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At least 19 recordsLinked to original sources
PubMed2026

Early-stage trajectories of social-occupational functioning and long-term functional outcome prediction in early psychosis: A 12-year follow-up of the randomized controlled trial on extended early intervention.

BACKGROUND: Functional impairment in psychosis often persists despite symptomatic remission. There is a paucity of research examining early-course psychosocial functioning trajectories, and none has been conducted to examine relationship between the trajectories and prospective long-term functional outcomes in early psychosis sample. METHODS: We conducted 12-year follow-up of a randomized controlled trial on extended early intervention for first-episode psychosis to identify early-course social-occupational functioning trajectories and their baseline predictors and associations with 12-year outcomes. Participants who completed Social and Occupational Functioning Scale (SOFAS) scores at three or more timepoints between baseline and 3-year follow-up were included in the study. Premorbid adjustment, illness characteristics, symptom severity, functioning, and treatment profiles were assessed. Latent growth mixture modeling was employed to derive early-course social-occupational functioning trajectories based on SOFAS scores over 3-year follow-up. RESULTS: A total of 148 participants were included in this study, with 106 patients having completed the 12-year follow-up. Our results identified four distinct trajectories, including persistently-good class, gradually-improved class, suboptimal-stable class, and persistently-poor class. Patients in persistently-poor class had more severe negative symptoms at baseline compared to patients in persistently-good class. Patients with persistently-poor trajectory had worse long-term outcomes than those with other classes in the majority of functional measures at 12-year follow-up. CONCLUSIONS: The majority of patients were classified in early-stage suboptimal or poor functional trajectories. Above one-fourth of the participants exhibited persistently-poor social-occupational functioning trajectory, which predicted worse functional outcomes at 12-year follow-up. These findings highlighted the importance of tracking functional changes during the initial years of illness.

Humans↗
PubMed2026

The metastatic spectrum in functional and non-functional NENs: mechanistic insights from multi-omics.

Neuroendocrine neoplasms (NENs) are biologically heterogeneous tumors in which differentiation/grade and hormonal functionality are intersecting but non-equivalent axes. This review focuses on functional and non-functional well-differentiated neuroendocrine tumors (NETs), principally gastroenteropancreatic and pancreatic NETs, and critically evaluates how site, lineage, stage, tumor burden, genomic and epigenetic alterations, immune-stromal remodeling, metabolic adaptation, microbiome-associated signals, and treatment pressure converge on metastasis and recurrence. Apparent outcome differences by functionality are inconsistent after clinicopathological adjustment: non-functional presentation is often enriched for delayed diagnosis and adverse features, whereas functional subtypes range from typically indolent insulinomas to clinically aggressive hormone-producing tumors. We reconcile these observations through a layered model in which lineage-defining alterations and chromatin/telomere programs establish cellular state; signaling and metabolic plasticity enable stress adaptation; and hypoxia, angiogenesis, immune cells, fibroblasts, extracellular matrix, and therapy create selective niches for dissemination and relapse. We also define computational strategies for heterogeneous multi-omics integration and a staged biomarker-validation pathway. Evidence remains dominated by pancreatic NETs, and causal support is weakest for microbiome-functionality relationships and several proposed cross-omic links. A spectrum-based framework is therefore most useful when it generates testable, site- and grade-specific hypotheses rather than treating functionality as an isolated prognostic variable.

Humans↗
PubMed1977

Differentiation of functionally active mouse T-lymphocytes from functionally inactive bone marrow precursors.

An investigation has been made of the development of various T cell functions in lethally irradiated mice reconstituted with anti-0 treated spleen or bone marrow cells. Evidence is presented to show that both organs contain a post-thymic precursor pool able to regenerate by 15 days limited T cell responses in thymectomized recipients. A prethymic pool also exists in each organ able to regenerate, at a later date, first a suppressor T cell population and probably later, mature functional T cells involved in helper functions and cell mediated lympholysis. The spleen is apparently a better source of precursors of the suppressor cells than bone marrow, while a poorer source of precursors of the other T cell functions. All T cell functions investigated apparently first appear in large cells which undergo a reversion to small cells without necessarily maturing to their full potential reactivity. By following the kinetics of appearance of T cell functions, and the physical parameters of the cells with which these functions are associated, it is shown that PHA responding and Con A responding cells, cytotoxic T cell progenitors, helper T cells for antibody production and helper T cells for cytotoxicity induction can all at some stage of differentiation be separated from one another.

