PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Restrictive”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,153 records · Page 64Linked to original sources

Support among smokers and nonsmokers for restrictions on smoking.

The responses of 387 smokers and 988 nonsmokers obtained in a population-based survey in Ontario, Canada, were compared with regard to knowledge, attitudes, and predicted behavior concerning restrictions on smoking. Responses were tabulated as percentages and weighted according to the sample design. Nonoverlapping 95% confidence intervals provided evidence to reject the null hypothesis. Although smokers were found to be less knowledgable about the health effects of smoking and environmental tobacco smoke, more than 90% of both smokers and nonsmokers agreed with restrictions on smoking in 14 specific settings; for some settings, they disagreed on the extent of restrictions. The groups differed concerning specific bans on cigarette sales, but support was uniformly strong for bans in hospitals, controls on vending machines, and enforcement of the law prohibiting sales to minors. Clear majorities of both groups agreed that local government should enact and enforce restrictions. Smokers were more likely than nonsmokers to predict that smokers would comply with more restrictions, and most smokers indicated that they, themselves, would comply. We conclude that general health education should be bolstered by strategies specifically targeted at smokers. There is a strong basis across the population for restrictions to reduce exposure to environmental tobacco smoke; support for the role of local government in this regard is clear. Noncompliance with more restrictions is unlikely to present enforcement problems. Measures limiting the physical access of youths to tobacco will be widely supported, but strategies to increase support for tax measures are needed.

Adult↗

Effect of dietary restrictions and source of rats on growth rate and efficiency of conversion of food into muscles, bones and organs.

Differences in weight of the body, six different skeletal muscles, epididymal fat pads, three different bones, spleen, heart, kidneys, testes and liver were observed in 21-day-old male Sprague-Dawley rats from two different suppliers. All rats were pair-fed a 10% casein diet ad libitum, 10%, 20%, 30% restricted for 4 or 8 weeks. Original body and tissue weight differences between the two strains of rats were maintained in all diets during the 4 and 8 week feeding periods. Trends in body and tissue weight changes due to dietary restriction were similar in both strains of rats. Diet restrictions for 4 or 8 weeks caused similar patterns of weight decrease in most tissues. Feed efficiency ratio (FER) was reduced significantly at the 20% and 30% restriction for 4 weeks only in the lighter strain of rats. FER was higher in the heavier strain than in the lighter strain of rats at all levels of diet restriction. Food conversion efficiency with reduced food intake was constant or decreased depending on the skeletal muscle studied; decreased significantly for epididymal fat pad, bone weight (one strain only), kidneys and liver (one strain only) with the 30% reduced diet for 4 weeks; and increased for bone length and testes weight. Therefore, significant deviations from ad libitum controls were found only at 30% diet restriction, and the wide differences in body and tissue weight of two strains of Sprague-Dawley rats did not affect the interpretation of results when fed the same restricted diets.

Adipose Tissue↗

The use of feed restriction for mortality control of chickens in broiler farms.

Feed restriction was attempted for the control of mortality at broiler farms. Respiratory signs were observed in both restricted-feed flocks and fully fed flocks, but they were less severe in the restricted-feed flocks. The death rate in the fully fed flocks began to rise at the age of 4 wk but did not do so in the restricted-feed flocks. Mortality in the restricted-feed flocks was significantly lower than in the fully fed flocks aged from 3 to 7 wk. The economic performance with restriction feeding was better than that with full feeding as a result of improvements in viability and feed conversion rates. Feed restriction appeared to be beneficial in decreasing the death losses.

Age Factors↗

Food restriction enhances the central rewarding effect of abused drugs.

