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Results for “transient HR enhancement”

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PubMed2026

A CRISPR-Cas9 Toolkit Enabling Tunable Integration and Transient Homologous Recombination Enhancement in Yarrowia lipolytica.

Although the oleaginous yeast Yarrowia lipolytica is a promising microbial cell factory, its application remains constrained by inefficient homology-directed repair (HDR) and a lack of precise genomic integration tools. To address these limitations, we developed a comprehensive genetic toolkit featuring three synergistic advancements. First, we systematically identified 55 neutral integration sites with tunable expression profiles, enabling stable, position-independent gene integration with predictable transcriptional output across a 12.88-fold dynamic range. Second, we established a dual-readout high-throughput screening platform combining colony morphology analysis with hrGFP fluorescence. This approach accurately measures locus-specific homologous recombination (HR) efficiency while eliminating false positives by dominant non-homologous end joining (NHEJ). Third, we engineered a transient HR enhancement system by fusing the Sae2 exonuclease to Cas9 via a flexible (GGGGS)3 linker. This fusion significantly boosts HR efficiency and surpasses the cleavage activity of unmodified Cas9 without introducing permanent genomic modifications or compromising cellular fitness. Finally, HR efficiency for single-gene integration was increased from 46.5% to 77.5% while the dual-locus editing efficiency reached 64.1% when using 500-bp homology arms, and the engineered strains demonstrated improved genetic stability compared to those with constitutive HR enhancement.

Yarrowia↗

PubMed1976

An analysis of the mode of action of carbachol on the chick biventer cervicis nerve--muscle preparation.

The mechanism of contracture evoked by carbachol in the isolated chick biventer cervicis nerve--muscle preparation was studied. At concentrations lower than 11 muM, carbachol progressively induced contracture at a rate much slower than did acetylcholine. A spontaneous increase of the response to carbachol, but not to acetylcholine, was observed 2-4 hr after isolation of the muscle. By contrast, no change of the response occurred in the denervated muscle. Anticholinesterase treatment shifted the dose-response curve for carbachol markedly to the left as far as the contracture attained after 4-6 min incubation was concerned. The shift was much less marked for the dose-response curve plotted against the initial rate of response defined as the contracture obtained after 1 min incubation. No enhancement of response was detected by inhibition of acetylcholinesterase in the denervated muscle. beta-Bungarotoxin which blocked neuromuscular transmission within 30 min, caused a transient enhancement of the response to carbachol. After 2-3 hr treatment, however, the spontaneous increase of response to carbachol was counteracted by the toxin. No potentiation of the response by anticholinesterase agents was observed after toxin treatment. When added in the presence of physostigmine or echothiophate, beta-bungarotoxin reduced the response to carbachol to the control level in 2 hr. The response to carbachol in the muscle treated with alpha-bungarotoxin and washed subsequently was also not potentiated by anticholinesterase treatment. Repetitive nerve stimulation in the presence of hemicholinium-3 caused a neuromuscular blockade but did not appreciably antagonize the response to carbachol more than that to acetylcholine either in the absence or presence of physotigmine. When calcium ion in the medium was decreased from 2.7 to 0.54 mM, ther response to nerve stimulation was nearly completely inhibited, but the response to carbachol was not affected and could still be potentiated by anticholinesterase. It is concluded that carbachol has both direct and indirect effects on the chick biventer cervicis muscle. At a low concentration, particularly in the presence of an anticholinesterase and if sufficient time of incubation is allowed, the indirect effect caused by release of acetylcholine may become more prominent than the direct action on the post-synaptic receptor. Both the mechanism and the store of acetylcholine for this indirect action appear to be different from those for the nerve impulse.

Acetylcholine↗

PubMed1978

Quantitative methods in the evaluation of thallium-201 myocardial perfusion images.

Methods have been developed for on-line computer enhancement of a scintillation camera's myocardial images and for a graphical presentation showing relative thallium-201 activity in the myocardium. Enhancement uses fast Fourier transform techniques. The methods have been applied to multiple images obtained after stress and 4--5 hr rest. Patients with myocardial infarction and/or transient ischemia were evaluated and typical examples are presented.

Computers↗

PubMed1977

Cell wall extension in Nitella as influenced by acids and ions.

The giant internode cells of Nitella axillaris exhibit acid-induced growth similar to that found in higher plants. The threshold pH is 4.5, with a maximum at 3.5. The acid growth effect is transient, lasting no more than 32 min. Extensibility measurements of isolated cell walls showed a similar pattern of acid enhancement. Prolonged boiling in water (12 hr) only partially inhibited the acid-induced wall extensibility and actually increased the extensibility at pH 6. It was concluded that physical, rather than enzymatic, processes were responsible for acid-enhanced continuous extension ("creep") in Nitella walls. A complex cation-sensitive mechanism that affects extensibility was also characterized. Among the stimulatory (wall-softening) cations, divalents were generally more effective than monovalents, with magnesium being the most stimulatory. The inhibitory (wall-hardening) cations included divalents and trivalents, aluminum being the most inhibitory. Ionic effects on extensibility were even less sensitive to prolonged boiling in water than acid effects.

