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PubMed1975

Integrator enzyme hypothesis for replication of hepatitis-B virus.

A hypothetical model for the replication of hepatitis-B virus is presented. It is suggested that the D.N.A. polymerase associated with Dane particles facilitates integration of viral D.N.A. into the genome of the liver cell. The viral D.N.A. is then replicated with the host genome. The hypothesis accounts for certain curious experimental and clinical observations and makes several predictions which are amenable to laboratory investigation.

Cell Membrane↗
PubMed1976

Further studies on the interaction of actin with heavy meromyosin and subfragment 1 in the presence of ATP.

It has been postulated that, during the hydrolysis of ATP, both normal and SH1-blocked heavy meromyosin undergo a rate-limiting transition from a refractory state which cannot bind to actin to a nonrefractory state which can bind to actin. This model leads to several predictions which were studied in the present work. First, the fraction of heavy meromysin or subfragment 1 which remains unbound to actin when the ATPase equals Vmax should have the same properties as the original protein. In the present study it was determined that the unbound protein has normal ATPase activity which suggests that it is unbound to actin for a kinetic reason rather than because it is a permanently altered form of the myosin. Second, if the heavy meromyosin heads act independently half as much subfragment 1 as heavy meromyosin should bind to actin. Experiments in the ultracentrifuge demonstrate that about half as much subfragment 1 as heavy meromyosin sediments with the actin at Vmax. Third, the ATP turnover rate per actin monomer at infinite heavy meromyosin concentration should be much higher than the ATP turnover rate per heavy meromyosin head at infinite actin concentration. This was found to be the case for SH1-blocked heavy meromyosin since, even at very high concentrations of SH1-blocked heavy meromyosin, in the presence of a fixed actin concentration, the actin-activated ATPase rate remained proportional to the SH1-blocked heavy meromyosin concentration. All of these results tend to confirm the refractory state model for both SH1-blocked heavy meromyosin and unmodified heavy meromyosin and subfragment 1. However, the nature of the small amount of heavy meromyosin which does bind to actin in the presence of ATP at high actin concentration remains unclear.

Actins↗
PubMed2026

Somatic mutations and genome mosaicism in aging and disease.

Age-related genome mosaicism is an inherent feature of multicellularity and genomic instability. It occurs because of DNA mutations, the accumulation of which leads to diverse genomic landscapes across different tissues. DNA mutations in the genome are consequences of DNA damage, changes in the chemical structure of DNA, such as strand breaks or loss of bases. DNA damage is very frequent and normally repaired quickly. However, errors intrinsic to DNA repair or replication can give rise to permanent changes in genome sequence information. Such DNA mutations are diverse and include single-nucleotide variants, small insertions and deletions, and larger genome structural variants. Since the 1950s, somatic mutations have been proposed to be a major cause of aging. Indeed, somatic mutations are the cause of cancer, the risk of which increases exponentially with age, and possibly other age-related diseases, such as neurodegenerative diseases and cardiomyopathies. Somatic mutations vary from cell to cell owing to the innate stochasticity of their occurrence, from error-prone processing of randomly inflicted DNA damage. With the emergence of single-cell and single-molecule sequencing, it has become possible to quantitatively analyze somatic mutations in human cells and tissues. Here, we discuss a possible causal relationship between mutation-driven mosaicism of the somatic genome and aging-related functional decline and disease by exploring several predictions of the somatic mutation theory of aging.

Humans↗
PubMed2000

OTOF encodes multiple long and short isoforms: genetic evidence that the long ones underlie recessive deafness DFNB9.

We have recently reported that OTOF underlies an autosomal recessive form of prelingual sensorineural deafness, DFNB9. The isolated 5-kb cDNA predicted a 1,230 amino acid (aa) C-terminus membrane-anchored cytosolic protein with three C2 domains. This protein belongs to a family of mammalian proteins sharing homology with the Caenorhabditis elegans fer-1. The two other known members of this family, dysferlin and myoferlin, both have six predicted C2 domains. By northern blot analysis, a 7-kb otoferlin mRNA could be detected in the human brain. We isolated the corresponding cDNA, which is expected to encode a 1,977-aa-long form of otoferlin with six C2 domains. A 7-kb cDNA derived from the murine orthologous gene, Otof, was also identified in the inner ear and the brain. The determination of the exon-intron structure of the human and murine genes showed that they are composed of 48 coding exons and extend approximately 90 kb and approximately 80 kb, respectively. Alternatively spliced transcripts could be detected that predict several long isoforms (six C2 domains) in humans and mice and short isoforms (three C2 domains) only in humans. Primers were designed to explore the first 19 OTOF exons, henceforth permitting exploration of the complete coding sequence of the gene in DFNB9 patients. In a southwestern Indian family affected by DFNB9, a mutation in the acceptor splice site of intron 8 was detected, which demonstrates that the long otoferlin isoforms are required for inner ear function.