Chronic food restriction increases the systemic self-administration and locomotor-stimulating effect of abused drugs. However, it is not clear whether these behavioral changes reflect enhanced rewarding potency or a CNS-based modulatory process. The purpose of this study was to determine whether food restriction specifically increases the rewarding potency of drugs, as indexed by their threshold-lowering effect on lateral hypothalamic self-stimulation, and whether any such effect can be attributed to an enhanced central response rather than changes in drug disposition. When drugs were administered systemically, food restriction potentiated the threshold-lowering effect of amphetamine (0.125, 0.25, and 0.5 mg/kg, i.p.), phencyclidine (1.0, 2.0, and 3.0 mg/kg, i.p.), and dizocilpine (MK-801) (0.0125, 0.05, and 0.1 mg/kg, i.p.) but not nicotine (0.15, 0.3, 0.45 mg/kg, s.c.). When amphetamine (25.0, 50.0, and 100.0 microgram) and MK-801 (5.0, 10.0, and 20.0 microgram) were administered via the intracerebroventricular route, food restriction again potentiated the threshold-lowering effects and increased the locomotor-stimulating effects of both drugs. These results indicate that food restriction increases the sensitivity of neural substrates for rewarding and stimulant effects of drugs. In light of work that attributes rewarding effects of MK-801 to blockade of NMDA receptors on medium spiny neurons in nucleus accumbens, the elements affected by food restriction may lie downstream from the mesoaccumbens dopamine neurons whose terminals are the site of amphetamine-rewarding action. Possible metabolic-endocrine triggers of this effect are discussed, as is the likelihood that mechanisms mediating the modulatory effect of food restriction differ from those mediating sensitization by intermittent drug exposure.

Amphetamine↗

Restriction enzymes have limited access to DNA sequences in Drosophila chromosomes.

Sequence specific DNA binding proteins in eukaryotic cells must efficiently locate their binding sites in chromosomes. Restriction enzymes provide a simple model system with which to investigate the factors which influence this process. We have used P element mediated transformation to introduce a DNA fragment containing a set of characterized restriction sites into the Drosophila germline. Embryonic nuclei prepared from these transgenic animals were treated with restriction enzymes to probe the accessibility of the target restriction sites. The results show that the insert is within an accessible region of the chromosome and that restriction sites within the inserted sequence can be cut. However, the rate of cutting is biphasic. At each restriction site, a fraction of the chromosomes is cut rapidly after which the remainder is refractory. Similar levels of incomplete cutting are obtained when the same P element construct is examined at a different chromosomal location, when different sequence elements are introduced into the P element vector or when the experiment is carried out on nuclei from different embryonic stages. These results are discussed in terms of how sequence specific DNA binding proteins may locate their genomic targets in vivo.

Animals↗

Hepatitis B virus genotype assignment using restriction fragment length polymorphism patterns.

Hepatitis B virus (HBV) is classified into genotypes A-F, which is important for clinical and etiological investigations. To establish a simple genotyping method, 68 full-genomic sequences and 106 S gene sequences were analyzed by the molecular evolutionary method. HBV genotyping with the S gene sequence is consistent with genetic analysis using the full-genomic sequence. After alignment of the S sequences, genotype specific regions are identified and digested by the restriction enzymes, HphI, NciI, AlwI, EarI, and NlaIV. This HBV genotyping system using restriction fragment length polymorphism (RFLP) was confirmed to be correct when the PCR products of the S gene in 23 isolates collected from various countries were digested with this method. A restriction site for EarI in genotype B was absent in spite of its presence in all the other genotypes and genotype C has no restriction site for AlwI. Only genotype E is digested with NciI, while only genotype F has a restriction site for HphI. Genotype A can be distinguished by a single restriction enzyme site for NlaIV, while genotype D digestion with this enzyme results in two products that migrates at 265 and 186 bp. This simple and accurate HBV genotyping system using RFLP is considered to be useful for research on HBV.

Base Sequence↗

In silico analysis of complete bacterial genomes: PCR, AFLP-PCR and endonuclease restriction.

