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Insulin-mechanistic target of rapamycin (mTOR) signaling drives anabolic growth during organismal development; its late-life dysregulation contributes to aging and limits lifespans. Age-related regulatory mechanisms and functional consequences of insulin-mTOR remain incompletely understood. Here, we identify LPD-3 as a megaprotein that orchestrates the tempo of insulin-mTOR signaling during C. elegans aging. We find that an agonist insulin, INS-7, is drastically overproduced from early life and shortens lifespan in lpd-3 mutants. LPD-3 forms a bridge-like tunnel megaprotein to facilitate non-vesicular cellular lipid trafficking. Lipidomic profiling reveals increased hexaceramide species in lpd-3 mutants, accompanied by up-regulation of hexaceramide biosynthetic enzymes, including HYL-1. Reducing the abundance of HYL-1, insulin receptor/DAF-2 or mTOR/LET-363, normalizes INS-7 levels and rescues the lifespan of lpd-3 mutants. LPD-3 antagonizes SINH-1, a key mTORC2 component, and decreases expression with age. We propose that LPD-3 acts as a megaprotein brake for organismal aging and that its age-dependent decline restricts lifespan through the sphingolipid-hexaceramide and insulin-mTOR pathways.

Background: Muscle Tension Dysphonia is a relatively new clinical entity that, despite being one of the most frequent causes of functional dysphonia, is little-known by many otorhinolaryngologists. Objective: The objective of the current work is to describe the evolution of Muscle Tension Dysphonia—the concepts and the ways it has been diagnosed and treated—from its first descriptions to our current knowledge. Design: A scoping review was conducted using the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. A search of three bibliographic databases was performed to identify original articles on Muscle Tension Dysphonia. Study selection and characterization was conducted by three independent reviewers and was further reviewed by a fourth individual. In case of relocating any of the studies, it was performed by agreement of two reviewers. We excluded articles not written in English or Spanish, letters to the editor, review articles, studies of the pediatric population, articles related to dysphagia, and other publications that were not relevant. Results: The search identified 1144 articles published from 1983 to December 2022. A total of 581 studies were repeated and another 462 were excluded because they were not written in English or Spanish, were not original articles, or were not relevant to the objective of the study. Finally, 101 articles were included in the review. The articles included in the review were divided into three groups considering the objective and conclusions of each study: 21 articles were classified as "Etiology and Physiopathology", 29 articles as "Diagnosis", and 51 articles were included in the "Treatment" group. Conclusions: The concept of Muscle Tension Dysphonia has been developed during the last forty years. For its diagnosis, endoscopic visualization of the larynx is crucial, but must be combined with the patient's clinical history and other methods can also be useful. This entity should be addressed in a multidisciplinary approach, with the active participation of speech therapists. Most therapeutic options include voice education, vocal hygiene, and rehabilitation of the voice. [ABSTRACT FROM AUTHOR]

In recent years, the direction associated with the study of maps from a finite set A to the set of all subsets of the set A, including the empty one, has been intensively developing. Such mappings are called multifunctions on A, as well as hyperfunctions on A, if an empty subset is excluded from the subsets under consideration. It is not difficult to see that the so-called undefined or undefined functions, which are studied in many works, are most directly related to this field of research. The power of the set A is called the rank of multifunction or hyperfunction. Obviously, multifunctions and hyperfunctions generalize well-known functions of k-valued logic, however, it should be noted that the usual superposition of functions of k-valued logic is not suitable for multifunctions and hyperfunctions. Two types of superpositions are most often considered here, one of them leads to sets closed relative to the superposition, which are called multiclones and hyperclones, and for the second type of superposition, closed sets are called ultraclones and partial ultraclones. In this article, the elements of the rank 2 ultraclone lattice are considered. By now, all the maximum and minimum elements of this lattice are known. For example, Panteleev V.I. described all maximal ultraclones in the predicate language, which allowed us to prove the completeness criterion of an arbitrary system of hyperfunctions of rank 2. We managed to prove the completeness criterion in the maximal ultraclone of linear hyperfunctions of rank 2. Thus, all submaximal ultraclones of linear hyperfunctions are described.