Cations, Divalent↗

PubMed1979

Human monocyte-lymphocyte interaction and its enhancement by levamisole.

We investigated the role of monocyte-lymphocyte interaction in the transformation of human peripheral blood lymphocytes by the mitogen concanavalin A (Con A). Human monocytes were separated from lymphocytes and were transiently exposed to Con A. The Con A-pretreated monocytes were able to subsequently bind autologus lymphocytes by a process that was selective for T cells. This interaction required the initial presence of Con A at the monocyte surface, and became independent of surface bound ligand after 72 hr. Levamisole, an agent thought to facilitate the participation of monocytes in the cellular immune response, enhanced the binding of lymphocytes to monocytes at low concentration of Con A (5--10 micrograms/ml). Levamisole did not lead to mitogen independent lymphocyte binding. The association between lymphocytes and Con A-pretreated monocytes resulted in the mitogenic transformation of lymphocytes in the absence of soluble Con A in the medium. These results suggest that, in addition to any possible soluble mediators, direct lymphocyte-monocyte contact is required for optimal mitogenic transformation. This T-cell-monocyte interaction over time becomes independent of cell-surface mitogen. The ability of levamisole to enhance this interaction may explain levamisole's capacity to stimulate lymphocyte proliferation.

Adult↗

PubMed1978

Effect of tumor promoters on the response of cultured embryonic chick ganglia to nerve growth factor.

The tumor-promoting plant diterpene 12-O-tetradecanoyl-phorbol-13-acetate (TPA) inhibits nerve growth factor (NGF)-provoked neurite outgrowth in cultured embryonic chick sensory and sympathetic ganglia. Other plant diterpenes that are tumor promoters on the mouse skin carcinogenesis system also inhibit ganglia response to NGF, but structurally related nonpromoting compounds are inactive. There is no evidence that the inhibitory effect of TPA is due to cytotoxicity. In fact, it appears that TPA can enhance the survival of neuronal and nonneuronal cells in culture. Although neurite outgrowth is prevented, established neurites do not retract in the presence of TPA. After 24 hr, ganglia can slowly overcome the block, even in the presence of fresh TPA; thus, inhibition is transient. The concentration of NGF that does induce a half-maximal neurite outgrowth response in sensory ganglia is approximately 0.6 X 10(-11) M. The antagonism of NGF by TPA is dose dependent and apparently noncompetitive. TPA concentrations that extensively inhibit neurite outgrowth do not affect the amount of 125I-labeled NGF bound to specific sites on dissociated dorsal root ganglion cells, which supports the contention that TPA acts at a stage beyond the initial interaction of the factor with its receptive site.

Animals↗

PubMed1975

Behavioral activities and cardiovascular functions. II. Effects of sustained static work in squirrel monkeys.

Mean arterial blood pressure (MABP) and heart rate (HR) were measured in unanesthetized squirrel monkeys trained to sustain for 20 seconds a forceful downward pull on an inverted T-bar. The MABP change during the strong static contraction of skeletal muscles involved in the pull was polyphasic, consisting of a brief initial rise and fall followed by a rise to a level above resting values which was sustained. At the end of the pull, the pressure fell transiently below the resting level. HR was elevated throughout the pull, returning towards the resting value in the minute following the pull. After hexamethonium, which reduced the resting MABP from about 120 mm Hg to about 80 mm Hg, the fall in MABP following the initial rise was enhanced, the level sustained through the pull was less than the resting level, and MABP fell still lower following the end of the pull. Phentolamine caused similar changes. Hexamethonium reduced the resting HR and abolished the HR changes during pulling. Raising the MABP after hexamethonium with phenylephrine further enhanced the falls in pressure during and following the pull. It is concluded that the polyphasic MABP changes to pulling involve direct mechanical effects of contracting skeletal muscle (responsible for the initial rise and contributing to the sustained rise), sympathetic vasoconstrictor discharge (contributing to the sustained rise and opposing the falls in MABP during and after the pull) and vasodilatation in active skeletal muscle (opposing the sustained rise during the pull and causing the fall after the pull). Although the participation of these factors in cardiovascular responses to exercise are generally well recognized, comparison of the patterns of response in rhesus and squirrel monkeys reveals large quantitative differences in the contributions of different factors and emphasizes again the caution that should be exercised in inferring direct environmental, emotional or conditioning effects on cardiovascular function.

Acoustic Stimulation↗

PubMed1979

Regulation of the murine IgE antibody response. I. Characterization of suppressor cells regulating both persistent and transient responses and their sensitivity to low doses of X-irradiation.