Alternative Splicing↗
PubMed1979

Dependence of the effects of dietary cholesterol and experimental conditions on serum lipids in man. I. Effects of dietary cholesterol in a linoleic acid-rich diet.

In this experiment the effect of dietary cholesterol in a linoleic acid-rich diet on serum cholesterol was tested. In a cross-over design 41 young healthy students received a linoleic acid-rich diet for 4 weeks at two levels of dietary cholesterol. The diet contained 14 to 15 energy% linoleic acid. The high cholesterol diet was obtained by adding two egg yolks a day to the rations. Supplementation of the linoleic acid-rich diet with the egg yolk cholesterol caused a significant rise of serum cholesterol of about 11 mg/100 ml (0.29 mmole/liter). The dietary cholesterol did not influence serum triglyceride levels. The influence on serum cholesterol was much less than expected, based on several predictive formulas. It is concluded that the presence of a high content of linoleic acid in the diet reduces the effect of dietary cholesterol on serum cholesterol if the cholesterol is provided as egg yolk.

Adult↗
PubMed1975

Genetic control of phosphate-metabolizing enzymes in Neurospora crassa: relationships among regulatory mutations.

In Neurospora crassa, the phosphate-metabolizing enzymes are made during phosphate starvation, but not under phosphate sufficiency. The synthesis of these enzymes is controlled by three regulatory genes: pcon-nuc-2, preg and nuc-1, pcon-nuc-2 and preg are closely linked. A model of the hierarchical relationships among these regulatory genes is presented. Studies of double mutants and revertants confirm several predictions of the model. It has been found that nuc-2 (null) and pcon-c (constitutive) mutations reside in the same cistron. preg-c (constitutive) mutations are epistatic to nuc-2 mutations. nuc-1 (null) mutations are epistatic to all others.

Alkaline Phosphatase↗
PubMed1976

DNA replication in eukaryotes: a model for the specific involvement of chromatin subunits.

A model is proposed whereby eukaryotic DNA replication is specifically directed by the 200 base pair repeat structure of the DNA-histone complex. The model proposes a mechanism for the sequential, bidirectional replication of DNA from initial origin points on the chromatin fibre and is consistent with the known properties of eukaryotic DNA replication. Several predictions can be made from the model which are amenable to testing.

Animals↗
PubMed1978

Are tumor-associated transplantation antigens of chemically induced sarcomas related to alien histocompatibility antigens?

The hypothesis tested was that tumor-specific transplantation antigens of chemically induced tumors cross-react with allogeneic histocompatibility antigens. This hypothesis makes several predictions that can be tested experimentally. First, tumors should grow better and be less immunogenic in certain F1 hybrids than in their syngeneic parents, owing to the hypothecated cross-reactivity of the tumor-specific transplantation antigens with F1 antigens. This is in contrast to the more common observation that parental strain tumors grow worse in the F1 hybrids than they do in the parent. Also certain allogeneic skin grafts might immunize the parental strain mice against their syngeneic tumors, and, finally, immunizing parental mice with syngeneic tumor might cause accelerated rejection of certain skin allografts. The results show that certain tumors grew better in the F1 mice than they did in the parents but that the tumors were not less immunogenic in the F1 hybrids. Mice immunized against alloantigens showed a dose-dependent enhancement of syngeneic tumor growth. Finally, mice immunized with syngeneic tumors demonstrated an apparent prolongation of certain skin allografts. The discussion considers possible alternatives explaining these results.

Animals↗
PubMed1976

The spread of the action potential through the T-system in hagfish twitch muscle fibres.

The input impedance of twitch muscle fibres of the Atlantic hagfish has been measured with sinusoidal transmembrane currents. The apparent specific membrane resistance and capacitance decreased markedly with frequency, and were relatively independent of fibre diameter. A model of the T-system based on anatomical observations, was used to predict the input impedance in the normal solution (artificial sea water). The changes in input impedance produced by glycerol treatment, low chloride solution, reduced pH and isotonic solutions with low ionic strength were easily interpreted in terms of the same model. The model predicts severe attenuation of the action potential if conducted electrotonically by the transverse tubules towards the center of the fibre.

Action Potentials↗
PubMed2025

Multi-omics Mendelian randomization integrating RNA-seq, eQTL and pQTL data revealed CPXM1 as a potential drug target for osteoporosis.