Background: Injecting botulinum neurotoxin (BoNT) into the salivary glands is a common treatment for certain diseases. Green tea's active compound, epigallocatechin-3-gallate (EGCG), has been linked to a variety of health benefits, including the reduction of free radicals and inflammation. This study compared the effects of BoNT and BoNT/EGCG on the submandibular salivary glands (SMG) histology and ultrastructure. Methods: Both BoNT and BoNT/EGCG nanoemulsions were injected into the submandibular salivary glands (SMGs) in adult male albino rats, which were then euthanized, and the right SMGs were thoroughly dissected and prepared for histological, immunohistochemical, and transmission electron microscopic analysis. Results: When compared to the BoNT group, the BoNT/EGCG nanoemulsion group significantly improved SMG acinar and ductal cells using both H&E and immunohistochemical stainings. Ultrastructural findings of the BoNT/EGCG nanoemulsion group revealed marked improvement in the SMG structure, almost normal acini, and striated ducts. Conclusion: Salivary gland histological structures are significantly altered after BoNT administration, but the addition of EGCG causes only minor alterations and can be used to treat hyperfunction.

Background: Muscle Tension Dysphonia is a relatively new clinical entity that, despite being one of the most frequent causes of functional dysphonia, is little-known by many otorhinolaryngologists. Objective: The objective of the current work is to describe the evolution of Muscle Tension Dysphonia—the concepts and the ways it has been diagnosed and treated—from its first descriptions to our current knowledge. Design: A scoping review was conducted using the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. A search of three bibliographic databases was performed to identify original articles on Muscle Tension Dysphonia. Study selection and characterization was conducted by three independent reviewers and was further reviewed by a fourth individual. In case of relocating any of the studies, it was performed by agreement of two reviewers. We excluded articles not written in English or Spanish, letters to the editor, review articles, studies of the pediatric population, articles related to dysphagia, and other publications that were not relevant. Results: The search identified 1144 articles published from 1983 to December 2022. A total of 581 studies were repeated and another 462 were excluded because they were not written in English or Spanish, were not original articles, or were not relevant to the objective of the study. Finally, 101 articles were included in the review. The articles included in the review were divided into three groups considering the objective and conclusions of each study: 21 articles were classified as “Etiology and Physiopathology”, 29 articles as “Diagnosis”, and 51 articles were included in the “Treatment” group. Conclusions: The concept of Muscle Tension Dysphonia has been developed during the last forty years. For its diagnosis, endoscopic visualization of the larynx is crucial, but must be combined with the patient’s clinical history and other methods can also be useful. This entity should be addressed in a multidisciplinary approach, with the active participation of speech therapists. Most therapeutic options include voice education, vocal hygiene, and rehabilitation of the voice.

In this paper, we reformulate the quintic and sextic equations in the spaces of generalized functions. Using the pullbacks and the heat kernels, we investigate the approximate quintic and sextic mappings in the spaces of Schwartz tempered distributions and Fourier hyperfunctions. [ABSTRACT FROM AUTHOR]

