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PubMed1979

Regulation, professional responsibility, and market forces in the health care field.

In this paper, the author first deals briefly with the general interrelationship of market forces, government regulation, and professional responsibility. He then reviews the Federal Trace Commission's ongoing program involving competition in the health care field. Finally, he attempts to cover some prevalent concerns and what he believes are some misconceptions in the medical community about the commission's involvement in the health area.

Accreditation↗
PubMed1978

Inversion of a behavioral response in bacterial chemotaxis: explanation at the molecular level.

Certain cheU mutants of Salmonella show inverted chemotactic behavior, being repelled by attractants and attracted by repellents. Such a dramatic change in behavioral pattern would seem at first glance to require drastic and complex alterations in the sensory processing system. In fact, the behavior can be explained by a simple shift in the level of a response regulator and the subtle effects of this shift on flagellar function. Flagella can exist in either a left-handed or a right-handed structure depending on applied torsion. Wild-type cells swim smoothly by counterclockwise rotation of a left-handed helical bundle and tumble when the motors briefly reverse to clockwise rotation (normal random motility). The cheU mutation causes a shift in response regulator level relative to the critical threshold value, resulting in extended clockwise operation so that the flagella are fully converted to the right-handed helical form. These cells therefore swim smoothly by clockwise rotation of a right-handed bundle and tumble when the motor briefly reverses to counterclockwise rotation (inverse random motility). Thus, tumbling is associated with brief reversals and not with a particular sense of rotation. A wild-type cell, with its steady-state response regulator level placing it initially in normal random motility, will swim smoothly on addition of attractant, whereas a cheU mutant with inverse random motility will tumble given the same stimulus. The phenomenon illustrates the profound behavioral consequences that can result from a single mutation in a key gene.

Chemotaxis↗
PubMed2025

β1- and β2-adrenergic Receptor Haplotypes Regulate Therapeutic Responses to Placebo and the Biased Ligand β-blocker Bucindolol.

BACKGROUND: ADRB1 and ADRB2, encoding cardiac myocyte &#x3b2;1- and &#x3b2;2-adrenergic receptors (ARs) that mediate pathologic myocardial remodeling in response to chronically increased signaling, contain N-terminus haplotype variants capable of influencing agonist- or biased ligand-induced receptor internalization that uncouples canonical signaling and initiates EGFR/ERK1/2 cardioprotection. METHODS: In two heart failure (HF) clinical trial genetic substudies we investigated effects of internalizing vs. internalization-resistant ADRB1/ADRB2 haplotypes on clinical or biomarker responses to the biased ligand &#x3b2;-blocker bucindolol vs. placebo or vs. the nonbiased &#x3b2;1-antagonist metoprolol, and in haplotyped isolated human heart preparations we measured ERK1/2 activation in response to these same interventions. RESULTS: In subjects with &#x2265;3 internalizing ADRB1+ADRB2 haplotypes (6.7% subcohort) placebo treatment was associated with fewer clinical events compared to subjects with internalization-resistant haplotypes (Odds Ratio (OR) 0.28, 95% CI (0.10, 0.82)). In contrast, placebo treatment in subjects with &#x2265;3 internalization-resistant haplotypes (70% subcohort) was associated with more clinical events in comparison to subjects with internalizing haplotype counterparts (OR 1.64 (1.46, 1.84)). Bucindolol treatment was equal to placebo in the &#x2265;3 internalizing subcohort, but was superior to placebo in the internalization-resistant subcohort (bucindolol vs. placebo OR 0.49 (0.41, 0.58)). In subjects with all 4 haplotypes internalization-resistant (25% subcohort), bucindolol vs. placebo reduced time to first event rates by 62.3&#xb1;17.5% (P <0.01, 1.68&#xb1;0.34 fold > the all-haplotypes parent population and additive to 1.92&#xb1;0.58 fold when the ADRB1 haplotype contained Arg389 rather than Gly389). The same bucindolol vs. placebo pattern was observed for NT-proBNP or norepinephrine reduction vs. metoprolol. In these comparisons ADRB2 and ADRB1 haplotypes behaved similarly, and although the haplotypes differed in frequency between Black and non-Black subjects, within haplotypes there were no by-race differences in therapeutic effects. Bucindolol but not metoprolol activated ERK1/2 signaling in isolated ventricular preparations with &#x2265;3 internalization-resistant haplotypes. CONCLUSIONS: 1) Both &#x3b2;1- and &#x3b2;2-AR haplotypes regulate therapeutic responses in HF; internalizing species confer protection against clinical events in placebo-treated subjects, while in internalization-resistant haplotypes the biased ligand &#x3b2;-blocker bucindolol but not the non-biased ligand metoprolol is associated with favorable effects. 2) The biased ligand cardioprotective effect may be related to internalization-dependent or -independent ERK1/2 activation.