Animals↗
PubMed2026

Structural modeling and functional characterization of a novel gain-of-function TLR8 variant causing severe inflammatory syndrome.

With the increasing use of genetic sequencing to investigate inborn errors of immunity, rare variants are frequently identified, yet their clinical relevance often remains uncertain. Establishing pathogenicity requires a multidisciplinary approach that integrates genetic, structural, functional, and clinical data. Here, we used such a strategy to investigate a previously unreported hemizygous missense variant - alanine (A) to threonine (T) at residue 518 - in Toll-like receptor 8 (TLR8), identified in 2 male siblings with recurrent infections and systemic inflammation, characterized by a proinflammatory immune signature and B cell dysregulation. Functional studies showed that the TLR8 A518T variant enhanced NF-κB activation and increased secretion of proinflammatory cytokines compared with WT TLR8 upon stimulation, consistent with a gain-of-function effect. Protein degradation and turnover assays revealed reduced abundance of the mutant TLR8 protein due to faster turnover and increased proteasomal degradation. Computational modeling predicted enhanced structural stabilization of the active TLR8 homodimer interface via additional water-mediated hydrogen bonds introduced by the A518T substitution. Together, these findings integrating structural modeling with functional assays identify a novel TLR8 ligand-specific gain-of-function mutation resulting in complex immunopathology in 2 siblings.

Humans↗
PubMed1978

Experimental evolution of a new enzymatic function. II. Evolution of multiple functions for ebg enzyme in E. coli.

The evolution of ebgo enzyme of Escherichia coli, an enzyme which is unable to hydrolyze lactose, lactulose, lactobionate, or galactose-arabinoside effectively, has been directed in successive steps so that the evolved enzyme is able to hydrolyze these galactosides effectively. I show that in order for a strain of E. coli with a lacZ deletion to evolve the ability to use lactobionate as a carbon source, a series of mutations must occur in the ebg genes, and that these mutations must be selected in a particular order. The ordered series of mutations constitutes an obligatory evolutionary pathway for the acquisition of a new function for ebgo enzyme. A comparison of newly evolved strains with parental strains shows that when ebg enzyme acquires a new function, its old functions often suffer; but that in several cases old functions are either unaffected or are improved. I conclude that divergence of functions catalyzed by an enzyme need not require gene duplication.

Biological Evolution↗
PubMed1978

Adherent cell function in murine T lymphocyte antigen recognition. II. Definition of genetically restricted and nonrestricted macrophage functions in T cell proliferation.

The mechanisms by which adherent cells, presumably of mononuclear phagocytic lineage, influence in vitro antigen-specific activation of murine T lymphocytes was examined. Two distinct functions for macrophages could be discerned. One macrophage function is dependent on a soluble factor produced by cultured adherent cells and is most easily studied with complex multideterminant antigens. This factor is neither antigen-specific nor MHC-restricted in its action in that PEC, regardless of haplotype, produce factor in the absence of antigen. A second function, antigen-specific T cell activation, is seen when antigens of more restricted heterogeneity are used, such as those under the control of Ir genes. This latter activity demands identity or partial identity between the antigen-presenting cell and the primed T cell, thus suggesting an additional specific, genetically restricted function for macrophages in in vitro antigen recognition. Whether these adherent cell functions are mediated by all or distinct subsets of cells was not established.

Animals↗
PubMed1977

Kinetics of hepatocellular proliferation as a function of the microvascular structure and functional state of the liver.