Currently, concern about facial attractiveness is increasing, and this fact has led to orthodontics in adult patients being an increasingly demanded treatment, and with it, multi-disciplinary work. When it is caused by a vertical excess of the maxilla, the ideal solution is orthognathic surgery. However, in borderline cases and when the cause is hyperactivity of the upper lip levator muscle complex, alternative conservative solutions can be considered, such as the application of botulinum toxin A (BTX-A). Botulinum toxin is a protein produced by a bacterium and causes a reduction in the force of muscle contraction. The multi-factorial nature of the smile requires an individualized diagnosis in each patient, since there are multiple ways to treat the gummy smile (orthognathic surgery, gingivoplasty, orthodontic intrusion). In recent years, interest has grown in the simplest techniques that allow the patient to quickly return to their usual routine, such as lip replacement. However, this procedure shows recurrences in the first 6–8 post-operative weeks. The main objective of this systematic review and meta-analysis is to analyze the effectiveness of BTX-A in the treatment of gummy smile in the short term, to study its stability, and to evaluate potential complications. A thorough search of the PubMed, Scopus, Embase, Web of Science, and Cochrane databases and a grey literature search were conducted. The inclusion criteria were studies with a sample size greater than or equal to 10 patients with gingival exposure greater than 2 mm in smile, treated with BTX-A infiltration. Those patients whose exclusive etiology of their gummy smile was related to altered passive eruption, gingival thickening, or overeruption of upper incisors were excluded. In the qualitative analysis, the mean pre-treatment gingival exposure ranged between 3.5 and 7.2 mm, reaching a reduction of up to 6 mm after infiltration with botulinum toxin at 12 weeks. Although multiple muscles are involved in the facial expression, the muscles par excellence selected for blockade with BTX-A were levator labii superioris, levator labii superioris ala nasalis, and zygomaticus minor, infiltrating from 1.25 to 7.5 units per side. In the quantitative analysis, the difference in mean reduction between both groups was −2.51 mm at two weeks and −2.24 mm at three months. The benefit of BTX-A in terms of improvement of gummy smile is demonstrated, as a significant reduction in gummy smile is estimated by BTX-A therapy two weeks after its application. Its results gradually decrease over time, however, they stay satisfactory without returning to their initial values after 12 weeks. [ABSTRACT FROM AUTHOR]

Purpose: To assess the preliminary outcomes of inferior oblique (IO) disinsertion-distal myectomy and tucking combined with superior oblique (SO) full tendon advancement in patients with Knapp II or III superior oblique palsy. Methods: This single-centered retrospective study included 16 eyes from 13 patients with Knapp Class II or III SO palsy. All patients underwent IO disinsertion-distal myectomy and tucking combined with SO full tendon advancement while under general anesthesia. Pre- and post-operative levels of vertical deviation in the primary position, abnormal head position, IO hyperfunction and SO hypofunction, torsion, as well as the presence of diplopia, were all measured, and the differences were statistically compared. Results: Pre-operatively, 12 patients had abnormal head positions, and two had diplopia. The pre-and post-operative levels of IO hyperfunction and SO hypofunction, as well as a vertical deviation in the primary position and torsion, all differed statistically significantly (p < 0.01). Conclusions: Inferior oblique disinsertion distal myectomy and tucking combined with SO full tendon advancement surgery appears to be an effective procedure in patients with congenital and acquired Knapp Class II or III SO palsy. [ABSTRACT FROM AUTHOR]