Beta Adrenergic Receptors↗
PubMed2026

Tumor microbial burden drives immune responses through regulation of Interferon signaling.

Tumor microbes are increasingly recognized for modulating tumor behavior and therapy responses. Intratumoral microbial burden (ITMB) analysis across cancers revealed regulation of immune pathways, and activated mast cells, mostly in colorectal (CRC) and gastric (STAD) cancers. High ITMB CRC leads to interferon regulation and is associated with improved outcomes in advanced disease. Single-cell sequencing revealed induction of interferon-related genes (IRGs) within microbes-containing human CRC. GI-luminal mismatch repair deficiency (MMRd) tumors had higher ITMB than proficient tumors (MMRp). In a rectal MMRd cohort with 100% remission after immune checkpoint blockade (ICB), tumor microbes and microbes-containing mast cells increased. In ICB-sensitive syngeneic murine MMRd tumor models, local tumor microbial depletion, impaired ICB efficacy while downregulating IFN signaling. Forced upregulation of IRGs in ADAR1-deficient cancer cells restored immunotherapy responses during microbial ablation. These data highlight dynamic interplay between ITMB, host defense, and immunogenicity which seems key to determine therapy responses.

Journal Article↗
PubMed1978

Cellular and genetic control of antibody responses in vitro. III. Immune response gene regulation of accessory cell function.

The possibility was investigated that Ir genes regulate the function of cells other than T or B cells in the primary IgM responses to the synthetic antigens trinitrophenylated poly-L-(Tyr,Glu)-poly-D,L-Ala--poly-L-Lys [TNP-(T,G)-A--L]and trinitrophenylated poly-,-(His,Glu)-poly-D, L-Ala--poly-L-Lys [TNP-(H,G)-A--L]. The primary responses of (B10 x B10.A)F(1) spleen cells to both antigens were abrogated by Sephadex G-10 passage, and restored by the addition of spleen adherent cells. The cell type in the spleen adherent cell population active in reconstituting the responses to TNP-(T,G)-A--L and TNP-(H,G)-A--L was a non-T, non-B, radiation-resistant, glass-adherent spleen cell. The responses of Sephadex G-10-passed (responder x nonresponder)F(1) spleen cells to TNP-(T,G)-A--L or TNP-(H,G)-A--L were reconstituted by spleen adherent cells from only responder strains. Spleen adherent cells from F(1) mice reconstituted the responses to both antigens. Spleen adherent cells from each of the strains tested reconstituted the non- Ir gene-controlled response to a third antigen, TNP-keyhole limpet hemocyanin. The inability of spleen adherent cells from nonresponder strains to reconstitute the responses to either TNP-(T,G)-A--L or TNP-(H,G)-A--L was not a result of active suppression induced by the presence of nonresponder adherent cells, since a mixture of responder and nonresponder spleen adherent cells reconstituted the responses to both antigens. The use of spleen adherent cells from recombinant strains demonstrated that the autosomal dominant genes controlling the ability of spleen adherent cells to function as accessory cells in the responses to TNP-(T,G)-A--L and TNP-(H,G)-A--L are located in the K or I-A regions of the responder H-2 complex, the same region(s) of H-2 as the Ir genes controlling overall in vitro and in vivo responsiveness to these antigens.

Animals↗
PubMed1978

Cyclic GMP regulation and responses of Polysphondylium violaceum to chemoattractants.