Osteoporosis, a prevalent skeletal disorder characterized by decreased bone mineral density and increased fracture risk, continues to be a major global health concern. Traditional treatments for osteoporosis have limited efficacy and safety profiles, highlighting the need for novel therapeutic targets. This study integrates multi-omics data, including RNA-seq, expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) data, through Mendelian randomization (MR) to identify potential drug targets for osteoporosis. By leveraging bidirectional two-sample MR analysis, we identified CPXM1 (Carboxypeptidase X, M14 family member 1) as a novel gene that is causally linked to osteoporosis risk. Through transcriptomic and proteomic validation, we demonstrate that CPXM1 was upregulated in aged bone tissues and osteoporotic conditions in both human and murine models. Gene set enrichment analysis (GSEA) revealed significant dysregulation of bone homeostasis pathways, including increased extracellular matrix degradation and suppression of osteoblast differentiation in aged mice. Furthermore, phenome-wide association studies (PheWAS) confirmed minimal off-target effects of CPXM1, reinforcing its potential as a therapeutic target. Finally, computational drug repurposing predicted several promising drug candidates, including Doxorubicin, 5-Fluorouracil, and 2-Methylcholine, which may target CPXM1 pathways for osteoporosis treatment. These findings highlight CPXM1 as a potential biomarker and therapeutic target, offering new avenues for osteoporosis therapy.

Osteoporosis↗
PubMed1977

Development of a mechanism for detection of error and retention of a graded motor response.

Several methods for developing an internal mechanism for error detection were compared to determine the extent to which a self-paced response could be acquired and retained without knowledge of results. During training, blindfolded subjects attempted to learn a positioning response under one of three conditions. One group was presented with the criterion end location by means of a stop and then required to recall the location with the stop removed. A second group moved the total distance of the track and then was instructed to replace the slide in a location representing a specific fraction of the total. A final group of subjects learned the criterion location by using post-response knowledge of results administered on each trial. Following acquisition subjects were give retention trials involving only repetition of the acquired response. The development of a strong mechanism for error detection was indicated only for those groups presented with the standard or with post-response knowledge of results. During retention trials (without knowledge of results), performance of the group required to learn the criterion by estimating a fraction of the total range was characterized by significanlty greater response biasing and less consistency than the other conditions. The findings were discussed in terms of several predictions from Adams' (1971) closed-loop theory of motor learning.

Cognition↗
PubMed1978

Neuropsychological and MMPI correlates of patients' future employment characteristics.

Previous research has suggested that patients' neuropsychological test scores correlate not only with neurologic status but also with their success in coping with some of the demands of daily living. This study investigated the utility of such laboratory test scores in predicting several vocational variables. Patients who had recieved neuropsychological evaluations were recontacted and questioned about their employment over the previous 6 mo. Of the 78 individuals who participated, 25 had been chronically unemployed. The remaining 53 were asked about job stability, hours worked, and wages earned, and were administered the Minnsota Job Requirements Questionnaire. Patients' scores on the Halstead-Reitan Battery, the WAIS and the MMPI were highly correlated with employment status (employed or chronically unemployed), income, and skills required on the jobs held. The results suggest that these tests may have clinical utility in assessing patients' employability, as well as the types of jobs for which they are suited.

Adult↗
PubMed2026

Xy-31 and Lat-1 regulate the induction of polysaccharide disintegrating genes by arabinose in Neurospora crassa OR74A.

BACKGROUND: Arabinose has been identified as a potent inducer of the cellulase regulon in filamentous fungi. However, the precise molecular mechanisms that drive this induction remain largely unknown. This study aimed to elucidate the mechanisms underlying the arabinose-induced activation of cellulase and hemicellulase enzyme clusters in the model filamentous fungus Neurospora crassa OR74A. RESULTS: Arabinose stimulates the secretion of cellulases and hemicellulases in N. crassa. While genome-wide scrutiny predicted several sugar transporters in N. crassa, expression studies under avicel and arabinan conditions indicated a notable upregulation of pentose transporters encoded by the lat-1 and xy-31 genes. The lat-1 and xy-31 deleted strains showed reduced arabinose uptake and diminished growth on arabinose media, highlighting their role in arabinose transport. Additionally, these transporter-deficient strains exhibited a significant decrease in endoglucanase and arabinase activity, which correlated with lower expression of cellulase-encoding transcripts, indicating the crucial roles of Lat-1 and Xy-31 in promoting the secretion of enzymes that degrade biomass. Consistent with these findings, overexpression of lat-1 and xy-31 in N. crassa resulted in a significant increase in cellulase secretion. CONCLUSION: We demonstrated that N. crassa has multiple pentose transporters. Furthermore, we validated that the Lat-1 and Xy-31 transporters play crucial roles in arabinose-mediated induction of polysaccharide-disintegrating enzymes in N. crassa. Both transporters are required for efficient arabinose uptake and for the subsequent arabinose-dependent induction of polysaccharide-disintegrating enzymes. Collectively, these findings significantly advance the molecular understanding of fungal hemicellulose utilization and identify key transporters that represent promising targets for enhancing fungal biomass bioconversion.

arabinose↗
PubMed1977

Treating acute acetaminophen poisoning with acetylcysteine.

