and tunable platform for the delivery of the macromolecules. However, a highly viscoelastic and adhesive mucus layer generally traps and rapidly removes most foreign substance from the mucosal surfaces, thereby limiting effectiveness of these nanocarriers. This Thesis is addressed to the development of engineering DNA delivery systems capable of high stability and transfection efficiency with low toxicity, and quickly crossing the mucus layer. Moreover, this Thesis is focused on design and development of methods and techniques in vitro in order to select more efficient delivery systems. A simple and efficient method, based on the use of the quartz crystal microbalance with dissipation (QCM-D) technique, is developed and evaluated the interaction of the polymers and nanoparticles with the mucin layer, resulting in the development of nanoparticle-based delivery systems to mucosal tissue. This highly sensitive technique also offers to evaluate the two opposing properties, needed for the design of efficient mucous permeation systems: mucoadhesion vs mucus penetration. Poly(β-amino ester)s (PBAEs) are currently considered of great interest as biodegradable polymeric carriers of DNA delivery, but they present limited stability in physiological conditions and the inability to penetrate the mucus layer. In this Thesis, we describe a novel surface-modified formulation of DNA delivery systems consisting of PBAE/DNA complexes and the coating agents, including: i) sugars (sucrose, trehalose or mannitol), ii) unmodified chitosan with a 22 kDa (CS) and a with a 60-120 kDa (CSM), iii) chitosan-thioglycolic acid (CS-TGA), and iv) poly(acrylic acid)-bromelain (PAA-BRO) conjugates. All novel formulations formed with different amounts of the coating agents are evaluated the physicochemical properties. The influence of coating agents on transfection efficiency and cytotoxicity is evaluated in COS-7 cells. Particle diffusion through porcine intestinal mucus (PImucus) is assessed by either rotating silicone tube technique or multiple particle tracking (MPT). The results highlight the superior stability, transfection efficiency and mucus permeability of the novel nanoparticle-based drug delivery systems. The effect of the amount of coating agents is also discussed

Russian assimilatory palatalization is incomplete neutralization

Incomplete neutralization refers to phonetic traces of underlying contrasts in phonologically neutralizing contexts. The present study examines one such context: Russian assimilatory palatalization in C+j sequences. Russian contrasts plain and palatalized consonants, with the plain consonants having a secondary articulation involving retraction of the tongue dorsum (velarization/uvularization). However, Russian also has stop-glide sequences that form near-minimal pairs with palatalized stops. In the environment preceding palatal glides, the contrast between palatalized and plain consonants is neutralized, due to the palatalization of the plain stop (assimilatory palatalization). The purpose of the study is to explore whether the neutralization is complete. To do so, we conducted an electromagnetic articulography (EMA) experiment examining temporal coordination and the spatial position of the tongue body in underlyingly palatalized consonants and those derived from assimilatory palatalization. Articulatory results from four native speakers of Russian revealed that gestures in both conditions are coordinated as complex segments, i.e., they are palatalized consonants. However, there are differences across conditions consistent with the residual presence of a tongue dorsum retraction gesture in the plain obstruents. We conclude that neutralization of the plain-palatal contrast in Russian is incomplete; consonants in the assimilatory palatalization condition exhibit inter-gestural coordination characteristic of palatalized consonants along with residual evidence of an underlying tongue dorsum retraction (velarization/uvularization) gesture

Synthesis of functionalized triblock copolyesters derived from lactic acid and macrolactones for bone tissue regeneration

