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PubMed2025

Defining the host dependencies and the transcriptional landscape of RSV infection and bystander activation.

Respiratory syncytial virus (RSV) is a globally prevalent pathogen, causes severe disease in older adults, and is the leading cause of bronchiolitis and pneumonia in the United States for children during their first year of life [1]. Despite its prevalence worldwide, RSV-specific treatments remain unavailable for most infected patients. Here, we leveraged a combination of genome-wide CRISPR knockout screening and single-cell RNA sequencing to improve our understanding of the host determinants of RSV infection and the host response in both infected cells, and uninfected bystanders. These data reveal temporal transcriptional patterns that are markedly different between RSV infected and bystander activated cells. Our data show that expression of interferon-stimulated genes is primarily observed in bystander activated cells, while genes implicated in the unfolded protein response and cellular stress are upregulated specifically in RSV infected cells. Furthermore, genome-wide CRISPR screens identified multiple host factors important for viral infection, findings which we contextualize relative to 29 previously published screens across 17 additional viruses. These unique data complement and extend prior studies that investigate the proinflammatory response to RSV infection, and juxtaposed to other viral infections, provide a rich resource for further hypothesis testing.

CRISPR screen↗
PubMed2025

Growth-limiting drought increases sensitivity of Asian rice (Oryza sativa) leaves to heat shock through physiological and spatially distinct transcriptomic responses.

Growth-limiting droughts (GLD) impair tissue expansion and delay developmental transitions but are often not considered as stressors, as many physiological traits are only slightly altered relative to well-watered counterparts. Concurrently, cell size, biochemical makeup, and transcriptome profiles vary along the leaf blade in accordance with the partitioning of distinct functions to spatially defined regions of the leaf. This suggests that because different parts of the leaf have underlying differences in their transcriptome profiles, they might respond to GLD in distinctive ways. Moreover, how antagonistic stressors influence physiology and gene expression in different zones of leaves is an open question. In this study, we profiled growth, anatomy, and gas exchange in Asian rice (Oryza sativa) leaves developed in well-watered and GLD conditions, with or without a secondary heat shock. We dissected leaves into seven equal-length segments for transcriptome analysis in these conditions. We hypothesized that GLD would make the leaves more sensitive to heat shock and would disrupt the underlying heterogeneity of the leaf transcriptome. GLD plants were more strongly affected by heat shock with respect to gas exchange and the number and types of genes that were differentially expressed and that these differences varied along the leaf blade. We developed an eFP browser tool with these data to facilitate exploration and hypothesis testing. These findings show that even mild drought treatments are sufficient to impact responses to antagonistic stressors and that substantial within-organ variance exists with respect to stress responses.

Oryza↗
PubMed1978

Infantile stimulation induces brain lateralization in rats.

The hypothesis tested was that the effects of early experiences are asymmetrically distributed in the two brain hemispheres. Litters were either handled or not handled between birth and weaning, and the weanlings were reared in either laboratory cages or enriched environments between 21 and 50 days. When approximately 135 days old, animals within each of the four treatment groups had a right neocortical ablation, a left neocortical ablation, a sham operation, or no surgery. About 1 month later, all animals were given the open-field test for emotionality and exploratory behavior. Ablating either the right or left neocortex increased the activity scores of nonhandled controls, but there was no evidence of lateralization. However, the groups handled in infancy did show lateralization. Ablating the left brain did not significantly increase activity, but ablating the right brain caused extreme scores: handled rats without enrichment experience were the most active, and handled rats also placed into the enriched environment had near-zero scores in the open field.

Animals↗
PubMed1976

Cerebral circulation and norepinephrine: relevance of the blood-brain barrier.

The systemic administration of norepinephrine has minimal effects on the cerebral circulation, perhaps due to blood-brain barrier mechanisms. To test hypothesis, the cerebrovascular effects of norepinephrine beyond the blood-brain barrier were studied in anesthetized baboons, Intraventricular norepinephrine (40 mug/kg) resulted in significant increases in cerebral blood flow (40%), cerebral oxygen consumption (21%), and cerebral glucose uptake (153%). Intracarotid hypertonic urea opens the blood-brain barrier by osmotic disruption; Consequent to hypertonic urea, the intracarotid infusion of norepinephrine, 50 ng/kg-min, significantly increase cerebral blood flow (49%), cerebral oxygen consumption (21%), and cerebral glucose uptake (76%), It appears probable that the cerebrovascular responses to norepinephrine are dependent on the integrity of the blood-brain barrier; It is likely that the increase in cerebral blood flow, associated with norepinephrine when it bypasses the barrier, is secondary to an increase in cerebral metabolism.

Animals↗
PubMed1979

Effects of ouabain on insulin release, adenosine 3',5'-monophosphate and guanine 3',5'-monophosphate in pancreatic islets.