An analysis of hepatocellular proliferation in regenerating rat liver reveals a dependence of kinetic parameters on the microvascular structure of the liver. Influx kinetics of hepatocytes into DNA synthesis as well as cell cycle phases vary in different parts of the liver lobule between the afferent and efferent vascular poles. Heterogeneity of the proliferative response and size limitations on cell cycle compartments appear to be intimately related to the actual functional state of the individual liver cell. Modifications of liver cell functions result in variations of the proliferative activity. Phenobarbital-induced hypertrophy of hepatocytes reveals a permissive action on G1- S influx. Selective destruction of the subpopulations, by allyl formate, leads to a new functional determination of the residual liver and to a change in proliferative compartments. Maximum modulation of cell cycle compartments is obtained by hydroxyurea-induced synchronization of hepatocytes after partial liver resection. During hydroxyurea treatment, the regenerating liver shows a pronounced cellular hypertrophy. After release from hydroxyurea block, cells embark on DNA synthesis simultaneously. The DNA synthesizing compartment comprises almost the entire liver cell population. Heptotrophic factors might play a part in regulating or modifying hepatocellular function and proliferative response after cell loss.

Allyl Compounds↗
PubMed2026

Divergent PXR function in seals: Endocrine adaptation or functional loss?

Seals accumulate xenobiotics through dietary biomagnification and exposure to polluted marine environments, with contaminants concentrating in their blubber. Biotransformation mitigates xenobiotic toxicity by converting lipophilic compounds into excretable hydrophilic metabolites, a process coordinated by nuclear receptors including the Pregnane X Receptor (PXR), whose plastic ligand-binding domain enables broad xenobiotic sensing. By examining PXR in pinnipeds, we investigated the evolutionary conservation and functional characterization of PXR using genomic sequence analysis, protein structural prediction, and transactivation assays, revealing broadly conserved structural features alongside species-specific functional divergence in receptor responsiveness to environmental stressors. Specifically, the obtained results highlight divergent gene and functional landscapes with ORF-disrupting mutations identified in Monachus monachus and Neomonachus schauinslandi that abolish receptor activation toward known PXR ligands. In contrast, Leptonychotes weddelli retained an intact PXR ORF but showed reduced receptor activity, revealing functional divergence in PXR among pinnipeds.

Biotransformation↗
PubMed1979

In vitro functional studies of mononuclear cells in patients with CLL: evidence for functionally normal T lymphocytes and monocytes and abnormal B lymphocytes.

In vitro functional studies of mononuclear cells from 34 patients with B-cell type CLL were investigated and the results of these studies were as follows: 1) The T lymphocytes from patients with CLL were capable of responding normally to PHA or PWM, of inducing allogeneic normal B lymphocytes to respond to these mitogens and of stimulating normally to allogeneic lymphocytes in "one-way" mixed lymphocyte reaction; 2) The monocytes from these patients were capable of enhancing the T lymphocyte response to mitogens and of stimulating normally to allogeneic lymphocytes; and 3) The leukemic B lymphocytes were incapable of responding to mitogens even in the presence of normal T lymphocytes and their enhancer cell activity on T lymphocyte response or their stimulating capacity on allogeneic lymphocytes was depressed. These observations suggest that the T lymphocytes and monocytes from patients with CLL are functionally normal while the leukemic B lymphocytes from these patients are functionally abnormal.

Adult↗
PubMed2026

Clinical and Functional Characterization of Gain-of-Function ABL1 Variants Expands the Phenotypic Spectrum of CHDSKM.

Germline gain-of-function (GOF) variants in ABL1 cause congenital heart defects and skeletal malformations syndrome (CHDSKM), a multisystem developmental disorder characterized by congenital heart disease, skeletal abnormalities, dysmorphic features, and variable developmental delay. More recently, biallelic loss-of-function variants and ABL haploinsufficiency have been associated with distinct phenotypes, expanding the allelic spectrum of ABL1-related disorders. We report three individuals with ABL1 variants. A female infant with tetralogy of Fallot, critical pulmonary stenosis, covered omphalocele, and a lethal outcome was found by rapid trio genome sequencing to harbor a de novo likely pathogenic ABL1 variant, NM_007313.2:c.354G>T p.(Trp118Cys). We also provide updated clinical follow-up of a previously reported individual and describe a third individual, both carrying the recurrent p.(Tyr245Cys) variant. Functional studies were performed and support a GOF mechanism. Similar activation was observed for Tyr245Cys despite the differences in clinical severity. Our findings expand the phenotypic spectrum of ABL1-related CHDSKM to include severe conotruncal heart disease and covered omphalocele. The comparison of two biochemically activating ABL1 variants demonstrates substantial clinical variability despite a shared molecular mechanism. Furthermore, the overlap between ventral body wall abnormalities in GOF disease and omphalocele associated with ABL1 haploinsufficiency suggests that precise regulation of ABL1 signaling is critical for normal ventral body wall formation.

