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PubMedDate not supplied

Conserved expression domains for genes upstream and within the HoxA and HoxD clusters suggests a long-range enhancer existed before cluster duplication.

The posterior HoxA and HoxD genes are essential in appendicular development. Studies have demonstrated that a "distal limb enhancer," remotely located upstream of the HoxD complex, is required to drive embryonic autopod expression of the posterior Hox genes as well as the two additional non-Hox genes in the region: Evx2 and Lnp. Our work demonstrates a similar mode of regulation for Hoxa13 and four upstream genes: Evx1, Hibadh, Tax1bp, and Jaz1. These genes all show embryonic (E11.5-E13.5) distal limb and genital bud expression, suggesting the existence of a nearby enhancer influencing the expression of a domain of genes. Comparative sequence analysis between homologous human and mouse genomic sequence upstream of Hoxa13 revealed a remote 2.25-kb conserved noncoding sequence (mmA13CNS) within the fourth intron of the Hibadh gene. mmA13CNS shares a common 131-bp core identity within a conserved noncoding sequence upstream of Hoxd13, which is located within the previously identified distal limb enhancer critical region. To test the function of this conserved sequence, we created mmA13CNS-Hsp86-lacZ transgenic mice. mmA13CNS directed a wide range of tissue expression, including the central nervous system, developing olfactory tissue, limb, and genital bud. Limb and genital bud expression directed by mmA13CNS is not identical to the patterns exhibited by Hoxa13/Evx1/Hibadh/Tax1bp1/Jaz1, suggesting that mmA13CNS is not sufficient to fully recapitulate their expression in those tissues. The Evx1- and Evx2-like central nervous system expression observed in these mice suggests that the long-range regulatory element(s) for the Hox cluster existed before the cluster duplication.

Animals↗
PubMed1999

Participation of imidazoline receptors and alpha(2-)-adrenoceptors in the central hypotensive effects of imidazoline-like drugs.

The central hypotensive effect of imidazoline-like drugs (IMs) involves non-adrenergic imidazoline receptors (IRs). IMs cause hypotension irrespective of their affinity and selectivity for one or the other alpha-adrenoceptor subtypes. LNP 509, which binds to I1Rs (Ki = 5.10(-7) M) but roughly not to alpha 2-adrenoceptors (A2Rs) (Ki > 10(-5) M), causes hypotension when injected alone into the brainstem. As far as hybrid drugs, that is, those with mixed binding profiles (I1/alpha 2), are concerned, a significant correlation was reported between their central hypotensive effect and their affinity for IRs. Imidazoline antagonists such as idazoxan competitively antagonized the centrally induced hypotensive effect of IMs. Yohimbine, an A2Rs antagonist, blocks the hypotensive effect of hybrids but usually in a noncompetitive manner. Mutation of A2Rs prevented the hypotensive effects of drugs highly selective for A2Rs, but also that of hybrids such as clonidine. These data indicate that triggering of the hypotensive effects of IMs (1) needs implication of IRs; (2) appears to be facilitated by additional activation of A2Rs; and (3) requires integrity of A2Rs along the sympathetic pathways.

Animals↗
PubMed2024

In vivo editing of lung stem cells for durable gene correction in mice.

In vivo genome correction holds promise for generating durable disease cures; yet, effective stem cell editing remains challenging. In this work, we demonstrate that optimized lung-targeting lipid nanoparticles (LNPs) enable high levels of genome editing in stem cells, yielding durable responses. Intravenously administered gene-editing LNPs in activatable tdTomato mice achieved >70% lung stem cell editing, sustaining tdTomato expression in >80% of lung epithelial cells for 660 days. Addressing cystic fibrosis (CF), NG-ABE8e messenger RNA (mRNA)-sgR553X LNPs mediated >95% cystic fibrosis transmembrane conductance regulator (CFTR) DNA correction, restored CFTR function in primary patient-derived bronchial epithelial cells equivalent to Trikafta for F508del, corrected intestinal organoids and corrected R553X nonsense mutations in 50% of lung stem cells in CF mice. These findings introduce LNP-enabled tissue stem cell editing for disease-modifying genome correction.