Synthetic and functional grafts are a great alternative to conventional grafts. They can provide a physical support and the precise signaling for cells to heal damaged tissues. In this study, a novel RGD peptide end-functionalized poly(ethylene glycol)-b-poly(lactic acid)-b-poly(globalide)-b-poly(lactic acid)-b-poly(ethylene glycol) (RGD-PEG-PLA-PGl-PLA-PEG-RGD) is synthetized and used to prepare functional scaffolds. The PGl inner block is obtained by enzymatic ring-opening polymerization of globalide. The outer PLA blocks are obtained by ring-opening polymerization of both, l-lactide or a racemic mixture, initiated by the a-¿-telechelic polymacrolactone. The presence of PGl inner block enhances the toughness of PLA-based scaffolds, with an increase of the elongation at break up to 300% when the longer block of PGl is used. PLA-PGl-PLA copolymer is coupled with a-¿-telechelic PEG diacids by esterification reaction. PEGylation provides hydrophilic scaffolds as the contact angle is reduced from 114° to 74.8°. That difference improves the contact between the scaffolds and the culture media. Moreover, the scaffolds are functionalized with RGD peptides at the surface significantly enhancing the adhesion and proliferation of bone marrow-derived primary mesenchymal stem cells and MC3T3-E1 cell lines in vitro. These results place this multifunctional polymer as a great candidate for the preparation of temporary grafts.The authors would like to acknowledge AGAUR for the financial support by the Doctorats Industrials grant (Project No. 2018 DI 003) and the Ministerio de Ciencia, Innovación y Universidades of Spain (MCIU/AEI/FEDER, UE) (Project No. RTI2018-095041-B-C33). This research was also supported by grants PDC2021-121776-I00 and PID2020-117278GB-I00 from MCIN/AEI/10.13039/501100011033, co-funded by FEDER “Una manera de hacer Europa” or “NextGenerationEU”/PRTR. Globalide, l-lactide/d,l-lactide, and N435 biocatalyst were kindly provided by Symrise, Corbion, and Novozymes, respectively.  Peer ReviewedPostprint (published version

Ninjurin1 positively regulates osteoclast development by enhancing the survival of prefusion osteoclasts

Osteoclasts (OCs) are bone-resorbing cells that originate from hematopoietic stem cells and develop through the fusion of mononuclear myeloid precursors. Dysregulation of OC development causes bone disorders such as osteopetrosis, osteoporosis, and rheumatoid arthritis. Although the molecular mechanisms underlying osteoclastogenesis have been well established, the means by which OCs maintain their survival during OC development remain unknown. We found that Ninjurin1 (Ninj1) expression is dynamically regulated during osteoclastogenesis and that Ninj1(-/-) mice exhibit increased trabecular bone volume owing to impaired OC development. Ninj1 deficiency did not alter OC differentiation, transmigration, fusion, or actin ring formation but increased Caspase-9-dependent intrinsic apoptosis in prefusion OCs (preOCs). Overexpression of Ninj1 enhanced the survival of mouse macrophage/preOC RAW264.7 cells in osteoclastogenic culture, suggesting that Ninj1 is important for the survival of preOCs. Finally, analysis of publicly available microarray data sets revealed a potent correlation between high NINJ1 expression and destructive bone disorders in humans. Our data indicate that Ninj1 plays an important role in bone homeostasis by enhancing the survival of preOCs

Quantum Implementation of AIM: Aiming for Low-Depth

Security vulnerabilities in the symmetric-key primitives of a cipher can undermine the overall security claims of the cipher. With the rapid advancement of quantum computing in recent years, there is an increasing effort to evaluate the security of symmetric-key cryptography against potential quantum attacks. This paper focuses on analyzing the quantum attack resistance of AIM, a symmetric-key primitive used in the AIMer digital signature scheme. We presents the first quantum circuit implementation of AIM and estimates its complexity (such as qubit count, gate count, and circuit depth) with respect to Grover\u27s search algorithm. For Grover\u27s key search, the most important optimization metric is the depth, especially when considering parallel search. Our implementation gathers multiple methods for a low-depth quantum circuit of AIM in order to reduce the Toffoli depth and full depth

Directly converted patient-specific induced neurons mirror the neuropathology of FUS with disrupted nuclear localization in amyotrophic lateral sclerosis