Understanding mechanisms of ageing remains a complex challenge for biogerontologists, but recent adaptations of evolutionary ageing theories offer a compelling lens in which to view both age-related molecular and physiological deterioration. Ageing is commonly associated with progressive declines in biochemical and molecular processes resulting from damage accumulation, yet the role of continued developmental gene activation is less appreciated. Natural selection pressures are at their highest in youthful periods to modify gene expression towards maximising reproductive capacity. After sexual maturation, selective pressure diminishes, subjecting individuals to maladaptive pleiotropic gene functions that were once beneficial for developmental growth but become pathogenic later in life. Due to this selective 'shadowing' in ageing, mechanisms to counter such hyper/hypofunctional genes are unlikely to evolve. Interventions aimed at targeting gene hyper/hypofunction during ageing might, therefore, represent an attractive therapeutic strategy. The nematode Caenorhabditis elegans offers a strong model for post-reproductive mechanistic and therapeutic investigations, yet studies examining the mechanisms of, and countermeasures against, ageing decline largely intervene from larval stages onwards. Importantly, however, lifespan extending conditions frequently impair early-life fitness and fail to correspondingly increase healthspan. Here, we consolidate multiple evolutionary theories of ageing and discuss data supporting hyper/hypofunctional changes at a global molecular and functional level in C. elegans , and how classical lifespan-extension mutations alter these dynamics. The relevance of such mutant models for exploring mechanisms of ageing are discussed, highlighting that post-reproductive gene optimisation represents a more translatable approach for C. elegans research that is not constrained by evolutionary trade-offs. Where some genetic mutations in C. elegans that promote late-life health map accordingly with healthy ageing in humans, other widely used genetic mutations that extend worm lifespan are associated with life-limiting pathologies in people. Lifespan has also become the gold standard for quantifying 'ageing', but we argue that gerospan compression (i.e., 'healthier' ageing) is an appropriate goal for anti-ageing research, the mechanisms of which appear distinct from those regulating lifespan alone. There is, therefore, an evident need to re-evaluate experimental approaches to study the role of hyper/hypofunctional genes in ageing in C. elegans. [Display omitted] • Views that ageing stems from molecular damage has narrowed our view that hyperactive wild-type genes drive physiological decline. • Systems biology will uncover hyperfunctional expression changes in ageing, enabling late-life gene optimisations to improve health. • Healthy phenotypes of long-lived Caenorhabditis elegans mutants are bound within evolutionary constraints. • There is an urgent need to employ pharmaco-genetic interventions commencing in post-reproductive animals to study healthy ageing. [ABSTRACT FROM AUTHOR]

Objective: The objective of the present study was to investigate the effect of fast speaking on pause duration, breath group duration, and fundamental frequency (F O ) in rote speech (counting)., Method: Twenty-eight healthy women (age 18-39) who had no experience of voice training, repeated a counting task in both a habitual and fast speaking rate. Pause duration, breath group duration, and mean fundamental frequency were measured from audio recordings. Differences in the study variables between habitual and fast speaking rates were analyzed and tested for statistical significance., Results: In fast speaking rate, mean pause duration was shorter and mean breath group duration longer as compared with habitual speaking rate, both with statistical significance at the group level. Surprisingly, mean fundamental frequency was significantly lower in the fast-speaking rate condition., Conclusion: The results overall supported the hypothesis that pause duration becomes shorter and breath group duration longer with a fast-speaking rate. This may have clinical relevance for voice therapy and supports the importance of speaking rate for the understanding and treatment of some hyperfunctional voice disorders. Notably, however, our findings indicated that counting as a speech task induces a specific pattern which may not be comparable to other speech tasks, nor representative of spontaneous speech in every-day-life., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Currently, concern about facial attractiveness is increasing, and this fact has led to orthodontics in adult patients being an increasingly demanded treatment, and with it, multi-disciplinary work. When it is caused by a vertical excess of the maxilla, the ideal solution is orthognathic surgery. However, in borderline cases and when the cause is hyperactivity of the upper lip levator muscle complex, alternative conservative solutions can be considered, such as the application of botulinum toxin A (BTX-A). Botulinum toxin is a protein produced by a bacterium and causes a reduction in the force of muscle contraction. The multi-factorial nature of the smile requires an individualized diagnosis in each patient, since there are multiple ways to treat the gummy smile (orthognathic surgery, gingivoplasty, orthodontic intrusion). In recent years, interest has grown in the simplest techniques that allow the patient to quickly return to their usual routine, such as lip replacement. However, this procedure shows recurrences in the first 6–8 post-operative weeks. The main objective of this systematic review and meta-analysis is to analyze the effectiveness of BTX-A in the treatment of gummy smile in the short term, to study its stability, and to evaluate potential complications. A thorough search of the PubMed, Scopus, Embase, Web of Science, and Cochrane databases and a grey literature search were conducted. The inclusion criteria were studies with a sample size greater than or equal to 10 patients with gingival exposure greater than 2 mm in smile, treated with BTX-A infiltration. Those patients whose exclusive etiology of their gummy smile was related to altered passive eruption, gingival thickening, or overeruption of upper incisors were excluded. In the qualitative analysis, the mean pre-treatment gingival exposure ranged between 3.5 and 7.2 mm, reaching a reduction of up to 6 mm after infiltration with botulinum toxin at 12 weeks. Although multiple muscles are involved in the facial expression, the muscles par excellence selected for blockade with BTX-A were levator labii superioris, levator labii superioris ala nasalis, and zygomaticus minor, infiltrating from 1.25 to 7.5 units per side. In the quantitative analysis, the difference in mean reduction between both groups was −2.51 mm at two weeks and −2.24 mm at three months. The benefit of BTX-A in terms of improvement of gummy smile is demonstrated, as a significant reduction in gummy smile is estimated by BTX-A therapy two weeks after its application. Its results gradually decrease over time, however, they stay satisfactory without returning to their initial values after 12 weeks.