In cells of the cellular slime mold Polysphondylium violaceum an attractant, which is released during the aggregation stage, causes a transient rise of the cyclic GMP concentration. Cells of this organism develop in shaken suspensions after they have finished growth. Cell development is not accompanied by an increase in the EDTA stability of cell adhesion. Both the developmental regulation and the specificity of chemotactic responses is reflected in the light scattering patterns recorded in cell suspensions: Folic acid causes a strong response in early preaggregation cells and the Polysphondylium attractant does the same in aggregation competent cells, whereas cyclic AMP is inactive in both stages.

Cell Aggregation↗
PubMed2026

A CqbZIP55-CqPIF3 regulatory module associated with light-responsive flavonoid biosynthesis during quinoa seedling de-etiolation.

Quinoa (Chenopodium quinoa) is an emerging leafy vegetable and microgreen crop rich in health-promoting flavonoids, yet the regulatory mechanisms linking light perception to early metabolic adaptation remain unclear. Here, we integrated phenotypic, transcriptomic, metabolomic, and molecular analyses to investigate early de-etiolation responses in quinoa seedlings. Short-term light exposure rapidly promoted seedling establishment and induced transcriptional programs associated with photosynthesis, carbon metabolism, hormone signaling, and flavonoid biosynthetic gene expression, whereas metabolite changes were more limited, indicating temporal uncoupling between transcriptional activation and metabolic accumulation. Genome-wide bZIP analysis identified CqbZIP55 as a light-responsive regulator that directly binds and activates the CqCHS promoter. CqPIF3 also bound the CqCHS promoter and showed stronger transactivation activity than CqbZIP55 in transient reporter assays. Protein interaction and dual-luciferase assays showed that CqbZIP55 physically interacts with CqPIF3 and modulates CqPIF3-associated promoter activity. Exogenous quercetin upregulated CqbZIP55 and prolonged CqCHS expression, suggesting a candidate metabolite-associated reinforcement mechanism. Together, these findings support functional interplay between CqbZIP55 and CqPIF3 in light-responsive regulation of flavonoid biosynthetic gene expression in quinoa seedlings, while further quinoa-based perturbation and in vivo promoter-occupancy assays are required to establish their physiological role in planta. This study provides a framework for further investigation of photoprotective metabolic regulation in quinoa.

Chenopodium quinoa↗
PubMed2026

Proteomic Analysis of Three Independent Series of Sequential Cystic Fibrosis Strains in an International Pseudomonas aeruginosa Reference Panel Indicates Positive Selection in Late Infection Strains.

Pseudomonas aeruginosa is a highly diverse, adaptable Gram-negative bacterium that thrives in many environments and is a frequent cause of chronic opportunistic infections in people with cystic fibrosis (CF). P. aeruginosa adapts over time of colonization to facilitate chronic infection, including loss of virulence factors; however, proteomic analyses of the adaptation to chronic infection have been limited. We previously assembled and characterized an international panel of P. aeruginosa strains from diverse clinical and geographical sources, including three sets of sequential CF isolates, enabling identification of conserved adaptations linked to chronic CF lung colonization. We compared the proteomes of eight strains (three early and five late infection) to assess whether common proteomic changes emerged during colonization across the sequential isolates. We identified 11 proteins showing increased abundance in late isolates in all three series, many of which are associated with virulence, regulation of virulence, or response to hypoxia. These include CF inhibitory factor repressor (CifR); WspR; 2 two-component response regulators (PA2572 and PA3702), and transcriptional regulator (PA2551). Moreover, we identified three proteins (PA2572, PA3819, and PA5028) that showed increased abundance in all five late isolates. The probability of this being random is 5.06&#x2009;&#xd7;&#x2009;10-53 and therefore, strong evidence of positive selection. The increased abundance of PA2573 and PA3819 appears to improve the fitness of P. aeruginosa in response to antibiotics and oxidative stress. All three proteins share a tyrosine phosphorylation motif, suggesting a common regulatory mechanism. Overall, despite substantial diversity across P. aeruginosa, common adaptations occur in the CF lung.

Pseudomonas aeruginosa↗
PubMed2026

A Novel PTPN2 Isoform Differentially Regulates Immune Response.