Anti-ovalbumin (OA) IgE antibody responses were measured in B6D2F1 mice as a function of time and antigen dose. One hundred to 200 microgram of OA in Al(OH)3 elicited transient responses, whereas 1 to 10 microgram of OA in Al(OH)3 elicited persistent anti-OA IgE responses of high titer. T cells isolated from the spleens of mice mounting either a persistent or a transient response strongly suppressed primary anti-DNP IgE responses in unirradiated recipient mice that were immunized with DNP-OA in Al(OH)3; it was, therefore, concluded that suppressor T cells (Ts cells) were activated during both the persistent and transient IgE responses. Nevertheless, in the present study it was not possible to completely rule out the contention that IgG antibodies may also have been suppressing the IgE response. With a modified adoptive transfer system, it was shown that these Ts cells were sensitive to low doses (250 R) of x-irradiation. The suppressive activity of long-term OA primed cells was also shown to be markedly enhanced when cultured for 24 hr with soluble OA; this finding was interpreted to indicate the presence of memory suppressor cells.

Animals↗

PubMed1978

Depression of sympathetic preganglionic neurons by clonidine: evidence for stimulation of 5-HT receptors.

In unanesthetized spinal cats, clonidine HCl (5-50 microgram/kg, i.v.) rapidly and markedly depressed excitatory transmission through two spinal pathways to sympathetic preganglionic neurons. Depression through either pathway was dose-dependent and persisted for more than 3 hr but could be rapidly antagonized at any stage by tolazoline HCl in a dose-ratio of about 1:100. The two spinal pathways were also depressed transiently by L-dopa and for prolonged periods by 5-HTP; both precursors were shown to act by releasing 5-HT from bulbospinal 5-HT terminals and their depressant effects were also antagonized by tolazoline. In the absence of 5-HT-induced depression, L-dopa only enhanced transmission through both pathways by inducing release of catecholamines from bulbospinal NE terminals. These results indicate that clonidine depresses sympathetic activity by stimulating inhibitory 5-HT receptors on sympathetic preganglionic neurons, a mechanism that adequately accounts for its central vasodepressor effect.

Afferent Pathways↗

PubMed2026

Human papillomavirus viral load as promising surrogate biomarker of cervical cancer risk and clinical outcome.

INTRODUCTION: Persistent high-risk human papillomavirus (HR-HPV) causes cervical precancerous lesions and cancer. While molecular HPV DNA testing offers superior sensitivity over cytology as a primary screening method, its limited specificity leads to unnecessary follow-up procedures. Therefore, identifying surrogate biomarkers to distinguish transient infections from clinically relevant, persistent ones is essential for improving risk stratification. A comprehensive literature search across PubMed/MEDLINE, Embase, Scopus, and Web of Science databases up to December 2025 identified studies evaluating HR-HPV viral load in cervical lesion progression. AREAS COVERED: Oncogenic HPV viral load, the quantity of HPV genomes in a sample, is a promising biomarker. Levels correlated positively with HR-HPV persistence, increasing the risk of high-grade lesions and invasive cervical cancer. Furthermore, quantification provides prognostic information regarding disease severity, therapeutic response, and post-treatment recurrence. EXPERT OPINION: Recent standardization and validation of multiplex real-time PCR techniques supports integrating HPV viral load into clinical pratice. Incorporating viral load assessment into screening and management algorithms could significantly enhance diagnostic precision, enable personalized follow-up, and guide therapeutic decisions for women with HR-HPV-associated cervical disease. Refining these protocols will ultimately minimize over-treatment while ensuring rigorous monitoring for high-risk patients.

Humans↗

PubMed1977

Acute hemodynamic alterations after aortic valve replacement with the glutaraldehyde-treated porcine heterograft prosthesis.

Twenty-two patients underwent aortic valve replacement for acquired valvular heart disease with the porcine heterograft prosthesis. In the immediate postoperative period, a transient decrease in the cardiac index (CI) (preoperative 3.0 +/- 0.14 to 2.45 +/- 0.16 L. per minute per square meter, p less than 0.05) and an increase in the systemic vascular resistance (SVR) (preoperative 1,078 +/- 62 to 1,287 +/- 103) dynes/sec./cm.-5, p greater 0.05) were seen; these values returned to preoperative levels by the first postoperative day. After valve replacement, an elevation in the heart rate (HR) (preoperative 75 +/- 2 to 87 +/- 4 beats per minute, p less than 0.05) and a reduction in the stroke volume (SV) and stroke work index (SWI) (preoperative 35 +/- 2 to 26 +/- 2 Gm.-M. per square meter, p less than 0.05) occurred which persisted throughout the study. The endocardial viability ration (EVR) increased after valve replacement. These findings suggest that, following aortic valve replacement, (1) an increase HR is the mechanism utilized to maintain cardiac output, (2) subendocardial perfusion is enhanced as indicated by an increase in the EVR, and (3) the hemodynamic alterations following insertion of the porcine heterograft prosthesis are not different from those observed when other valves are placed in similar patient populations.

Adult↗