Isolated pancreatic islets of noninbred ob/ob mice were used to test the hypothesis that adenylate cyclase responds to changes of the transmembrane milieu or electric field in intact beta-cells. In the presence of a phosphodiesterase inhibitor, ouabainstimulated both the release of insulin and the islet content of cAMP. Ouabain had no noticeable effect on the islet content of cGMP. These results support the hypothesis at test. However, because ouabain also had some stimulatory effect on cAMP in islet homogenates, a direct action of ouabain on adenylate cyclase cannot be ruled out.

1-Methyl-3-isobutylxanthine↗
PubMed1979

Statistical approaches to toxicological data.

Statistical techniques as applied to toxicological data are discussed. Issues concerning statistical hypothesis testing and combining studies are considered as well as design of experiments. The problems surrounding risk assessment are also mentioned.

Animals↗
PubMed1979

Multifactorial genetic models for quantitative traits in humans.

Quantitative traits measured in human families can be analyzed to partition the total population variance into genetic and environmental components, or to elucidate the genetic mechanism involved. We review the estimation of variance components directly from human pedigree data, or in the form of path coefficients from correlations between pairs of relatives. To elucidate genetic mechanisms, a mixed model that allows for segregation at a major locus, a polygenic effect and a sibling environmental correlation is described for nuclear families. In each case appropriate likelihoods are derived as a basis, using numerical maximum likelihood methods, for parameter estimation and hypothesis testing. A general model is then described that allows for several familial sources of environmental variation, assortative mating, and both major gene and polygenic effects; and an algorithm for calculating the likelihood of a pedigree under this model is indicated. Finally, some of the remaining problems in this area of biometric analysis are pointed out.

Genetic Variation↗
PubMed1977

Clinical evaluation of vertigo.

In attempting to outline the clinical evaluation of these patients with vertigo we have discussed examples which range in order from benign self-limited disease to those requiring emergency surgery or extensive diagnostic evaluation. We sought also to illustrate how the logic of hypothesis testing is generally employed by clinicians in approaching this or other diagnostic problems. The examples were chosen to illustrate the indications for, as well as the limitations of, the various diagnostic modalities--caloric testing, electronystagmography, audiometric testing, roentgenographic and nuclear medicine procedures--which may be employed by the clinician. Most of the skills discussed in our paper, though traditionally accorded to the fields of neurology and otolaryngology, would seem to be fundamental for any general physician, while the problem of vertigo is an example of how common ambulatory problems may require knowledgeable approach to sort self-limited from more serious illnesses as well as to utilize procedures with purpose and efficiency.

Adult↗
PubMed1978

Effect of endotoxin on glucose uptake by the isolated forelimb of the dog.

Recent research has demonstrated that an increase in glucose utilization by skeletal muscle occurs in hemorrhagic shock. It is conceivable that the hypoglycemia of gram-negative septic shock is, in part, due to increased glucose utilization by peripheral tissues. The hypothesis tested in this study was that there is an increase in glucose uptake by the isolated innervated and/or denervated forelimb of the dog subjected to endotoxin shock. Results indicate that endotoxin does not affect a net increase of glucose uptake by the isolated forelimb. No increase in uptake occurred when blood glucose concentration was normal. However, when endotoxin hypotension induced a significant hyperglycemia or when arterial glucose concentration was elevated by glucose administration an apparent increase in forelimb glucose uptake occurred. It is concluded that endotoxin does not increase the uptake of glucose by skin and muscle except that it causes hyperglycemia secondary to increased sympathoadrenal discharge in the shock state. Thus, if the dog becomes sufficiently hyperglycemic, an apparent increase in glucose uptake occurs, probably because of accumulation of glucose in the interstititial space of skin and muscle.

Animals↗
PubMed1976

Test of the hypothesis that embryonic face shape is a causal factor in genetic predisposition to cleft lip in mice.

It was proposed that embryonic face shape is one of the quantitative variables underlying the threshold trait, cleft lip. To test the hypothesis several facial dimensions were measured in photographs of embryos at an early stage of formation of the face in 3 lines of mice. The lines had been selected from one original population using frequency of cleft lip induced by 6-aminonicotinamide as the selection criterion. Line L was susceptible to spontaneous cleft lip; lines M and C were not. Line L had a significantly smaller distance between the nasal pits than the other 2 lines, but did not differ in overall head size. A trend towards reduced angle between the medial nasal processes in the L line was noted, though this was not statistically significant. These results were predicted by the face-shape hypothesis.

Animals↗
PubMed1978

Pancreatic excretion test and barrier hypothesis in progression of chronic pancreatitis.