Animals↗
PubMed1986

Structure of the exocellular D-glucan produced by Neisseria polysaccharea.

Neisseria polysaccharea (LNP 462, NCTC 11858), proposed as a prototype strain constituting a new taxon in the genus Neisseria, produces copious amounts of polysaccharide when grown on agar containing 1-5% sucrose. Plate-grown cells produced an exocellular polysaccharide which was composed of D-glucose, had [alpha]D +222 degrees (water), and was shown from composition, specific optical rotation, methylation, enzymic hydrolysis, and 13C nuclear magnetic resonance studies to have an amylopectinlike structure containing mainly 1,4-linked alpha-D-glucopyranosyl residues, but also containing ca. 6% 4,6-di-O-substituted alpha-D-glucopyranosyl branch points.

Centrifugation↗
PubMed2003

I(1) imidazoline receptors involved in cardiovascular regulation: where are we and where are we going?

Clonidine-like drugs (hybrid drugs) reduce blood pressure by acting centrally at both alpha(2)-adrenergic receptors (alpha(2)AR) and I(1) receptors (I(1)R). Some attempts at cloning I(1)R have failed, probably because of the lack of selectivity of the ligands. Recently, compounds acting exclusively at I(1)R were synthesized: LNP 911, LNP509, and S23515. For example, LNP911 has a K(d) value of 1.7 nmol/L at I(1)R. LNP509 and S23515 reduce blood pressure when injected centrally in anesthetized animals, whereas S23757 behaves as an antagonist of hypotensive imidazolines. LNP509 reduces blood pressure even in genetically engineered mice lacking functional alpha(2)AR. An exclusive action at central I(1)R is therefore sufficient to modify blood pressure. With the help of drugs selective for I(1)R and alpha-methylnoradrenaline, selective for alpha(2)AR, we showed that imidazoline and alpha(2)-adrenergic mechanisms interact synergistically in controlling the blood pressure. Such a synergism may explain the very powerful hypotensive effects of hybrid drugs. The new ligands selective for I(1)R will be very helpful to investigate the molecular features and the signaling system of I(1)R.

Animals↗
PubMed1992

Noise exposure level while operating electronic arcade games as a leisure time activity.

In order to study noise levels associated with electronic arcade games, noise measurements were made in 3 selected game centers and 192 samples were taken in each location. The background noise was recorded at a level of 61 dB(A) and 64 dB(C). When the electronic games were performed these levels of noise reached to 88 approximately 90 dB(A). The 1/3 octave bands analyzing sound pressure levels showed that more intense noise levels arose in a frequency range between 0.5 and 2.0 kHz. The computed values for noise pollution levels (LNP) and L90 (fast response A-weighted sound level exceeded 90% of the measurement time) ranged from 93.3 to 96.6 and from 85.1 to 87.3 dB(A), respectively. Concerning our results and according to Melnic (1979), it was estimated that these levels of noise might cause 4-8 dB temporary threshold shift (TTS) at 4.0 kHz in an individual with less than one hour of exposure to such a level of noise. As for the employees of the 3 game centers, the 8-hr equivalent continuous sound levels (Leq,8) were in the range of 80.3 approximately 87.5 dB(A), although their exposure time could not be exactly determined. It was suggested that: 1) The maximum levels should be limited to a reasonable level, either by the manufacturers or by the game center owners; 2) Education programs in industry should inform the employees about other factors outside the work that may affect their hearing; and 3) For policy-making on hearing conservation, recreational warning and standards should be established.

Auditory Threshold↗
PubMed1996

Calcutta metro: is it safe from noise pollution hazards?