Let P be a minimal parabolic subgroup of a real reductive Lie group G and H a closed subgroup of G. Then it is proved by Kobayashi and Oshima that the regular representation C ∞ (G / H) contains each irreducible representation of G at most finitely many times if the number of H -orbits on G / P is finite. Moreover, they also proved that the multiplicities are uniformly bounded if the number of H ℂ -orbits on G ℂ / B is finite, where G ℂ , H ℂ are complexifications of G , H , respectively, and B is a Borel subgroup of G ℂ . In this paper, we prove that the multiplicities of the representations of G induced from a parabolic subgroup Q in the regular representation on G / H are uniformly bounded if the number of H ℂ -orbits on G ℂ / Q ℂ is finite. For the proof of this claim, we also show the uniform boundedness of the dimensions of the spaces of group invariant hyperfunctions using the theory of holonomic X -modules. [ABSTRACT FROM AUTHOR]

Both individuals taking rapamycin, an anti-aging drug, and those not taking it will ultimately succumb to age-related diseases. However, the former, if administered disease-oriented dosages for a long time, may experience a delayed onset of such diseases and live longer. The goal is to delay a particular disease that is expected to be life-limiting in a particular person. Age-related diseases, quasi-programmed during development, progress at varying rates in different individuals. Rapamycin is a prophylactic anti-aging drug that decelerates early development of age-related diseases. I further discuss hyperfunction theory of quasi-programmed diseases, which challenges the need for the traditional concept of aging itself.

The process of senescence (aging) is predominantly determined by the action of wild-type genes. For most organisms, this does not reflect any adaptive function that senescence serves, but rather evolutionary effects of declining selection against genes with deleterious effects later in life. To understand aging requires an account of how evolutionary mechanisms give rise to pathogenic gene action and late-life disease, that integrates evolutionary (ultimate) and mechanistic (proximate) causes into a single explanation. A well-supported evolutionary explanation by G.C. Williams argues that senescence can evolve due to pleiotropic effects of alleles with antagonistic effects on fitness and late-life health (antagonistic pleiotropy, AP). What has remained unclear is how gene action gives rise to late-life disease pathophysiology. One ultimate-proximate account is T.B.L. Kirkwood's disposable soma theory. Based on the hypothesis that stochastic molecular damage causes senescence, this reasons that aging is coupled to reproductive fitness due to preferential investment of resources into reproduction, rather than somatic maintenance. An alternative and more recent ultimate-proximate theory argues that aging is largely caused by programmatic, developmental-type mechanisms. Here ideas about AP and programmatic aging are reviewed, particularly those of M.V. Blagosklonny (the hyperfunction theory) and J.P. de Magalhães (the developmental theory), and their capacity to make sense of diverse experimental findings is assessed. • Evolutionary (ultimate) and mechanistic (proximate) factors together cause aging. • The disposable soma theory is one integrated ultimate/proximate account of aging. • Recently new ultimate/proximate theories of aging have emerged. • They view programmatic mechanisms as more important to aging than damage. • Here the hyperfunction, developmental and ontogenetic theories are reviewed. [ABSTRACT FROM AUTHOR]