Simultaneous data of the pancreozymin-secretin test and the pancreatic excretion test with 5,5-dimethyl-2,4-oxazolidinedione DMO) were reported for 50 patients with chronic pancreatitis. The pancreozymin-secretin test was abnormal in 90% of the patients, while the pancreatic DMO excretion test showed abnormality in 100% of the patients. The dynamic process of pancreatic excretory dysfunction is discussed. Over 60% of patients with low to moderate grade chronic pancreatitis showed a discordant pattern of decreased DMO output with normal bicarbonate concentration or normal volume flow. Approximately 96% of patients with advanced grade chronic pancreatitis had a excretory pattern of decreased DMO output with low bicarbonate concentration and decreased volume flow. These findings may further develop a barrier hypothesis in chronic pancreatitis. In the early stage of chronic pancreatitis, when functional capacity of the duct is preserved fairly well, the extraductal barrier to the rapid DMO diffusion into the ducts (diffusion barrier) may be primarily responsible for impaired pancreatic DMO excretion. With progression of chronic pancreatitis, the intraductal barrier (outflow barrier) may become pronounced and precipitate pancreatic excretory dysfunction for DMO. The concept of pancreatic barriers may well serve to systematize major histologic alterations observed in chronic pancreatitis.

Adult↗
PubMed1978

Retrieval from long-term memory in presenile dementia:two tests of an hypothesis.

Recent experimental studies have suggested that patients with presenile dementia might have diffculty in retrieving information from memory as well as a reduced ability to acquire new information. The hypothesis that this retrieval difficulty might be due to an inability to inhibit the recall of irrelevant information was tested by two investigations. Free recall data failed to give clear support for the hypothesis but a prediction based upon recognition testing was confirmed.

Dementia↗
PubMed1977

A test of the hypothesis that the rate of fall in glucose concentration triggers counterregulatory hormonal responses in man.

The hypothesis that the rate of fall in glucose concentration triggers counterregulatory hormonal responses was tested in five subjects following one hour of sustained hyperglycemia. Despite a rapidly falling blood glucose concentration, no increase in plasma growth hormone, cortisol, glucagon, or catecholamines occurred as long as the blood glucose concentration remained above fasting levels. Plasma growth hormone, cortisol, and catecholamines were not released until the mean blood glucose reached 28 mg./100 ml., 39 mg./100 ml., and 39 mg./100 ml., respectively, below the fasting level. Plasma glucagon was suppressed during the period of hyperglycemia. As the blood glucose concentration fell below basal levels, a progressive increase in glucagon occurred. Plasma glucagon returned to fasting values when the nadir in blood glucose was attained. During the period of rapidly falling blood glucose, only plasma insulin showed any change; its response lagged behind the decline in blood glucose. By the time the fasting glucose level was attained, the plasma insulin was still almost three times the basal level. We concluded that under our experimental conditions the rate of fall in blood glucose and the degree of hypoglycemia achieved is primarily determined by the plasma insulin concentration.

Blood Glucose↗
PubMed1978

Psychological construing and thought disorder: another test of the 'difficulty' hypothesis.

Two versions of the grid test of thought disorder were derived which used similar elements, and were of equal difficulty, but one of which employed psychological, and the other non-psychological, constructs. They were administered to thought-disordered schizophrenic patients and to psychiatric and normal controls. On one measure (consistency), although not on the other (intensity), the results strongly supported the hypothesis that thought-disordered patients are maximally disordered in the area of psychological construing. The results support those of an earlier study (McPherson et al. 1975) and are compatible with those theories which postulate a role for social factors in the aetiology of thought disorder.

Adult↗
PubMed1978

Testing the lipid hypothesis. Clinical trials.

It is generally accepted that we still lack a conclusive answer, to whether lowering of the lipid level will prevent the development or reverse the progression of coronary atherosclerosis. Multiple risk factor intervention trials now have the merit of addressing themselves to probable and practical needs for intervening on several of the major risk factors to obtain the maximum impact on populations at risk.

Cholesterol, Dietary↗
PubMed1978

The children of Mexican-American migrant workers: a population at risk?

The present study assessed intellectual, academic, and emotional strengths and weaknesses for a group of Mexican-American children of migrant farm workers. In order to test the vulnerability hypothesis, the test profiles of these children were contrasted with those of two groups of black children with similar demographic makeup. The children of one group (Clinical Black) had been referred previously for a psychological consultation while the children of the other (Nonreferred Black) had not. Across dependent measures, between-groups contrasts tended to describe the scores of the Migrant children as similar to those of the Clinical Black children and significantly below those of the Nonreferred Black children. The findings suggested specific intellectual, academic, and emotional vulnerabilities of the Migrant children and demonstrated the need to develop ameliorative programs for these children.

Achievement↗