ABL1↗
PubMed1976

Structural and functional changes in an identified cricket neuron after separation from the soma. II. Functional changes.

Physiological and behavioural effects of separation from the soma were examined in isolated arborization and isolated axon segments of an identified motor neuron in the Polynesian field cricket, Teleogryllus oceanicus. The identified neuron, the contralateral dorsal longitudinal motor neuron of the metathoracic ganglion (CDLM), has an arborization most of which lies contralateral to its soma within the ganglion. Midline lesions in the ganglion separated CDLM into a distal segment composed of the axon and most of the arborization, and a proximal segment made up of the remaining arborization, neurite and soma. Isolated axonal segments were produced by cutting the nerve containing the CDLM axon. The function of the neuron-muscle system composed of CDLM, its pre-synaptic inputs, and its innervated muscle bundle was examined in contrl and experimentally operated animals. Extracellular recording assessed function in the axon. Electrical or tactil stimulation was used to excite pre-synaptic inputs to the CDLM arborization. Intracellular recording determined changes in post-synaptic potentials and miniature end-plate potentials in the muscle bundle innervated by CDLM. Normal axonal conduction, competence to respond to pre-synaptic input, neuron-muscle transmission, and miniature end-plate potential appearance can remain in the isolated arborization preparation. Physiological viability is longer in the cricket isolated arborization than in other insect distal segments described. Survival times of axonal conduction and the competence of the isolated arborization to respond to pre-synaptic input are roughly correlated with disappearance of the whole distal segment at 100 or more postoperative days. A naturally-occurring breakdown of the metathoracic dorsal longitudinal muscles in Teleogryllus eventually prevents measurements of post-synaptic potentials and miniature end-plate potentials. Normal post-synaptic function mediated by the distal arborization is maintained up to this breakdown, to a maximum of 44 days postoperative. The distal axonal segment of CDLM degenerates physiologically within four days postoperative, a time course approximating that of degeneration in vertebrate peripheral nerve distal axons.

Animals↗
PubMedDate not supplied

[Study of the somatotropic function of the pituitary gland and the glucocorticoid function of the adrenal glands in rats with alloxan diabetes].

The somatotropichormone (STH) content was studied in the hypophysis and the peripheral blood of rats with alloxan diabetes; the corticosterone content was determined in their peripheral blood. The STH content in the peripheral blood and the hypophysis of these rats failed to differ from that in the control group, but the blood STH content rose considerably in the sick animals. Exclusion of the insular apparatus function was accompanied by the adrenal gland hypertrophy, which correlated with the rise of the blood corticosterone level. The data obtained indicated that the insular apparatus insufficiency induced by alloxan was accompanied by changes in the somatotropic function of the hypophysis and of glucocorticoid function of the adrenal glands.

Adrenal Cortex↗
PubMed1979

Clinical significance of pulmonary function tests. Alterations in pulmonary function following respiratory viral infection.

Respiratory viral illness is a major cause of morbidity in both adults and children. This report focuses on both the acute and chronic effects on respiratory function of these ubiquitous infections. Infant airways are particularly vulnerable due to the relatively low conductance in immature peripheral airways. Bronchiolitis, caused predominantly by respiratory syncytial virus, is the most important of these viral illnesses and is emerging as a major risk factor for the subsequent development of obstructive airway diseases in adults, possibly by interference with normal alveolar proliferation. The basic pathogenic mechanism involved in adult respiratory viral infection is bronchial hyperreactivity, presumably secondary to epithelial damage and resultant sensitization of rapidly adapting airway receptors. In addition, there may be virus-related alterations in the autonomic and humoral regulation of airway tone. Viral infections may alter the effects of common air pollutants on respiratory function.

Adult↗
PubMed2026

Spatial transcriptomics of Ciona adult brains reveals functional zonalization and insights into neural gland function.