A modest assessment of noise was made in Calcutta Metro, India's first ever underground tube rail system, to examine if the range of noise levels present could endanger the hearing sensitivity of workers for the Metro. Sound measuring instruments of a sound level meter, an octave band analyzer, and a sound level calibrator were used for measuring the sound pressure levels in platforms of three stations: Esplanade, Kalighat and Tollygunge. The results indicated that the averaged A-weighted SPLs in these stations were in the range of 84-87 dBA. In the coaches of the moving train the Leq values ranged 92-99 dBA and LNP 105-117 dBA, all exceeding the safe limit of day time noise exposure of 55 dBA and 85 dBA of ACGIH. The SPLs at 4,000 Hz in the coaches were also in excess of safe exposure limit of 79 dB. The findings thus posed a potential threat to the workers.

Environmental Monitoring↗
PubMed1975

Community noise criteria.

In the fields of community noise abatement and municipal planning, there are new requirements to define an environment of varying noise level by a single number rating method that correlates well with the subjective response of human beings. Typical criteria, either in use of proposed, are LN numbers (noise levels exceeded N% of the time), Leq (the equivalent sound level in dB(A) ), LNP (the Noise Pollution Level), and Ldn (the day-night average sound level in dB(A) ). Instruments available include an environmental noise classifier, a statistical distribution analyzer/recorder combination, and a digital sampling system for field measurements for subsequent interrogation by a programmable calculator.

City Planning↗
PubMedDate not supplied

[Use of the lipolytic drug mevacor in the treatment of patients with diabetes mellitus].

Stable compensation of diabetes mellitus, including normolipidemia, underlies the therapy of diabetic angiopathies. Mevacor represents a nonactive lactone form of a certain hydroxy acid, a potent inhibitor of endogenous synthesis of cholesterol, conducive to blood cholesterol reduction. The aim of the present study was the assessment of the efficacy of this drug in therapy of patients with diabetes mellitus. Ten patients were administered mevacor in a dose of 20 mg for a month. Such therapy was conducive to a significant reduction of the levels of cholesterol, LNP cholesterol, triglycerides, and cholesterol/LVP ratio. It also promoted a reduction of the content of lipid peroxidation products in the blood, these products being an active factor of vessel destruction. The levels of hydroperoxides, blood serum and red cell malonic dialdehyde, and superoxide dismutase were also reduced. These results necessitate addition of mevacor to a complex of therapy for diabetes to normalize lipid metabolism.

Adult↗
PubMed2002

Road traffic noise in Calcutta metropolis, India.

A comprehensive study on traffic noise level at twenty four pre-selected road transaction of Calcutta Metropolis was carried out during 1993-94. Noise levels were measured at each of twenty four sites, based on predetermined sampling interval and altogether 2880 observations were generated by recording data continuously for 24 hours. The Lcq 24, exceedence levels, LD, LN, LDN, LNP and TNI were determined. Traffic flow density as measured along with noise data recording were then compared for establishing relationship with noise level. Finally the clustering of the sites were made based on variable viz. Lcq 24 and traffic follow density.

Environmental Monitoring↗
PubMed1988

[Effects of pentoxifylline on diastolic heart function in patients with angina pectoris and an increased left ventricular wall mass].