Genome-wide association studies implicate the PTPN2 gene locus (18p11.21) in risk for several autoimmune diseases, including inflammatory bowel disease. Through genetic fine mapping, we identified the single-nucleotide polymorphism rs80262450 in the PTPN2 gene as the putative causal variant. Analysis of GTEx tissue samples and genetically engineered myeloid cell lines carrying risk and nonrisk alleles of rs80262450 demonstrated increased expression of the PTPN2 splice isoform 4 (PTPN2.4), suggesting that the rs80262450 enhances disease susceptibility by favoring production of PTPN2.4. Furthermore, we found that PTPN2.4 contains a nuclear export sequence (NES) that leads to its retention in the cytoplasm. Differential localization of PTPN2.4 isoform results in a distinct protein binding profile revealed by mass-spectrometry analysis, and its overexpression increased TNF-&#x3b1;. PTPN2.4 knockdown reduced pro-inflammatory cytokines in human macrophages. Mutations within the NES motif abolished the unique localization and function of PTPN2.4. Lastly, increased expression of PTPN2.4 was found in Crohn's disease tissues, demonstrating its involvement in the disease. Together, we identified the pathogenic isoform PTPN2.4 as a novel driver of intestinal inflammation and a potential target to attenuate inflammation in IBD.

Humans↗
PubMed1978

The identification of the component in the inner membrane of brown adipose tissue mitochondria responsible for regulating energy dissipation.

The proton conductance of the inner membrane of hamster brown adipose tissue mitochondria can be regulated in vitro by exogenous purine nucleotides, which bind to a component on the outer face of the inner membrane. This unique mechanism has been proposed to represent the molecular site of non-shivering thermogenesis in this tissue. Using a photo-affinity analogue of ATP, we have identified the nucleotide binding component as a protein of 32,000 daltons.

Adipose Tissue, Brown↗
PubMed1976

Ribosome biosynthesis in Tetrahymena pyriformis. Regulation in response to nutritional changes.

Ribosome contents of growing and 12-h-starved Tetrahymena pyriformis (strain B) were compared. These studies indicate that (a) starved cells contain 74% of the ribosomes found in growing cells, (b) growing cells devote 20% of their protein synthetic activity to ribosomal protein production, and (c) less than 3% of the protein synthesized in starved cells is ribosomal protein. Ribosome metabolism was also studied in starved cells which had been refed. For the first 1.5 h after refeeding, there is no change in ribosome number per cell. Between 1.5 and 2 h, there is an abrupt increase in rate of ribosome accumulation but little change in rate of cell division. By 3.5 h, the number of ribosomes per cell has increased to that found in growing cells. At this time, the culture begins to grow exponentially at a normal rate. During the first 2 h after refeeding, cells devote 30-40% of their protein synthetic activity to ribosomal protein production. We estimate that the rate of ribosomal protein synthesis per cell increases at least 80-fold during the first 1-1.5 h after refeeding, reaching the level found in exponentially growing cells. This occurs before any detectable change in ribosome number per cell. The transit time for the incorporation of these newly synthesized proteins into ribosomes is from 1 to 2 h during early refeeding, whereas in exponentially growing cells it is less than 30 min. The relationship between ribosomal protein synthesis and ribosome accumulation is discussed.

Animals↗
PubMed1976

H-2 compatibility requirement for virus-specific T-cell-mediated cytolysis. Evaluation of the role of H-2I region and non-H-2 genes in regulating immune response.

Lymphocytic choriomeningitis virus (LCMV) and ectromelia virus-specific T-cell-mediated cytotoxicity was assayed in various strain combinations using as targets peritoneal macrophages which have been shown to express Ia antigens. Virus-specific cytotoxicity was found only in H-2K- or D-region compatible combinations. I-region compatibility was not necessary nor alone sufficient for lysis. Six different I-region specificities had no obvious effect on the capacity to generate in vivo specific cytotoxicity (expressed in vitro) associated with Dd. Low LCMV-specific cytotoxic activity generated in DBA/2 mice was caused by the non-H-2 genetic background. This trait was inversely related to the infectious virus dose and recessive. Non-H-2 genes, possibly involved in controlling initial spread and multiplication of virus, seem to be, at least in the examples tested, more important in determining virus-specific cytotoxic T-cell activity in spleens than are Ir genes coded in H-2.

Animals↗
PubMed1976

Adenylyl cyclase activities in ovarian tissues. II. Regulation of responsiveness to LH, FSH, and PGE1 in the rabbit.