The ascidian Ciona is a pivotal chordate model for illuminating the evolutionary origins of the vertebrate brain. Here, spatial transcriptomics of the adult Ciona neural complex, combined with image-based computational super-resolution mapping, resolved distinct tissue domains including the cerebral ganglion, neural gland, ciliated funnel, neural gland duct/dorsal strand, and body wall muscle. Within the cerebral ganglion, high-resolution mapping revealed clear molecular zonalization separating the cortex and medulla, alongside regional specialization within the cortex itself. The neural gland exhibited localized enrichment of genes associated with extracellular matrix and cell-cell interactions. These spatial features suggest that the neural gland functions as a homeostatic and signaling interface, reminiscent of primitive vertebrate meninges or choroid plexus. Overall, this spatially defined gene expression map provides a foundational framework for understanding functional regionalization in the tunicate brain and its evolutionary relationship to vertebrate nervous systems.

Ciona↗
PubMed2002

Pestivirus internal ribosome entry site (IRES) structure and function: elements in the 5' untranslated region important for IRES function.

The importance of certain structural features of the 5' untranslated region of classical swine fever virus (CSFV) RNA for the function of the internal ribosome entry site (IRES) was investigated by mutagenesis followed by in vitro transcription and translation. Deletions made from the 5' end of the CSFV genome sequence showed that the IRES boundary was close to nucleotide 65: thus, the IRES includes the whole of domain II but no sequences upstream of this domain. Deletions which invaded domain II even to a small extent reduced activity to about 20% that of the full-length structure, and this 20% residual activity persisted with more extensive deletions until the whole of domain II had been removed and the deletions invaded the pseudoknot, whereupon IRES activity fell to zero. The importance of both stems of the pseudoknot was verified by making mutations in both sides of each stem; this severely reduced IRES activity, but the compensating mutations which restored base pairing caused almost full IRES function to be regained. The importance of the length of the loop linking the two stems of the pseudoknot was demonstrated by the finding that a reduction in length from the wild-type AUAAAAUU to AUU almost completely abrogated IRES activity. Random A-->U substitutions in the wild-type sequence showed that IRES activity was fairly proportional to the number of A residues retained in this pseudoknot loop, with a preference for clustered neighboring A residues rather than dispersed As. Finally, it was found that the sequence of the highly conserved domain IIIa loop is, rather surprisingly, not important for the maintenance of full IRES activity, although amputation of the entire domain IIIa stem and loop was highly debilitating. These results are interpreted in the light of recent models, derived from cryo-electron microscopy, of the interaction of the closely related hepatitis C virus IRES with 40S ribosomal subunits.

5' Untranslated Regions↗
PubMed1979

[The Cerebral Function Monitor. Description, functioning and interpretation principles].

The Monitor of Cerebral Function enables continuous monitoring of the cerebral electrical activity and this over long periods due to the slow recording speeds. The cerebral electrical signals picked up by the electrodes attached to the scalp are registered in the form of a curve which fluctuates to a greater or lesser extent depending on the recording speed. The examination of the height of the curve with respect to zero and its amplitude indicates the voltage of the cerebral activity and yields information regarding polymorphism. It is thus possible to monitor variations in cerebral activity over a prolonged period during anaesthesia as well as during the revival phase with the Monitor of Cerebral Function, the electroencephalogram being reserved as an aid to precise diagnosis and for localization and close scruting of the anomalies.

Brain↗
PubMed1975

Carrier and hapten functions in immune deviation. I. Contrary effects of hapten and carrier on cellular and helper functions of T cells.

Carrier and hapten functions have been studied in the immune deviation phenomenon. Delayed hypersensitivity to the carrier and anaphylaxis and Arthus hypersensitivities to the hapten and to the carrier were studied in guinea-pigs injected intravenously with large doses of carrier, homologous and heterologous hapten-carrier conjugates and subsequently immunized with the hapten-carrier conjugate in Freund's complete adjuvant. Pretreatment with DNP-BSA or with HGG were found to modify, in opposite directions, the hypersensitivity reactions induced by DNP-HGG in adjuvant. It is suggested that the hapten and carrier moieties of the antigen molecule might have antagonistic effects on the T cells responsible for cellular immunity as well as on T cells involved in helper functions for B cells.

Anaphylaxis↗