A patient ingested 15.6 gm acetaminophen and sought medical attention after seven hours. At that time, her plasma acetaminophen level was 217 microng/ml. Treatment with acetylcysteine was begun eight hours after the ingestion. The clinical course of this patient was characterized by a mild illness with a minor elevation of liver enzyme values. A number of factors predicted severe hepatotoxicity for this patient had she not received treatment.

Acetaminophen↗
PubMed1976

Polarity and gradients in lepidopteran wing epidermis. II. The differential adhesiveness model: gradient of a non-diffusible cell surface parameter.

For explaining the Manduca wing gradient (Nardi & Kafatos, 1976) a model which postulates a proximo-distal gradient in cellular adhesiveness is considered. The model is based on Steinberg's (1963) differential adhesiveness hypothesis. Rosette formation in certain transposed and/or reoriented grafts can be adequately explained by this model. Several predictions, formulated by using the concept of surface free energy as a thermodynamic measure of adhesiveness, have been tested and proven correct. (1) Transposed grafts tend to assume circular forms, which are configurations of minimum free energy. (2) Because of the pressure difference expected across the interface of two cell populations with different surface free energies, cell densities increase in both distally and proximally transposed grafts. As a corollary to this rule, final size of a graft is a function of its distance from the original position. (3) Histological sections of host-graft boundaries suggest minimal cell contact at the interface. In proximal grafts placed in distal regions, cell density is far lower near the host-graft interface, as compared to the high interior density; the peripheries of distal grafts do not show this effect. (4) Juxtaposition of three different wing regions in all possible arrangements yields the expected two-dimensional configurations. (5) Differences in adhesiveness can be demonstrated by allowing two different wing grafts to interact in an essentially neutral environment (i.e. at a leg or antenna site). as the distance between two given graft regions increases, the extent of their final contact decreases. When applied to other insect systems, the model not only offers an alternative interpretation for results currently explained by diffusible substance models, but also accounts for certain features that were unexplained by other models.

Animals↗
PubMed1979

Skin reactivity in workers with and without itching from occupational exposure to glass fibres.

98 workers at a glass-wool factory were divided into three comparable groups: those with persistent troublesome itching from the fibres, those without itching, and those who had become 'hardened' to the itching. The three groups were compared with respect to the results of patch testing with glass fibres and six chemical irritants, a rubbing test with fibres, the Trafuril test, and provocation of dermographism. Anamnestic data with respect to atopy, itching from wool and synthetic fibres, sweating, and reactions to the sun were evaluated, as also was the general skin pigmentation. No statistically significant differences between the three groups were found in respect of any of these tests or factors except for a subjectively increased sensitivity in the rubbing test with fibres for the itching group. It is possible that similar itch-provocation tests might be useful for pre-employment assessment to predict severe occupational itching from glass fibres.

Allergens↗
PubMed2026

Plasma proteomics reveal SERPINA1 and CD59 as candidate biomarkers for COVID-19 severity stratification and prognosis prediction.

BACKGROUND: COVID-19 has been closely associated with coagulation abnormalities. However, existing biomarkers, including D-dimer and fibrin degradation products (FDP), exhibit limited accuracy in stratifying disease severity and predicting long-term clinical outcomes. OBJECTIVES: This study aimed to use proteomic analysis to identify plasma biomarkers associated with COVID-19 severity and prognosis, and validate their predictive utility for mortality and thromboembolic complications. METHODS: Plasma proteomic profiles were analyzed across three COVID-19 severity classes. Differential expression analysis and functional analysis were performed. Clustering analysis was used to identify proteins correlated with disease severity. Candidate biomarkers were validated in an independent cohort. Predictive performance of the biomarkers for mortality, sepsis and venous thromboembolism was evaluated using bootstrap-corrected ROC analyses and multivariable regression analyses. RESULTS: Proteomic analysis revealed progressive involvement of the coagulation and complement pathway with increasing disease severity. SERPINA1 and CD59 were identified as candidate biomarkers and exhibited significantly higher plasma levels in severe cases. Bootstrap-corrected ROC analyses demonstrated strong predictive performance: SERPINA1 achieved AUCs of 0.775 and 0.924 for 30-day and 12-month mortality, and CD59 achieved AUCs of 0.720 for sepsis; the combined model further improved prediction of 12-month mortality (AUC 0.946) and sepsis (AUC 0.904), outperforming D-dimer and FDP. Multivariable regression confirmed their independent prognostic value. CONCLUSION: This exploratory study identifies SERPINA1 and CD59 as candidate prognostic biomarkers in COVID-19, highlighting the role of coagulation and complement-related pathways in disease severity and warranting further prospective validation.

Humans↗