We conducted a study to determine whether a decline in the capacity of preovulatory follicles to accumulate cAMP in response to in vitro LH exposure, reported by Marsh et al. (1), is due to direct desensitization of the LH-hCG-responsive adenylyl cyclase (AC) system. Enzyme activity was determined in the absence and in the presence of 10 mug/ml of LH, FSH, and prostaglandin (PG) E1 in homogenates prepared from Graafian follicles dissected before and at various times after rendering them preovulatory either by mating (endogenous LH release) or by injection of hCG (100 IU/3.5-4.5 g rabbit, iv). Both of these treatments resulted in desensitization of the AC to LH and FSH stimulation, so that by the time of ovulation these responses were absent. hCG-induced desensitization was rapid (50% loss of LH-stimulated activity was obtained within 5 min of injection), was dose-dependent, requiring an ovulatory dose; was selective for LH- and FSH-stimulated activity, being without effect on basal and PGE1 as well as NaF-stimulated activities; and was induced specifically by LH (mating) and hCG-FSH and PRL being without effect. Desensitization of follicular AC does not seem to be mediated by PG, for doses of indomethacin that inhibited ovulation did not interfere with the loss of LH responsiveness. The incubation in vitro of dissected Graafian (estrous) follicles with LH (2 h) also resulted in desensitization to LH stimulation and indicated that this phenomenon was due to a direct effect of LH on the follicles and was not mediated by hormones derived from other endocrine structures. Newly formed corpora lutea (CL) in either pregnancy or pseudopregnancy (PSP) developed a new AC system that was highly responsive to LH and less responsive to FSH and PGE1. This new system persisted for the duration of pregnancy and PSP, and became inactive with regression of CL. The prolongation of PSP by hysterectomy was accompanied by the persistence of an active LH-responsive AC system. The injection of ovulatory doses of hCG into 6-day PSP rabbits produced, within 2 h, a 50% desensitization of the luteal AC systems to LH stimulation. After day 10 of pregnancy, the levels of LH-stimulated AC activity in CL and the levels of progesterone in serum, reported by Challis et al. (2), were found to parallel each other, suggesting that this enzyme activity may be a physiologic regulatory step in progesterone synthesis by the normal CL throughout most of the animal's pregnancy. This finding is discussed in the light of compelling evidence that estrogens are luteotrophic in the rabbit.

Adenylyl Cyclases↗
PubMed1976

Adenylyl cyclase activities in ovarian tissues. III. Regulation of responsiveness to LH, FSH, and PGE1 in the prepubertal, cycling, pregnant, and pseudopregnant rat.

In the ovaries of prepubertal rats, responsiveness of adenylyl cyclase (AC) to LH, FSH, and PGE1 is acquired at day 10, coinciding with the appearance of the ability to produce steroids in response to gonadotrophins. The activity and responsiveness of AC on day 11 were similar to those at puberty on day 40 and relatively stable in between. In the follicles of the cycle, the responsiveness of AC to LH and FSH was poor (ca 2-fold stimulation) on metestrus and diestrus, and became high (ca 10-fold stimulation) between 1000 h of diestrus and 1000 h of proestrus. Thereafter, the system slowly became desensitized to LH and FSH, being unresponsive by the morning of estrus. Nembutal injected at 1230 h and again at 1500 h on proestrus blocked ovulation and prevented the decline in LH- and FSH-stimulated AC activity. In the CL of the cycle, the AC was unresponsive to LH on day 1 (estrus), became responsive by the morning of day 2 (metestrus), and maintained responsiveness throughout that day. Thereafter, the responsiveness and basal AC activity declined rapidly. In the CL of pregnancy, LH-stimulated AC was indistinguishable from that of the CL of the cycle during days 1 and 2, then increased steadily until day 9, showing a transient decrease on days 10 and 11, followed by a sharp rise to maximal activity on days 15 and 16. Thereafter, activity declined as parturition approached. In the CL of pseudopregnancy (PSP), LH-stimulated AC was very similar to that of the CL of pregnancy during the first 11 days. Thereafter, it decreased coincident with the termination of PSP. Injections of PRL (100 mug SC twice daily, from metestrus through estrus, and from proestrus through proestrus) or estradiol-17 beta (20 mug, SC at 1230 h on metestrus) resulted in "rescue" of the CL-AC system, which remained at metestrus levels when measured on the days of expected proestrus or estrus. Injections of pregnant mare serum gonadotrophin into prepubertal rats at day 26 (3 IU, iv), induced by day 28 a highly responsive AC system in follicles, with activities equivalent to those found in Graafian follicles on proestrus. By day 29, synchronous ovulation had occurred with a concomitant loss of LH-stimulated AC such as seen in the 1-day-old CL of mature rats. Our results suggest that the LH-sensitive AC may be indicative of the final development of ovulability of the follicles, and that it may correlate with the functional capacity of CL during various reproductive stages of the rat.