The combination of coronary heart disease (CHD) with increased left ventricular wall mass (LVWM) appears associated with prolonged isovolumetric relaxation (IVR) and consequently, alterations in the rapid filling phase. Methylxanthine-substances may improve relaxation through inhibition of phosphodiesterase activity. Accordingly we examined multiple indexes of left ventricular diastolic function before and after administration of 200 mg pentoxifylline (Trental) intravenously to 18 patients (51.3 +/- 9.0 years, 15 males, three females) with stable angina pectoris and positive exercise-ECG in NYHA class I or II and LVWM greater than 160 g (n = 9) and less than or equal to 160 g (n = 9). Left ventricular pressure (P) and volume (V) measurements were made with a high-fidelity-micromanometer before and twelve minutes after administration of pentoxifylline. The time constant of left ventricular isovolumic relaxation (T), usual global left ventricular volumes and derived indexes such as peak filling rate (PFR), time to peak filling rate (TPFR), segmental (relaxation and rapid filling phases) and total pressure-volume relationship before and after pentoxifylline were calculated. Significant differences between these two groups (greater than/less than or equal to 160 g LVWM) were found for end-diastolic volume (68.7 +/- 19.0 to 90.8 +/- 22.6 ml/sqm), end-systolic volume (21.7 +/- 16.0 to 36.1 +/- 14.7 ml/sqm), end-diastolic pressure (15.0 +/- 4.8 to 15.7 +/- 5.1 mm Hg), PFR (3.25 +/- 1.18 to 2.66 +/- 0.71 s-1), T (46.0 +/- 5.7 to 52.7 +/- 7.2 ms), the linear regression of lnP-V (lny = -0.117 x + 4.59 to lny = -0.091 x + 4.75) in the IVR-phase (dp/dtmin less than or equal to x less than or equal to 80 ms) (leftward shift in p-V-relationship when less than or equal to 160 g) and the complet p-V-areas. After pentoxifyl-line-administration there were significant decreases in T in patients with increased LVWM (52.7 +/- 7.2 to 47.7 +/- 5.9 ms) and the P-V-product over the time in the rapid filling phase in patients with LVWM less than or equal to 160 g. Total peripheral resistance and heart rate did not change. These changes in parameters of left ventricular diastolic function in combination with significant improvement of pump function especially in patients with LVWM greater than 160 g after administration of pentoxifylline suggest that improved diastolic function is the result of a direct myocardial effect of pentoxifylline.

Adult↗
PubMed1986

Relative contributions of the facial processes to facial development: a microsurgical assay.

The facial processes, which consist of the medial nasal process (MNP), the lateral nasal process (LNP), and the maxillary process (MP), are basal components in facial morphogenesis, especially upper lip formation. To examine the relative role of each facial process in normal or abnormal facial development, rat embryos that had had a part of each facial process excised were cultured for 72 hr in vitro from gestational day 11.5 (plug day = day 0). At the termination of culture, although the epithelial wound was healed over, the defect was observed corresponding to excised region in form. Only in the MNP-excised group was cleft liplike malformation observed, but in other groups this malformation was absent or at a lower rate. This suggests that the medial nasal process in this stage plays a critical role in normal facial development as well as cleft lip formation.

Animals↗
PubMed1979

[New measurements of noise from road traffic in Rome carried out during 24 hours (author's transl)].

A new series of noise measurements in 10 points of the central zone in Rome, corresponding to residential areas with commercial activity, to parks, to hospitals, and to a subway, have been carried out. Investigation has been protracted during 24 hours and each measure has lasted 20 minutes. For the survey a mobile acoustic unity of the Environmental Hygiene Laboratory, Department of Sanitary Engineering, of Istituto Superiore di Sanità has been employed. The unity is fitted with instruments for statistical analysis of noise in connection with a minicomputer. The used program has allowed to calculate L1, L10, L50, L90, standard deviation, Leq, LNP, TNI. On the basis of such measurements Leq 24, Ldn, CNEL, have been calculated. Collected data have been compared with limits of stated rules and with noise levels measured in other seven Italian towns.

Automobiles↗
PubMed2026

Mechanisms of and mitigating strategies for cellular immune responses to CRISPR-associated nucleases in genome editing therapy.

Immunogenicity of CRISPR-associated nucleases (Cas) is a critical barrier to the development of safe and effective genome editing therapies. These proteins inherently pose a risk of immune recognition due to their prokaryotic origins. A multitude of factors, such as the delivery vehicle, the route of administration, components of the therapeutics, tissue microenvironment, and pre-existing immunity, also contribute to the complexity of the host immune response to Cas proteins. As CRISPR-based therapies advance into clinical settings, it is imperative to elucidate and address the immunogenicity of Cas proteins. Here, using Cas9 as an example, we review the current understanding of Cas protein immunogenicity, the challenges it poses for therapeutic application, and strategies to mitigate cellular immune responses to Cas proteins.

AAV↗