Background Mutations in the fused in sarcoma (FUS) gene have been linked to amyotrophic lateral sclerosis (ALS). ALS patients with FUS mutations exhibit neuronal cytoplasmic mislocalization of the mutant FUS protein. ALS patients fibroblasts or induced pluripotent stem cell (iPSC)-derived neurons have been developed as models for understanding ALS-associated FUS (ALS-FUS) pathology; however, pathological neuronal signatures are not sufficiently present in the fibroblasts of patients, whereas the generation of iPSC-derived neurons from ALS patients requires relatively intricate procedures. Results Here, we report the generation of disease-specific induced neurons (iNeurons) from the fibroblasts of patients who carry three different FUS mutations that were recently identified by direct sequencing and multi-gene panel analysis. The mutations are located at the C-terminal nuclear localization signal (NLS) region of the protein (p.G504Wfs*12, p.R495*, p.Q519E): two de novo mutations in sporadic ALS and one in familial ALS case. Aberrant cytoplasmic mislocalization with nuclear clearance was detected in all patient-derived iNeurons, and oxidative stress further induced the accumulation of cytoplasmic FUS in cytoplasmic granules, thereby recapitulating neuronal pathological features identified in mutant FUS (p.G504Wfs*12)-autopsied ALS patient. Importantly, such FUS pathological hallmarks of the patient with the p.Q519E mutation were only detected in patient-derived iNeurons, which contrasts to predominant FUS (p.Q519E) in the nucleus of both the transfected cells and patient-derived fibroblasts. Conclusions Thus, iNeurons may provide a more reliable model for investigating FUS mutations with disrupted NLS for understanding FUS-associated proteinopathies in ALS

Methods to determine the interactions of micro- and nanoparticles with mucus

The present review provides an overview of methods and techniques for studying interactions of micro- and nanoparticulate drug delivery system with mucus. Nanocarriers trapped by mucus are featuring a change in particle size and zeta potential that can be utilized to predict their mucus permeation behavior. Furthermore, interactions between nanoparticulate drug delivery systems and mucus layer modify the viscoelasticity of mucus which can be detected via rheological studies and quartz crystal microbalance with dissipation monitoring (QCM-D) analysis. To have a closer look at molecular interactions between drug carrier and mucus small-angle neutron scattering (SANS) is an appropriate analysis technique. Moreover, different methods to determine particle diffusion in mucus such as the newly established Transwell diffusion system, rotating silicone tube technique, multiple-particle tracking (MPT) and diffusion NMR are summarized within this review. The explanations and discussed pros and cons of collated methods and techniques should provide a good starting point for all those looking forward to move in this interesting field

Peroxiredoxin 3 deficiency induces cardiac hypertrophy and dysfunction by impaired mitochondrial quality control

Mitochondrial quality control (MQC) consists of multiple processes: the prevention of mitochondrial oxidative damage, the elimination of damaged mitochondria via mitophagy and mitochondrial fusion and fission. Several studies proved that MQC impairment causes a plethora of pathological conditions including cardiovascular diseases. However, the precise molecular mechanism by which MQC reverses mitochondrial dysfunction, especially in the heart, is unclear. The mitochondria-specific peroxidase Peroxiredoxin 3 (Prdx3) plays a protective role against mitochondrial dysfunction by removing mitochondrial reactive oxygen species. Therefore, we investigated whether Prdx3-deficiency directly leads to heart failure via mitochondrial dysfunction. Fifty-two-week-old Prdx3-deficient mice exhibited cardiac hypertrophy and dysfunction with giant and damaged mitochondria. Mitophagy was markedly suppressed in the hearts of Prdx3-deficient mice compared to the findings in wild-type and Pink1-deficient mice despite the increased mitochondrial damage induced by Prdx3 deficiency. Under conditions inducing mitophagy, we identified that the damaged mitochondrial accumulation of PINK1 was completely inhibited by the ablation of Prdx3. We propose that Prdx3 interacts with the N-terminus of PINK1, thereby protecting PINK1 from proteolytic cleavage in damaged mitochondria undergoing mitophagy. Our results provide evidence of a direct association between MQC dysfunction and cardiac function. The dual function of Prdx3 in mitophagy regulation and mitochondrial oxidative stress elimination further clarifies the mechanism of MQC in vivo and thereby provides new insights into developing a therapeutic strategy for mitochondria-related cardiovascular diseases such as heart failure. © 20221