Adenylyl Cyclases↗
PubMed2026

Engineering cold stress resilience in capsicum annuum through functional genomics and precision breeding.

This review synthesizes the molecular mechanisms of cold tolerance in pepper, integrating multi-omics data,genome editing, and precision breeding strategies to accelerate the development of cold-resilient cultivars. Cold stress is a significant environmental factor that affects the growth, productivity, and fruit quality of Capsicum annuum by impairing membrane integrity photosynthesis and cellular redox homeostasis. Although pepper has several endogenous cold-responsive regulators such as CaNAC035 and CabHLH035, along with antioxidant defense systems, its cold tolerance remains limited due to low transcriptional activation of key regulators, functional redundancy among cold-responsive genes, and the polygenicity of cold tolerance. These complexities, combined with low genetic diversity and linkage drag, have hindered the improvement of cold-resistant cultivars through conventional breeding. This review brings together the recent progress in understanding the molecular mechanisms of cold stress perception, signal transduction, transcriptional regulation, metabolic reprogramming, and phytohormone interactions in pepper. Precision Breeding 2.0 is a new innovation that combines the integration of multi-omics-based target identification with next-generation genome-editing techniques, allowing precise and multiplex engineering of complex and interconnected regulatory networks instead of single genes. We cover new approaches such as engineering the DREB/CBF pathway, allele-specific editing and targeted disruption of negative regulators to enhance the pathway(s) involved in cold response. Moreover, we propose a roadmap for integration of transcriptomics, proteomics, metabolomics, high-throughput phenomics, and speed breeding to accelerate the identification, validation, and deployment of superior alleles to boost cold tolerance. This review provides a foundation for developing climate-resilient pepper cultivars by connecting functional genomics with precision genome engineering approaches to maintain productivity under variable environmental conditions.

Capsicum↗
PubMed1979

Regulation of the immune response by macrophages.

Regulation of the immune response by macrophages was studied with cellular resistance to Listeria monocytogenes as parameter. The use of agents which suppress macrophage activity during the induction-phase of immunity enabled the induction of protective immunity with killed listeria. Fractionation of the cell content of listeria yielded an RNA'se sensitive fraction which in a dose of 300 ng and in combination with the cationic surfactant dimethyl dioctadecyl ammonium bromide induced protective immunity against listeria.

Adjuvants, Immunologic↗
PubMed2025

Multilevel regulation of c-di-GMP biosynthesis by cAMP signaling increases Shigella sonnei fitness and pathogenicity in response to bile salts.

It was previously demonstrated that intestinal pathogens have evolved different mechanisms to enhance their infection and colonization in the intestines of hosts. However, it is unclear how Shigella effectively survives in the presence of bile salts. Here, we report that the biofilm formation and pathogenicity of S. sonnei are induced by primary bile salts through the two-component system EvgS/EvgA. The response regulator EvgA controls the transcription of the cyclic AMP synthase-encoding gene. Furthermore, the effector protein CRP of the cyclic AMP (cAMP) signal not only positively controls the transcription of ydeH, a gene encoding cyclic di-GMP (c-di-GMP) synthase, but also forms a complex with YdeH to improve its catalytic production of c-di-GMP. Additionally, interacting with YdeH enhances the ability of CRP to bind to the promoter of ydeH. Our work provides insights into how S. sonnei utilizes cascade amplification of c-di-GMP to promote fitness and pathogenicity in response to primary bile salts.

Cyclic GMP↗