UNLABELLED: We have developed a website, www.in-silico.com, which runs a software program that performs three basic tasks in completely sequenced bacterial genomes by in silico analysis: PCR amplification, amplified fragment length polymorphism (AFLP-PCR) and endonuclease restriction. For PCR, after selection of the genome and introduction of primers, fragment size, DNA sequence and corresponding open reading frame (ORF) identity of the resulting PCR product is computed. Plasmids of sequenced species may be included in the analysis. Theoretical AFLP-PCR analyzes similar parameters, and includes a suggestion tool providing a list of commercial restriction enzyme pairs yielding up to 50 amplicons in the selected genome. Endonuclease restriction analysis of complete genomes and plasmids calculates the number of restriction sites for endonucleases in a given genome. If the number of fragments is 50 or fewer, pulsed field gel electrophoresis image and restriction maps are illustrated. Other tools that have been included in this site are ORF search by name and DNA to protein translation as well as restriction digestion of user-defined DNA sequences. AVAILABILITY: This is a new molecular biology resource freely available over the Internet at http://www.in-silico.com

Algorithms↗

Restriction of dietary energy and protein induces molecular changes in young porcine skeletal muscles.

Little is known about the molecular changes in response to dietary restriction (energy and/or protein) in young growing skeletal muscles. To profile such changes and to gain insights into the signaling molecules that could mediate the diet effects, a dedicated porcine skeletal muscle cDNA-microarray approach was used to characterize differential muscle gene expression between conventionally fed and diet-restricted (20% less protein and 7% less energy) growing pigs, reared from 9 to 21 wk of age. In both red and white muscles, diet restriction resulted in the accumulation of significantly more intramuscular fat, and in the increased expression of genes involved in substrate (protein, glycogen, and lipid) turnover, in translation and mitochondrial function, and in raising glycolytic and oxidative phosphorylation potentials. The unexpected increase in intramuscular lipids in diet-restricted growing pigs could have important health implications for restricted diets in childhood. Despite reduced circulating insulin, more genes, including several novel growth modulatory genes, had higher expression levels, indicating that the cellular response to dietary restriction is an active process. One such responsive gene, P311, was most highly expressed in striated muscles and had a differentiation-dependent increase of expression in murine C2C12 cells, suggesting a role in differentiation/postdifferentiation phenotype determination.

Animals↗

DNA restriction is a barrier to natural transformation in Pseudomonas stutzeri JM300.

Natural transformation is a mechanism for intra- and interspecific transfer of chromosomal DNA in Pseudomonas stutzeri. During this process a single strand derived from duplex DNA is transported into the cytoplasm and recombined with resident DNA. By electroporation, which introduces duplex DNA into cells, 100-fold lower transformation frequencies of P. stutzeri JM300 were observed with shuttle vector or broad-host-range plasmid DNA when the plasmids had replicated in Escherichia coli and not in P. stutzeri JM300. Moreover, the natural transformation with cloned chromosomal P. stutzeri JM300 DNA was reduced about 40-fold when the DNA had not been propagated in P. stutzeri JM300 but in E. coli. Restriction was also active during natural transformation by single-stranded DNA. Restriction during natural transformation and electroporation was abolished in mutants isolated from mutagenized JM300 cells after applying a multiple plasmid electroporation strategy for the enrichment of restriction-defective strains. The mutants had retained the ability for DNA modification. The P. stutzeri strain ATCC 17587 was found to have no restriction-modification system as seen in JM300. It is discussed whether restriction during natural transformation acts at presynaptic or postsynaptic stages of transforming DNA. Restriction as a barrier to transformation apparently contributes to sexual isolation and therefore may promote speciation in the highly diverse species P. stutzeri.

DNA Restriction-Modification Enzymes↗

Novel approach to mapping of resistance mutations in whole genomes by using restriction enzyme modulation of transformation efficiency.

Restriction enzyme modulation of transformation efficiencies (REMOTE) is a method that makes use of genome restriction maps and experimentally observed differences in transformation efficiencies of genomic DNA restriction digests to discover the location of mutations in genomes. The frequency with which digested genomic DNA from a resistant strain transforms a susceptible strain to resistance is primarily determined by the size of the fragment containing the resistance mutation and the distance of the mutation to the end of the fragment. The positions of restriction enzyme cleavage sites immediately flanking the resistance mutation define these parameters. The mapping procedure involves a process of elimination in which digests that transform with high frequency indicate that the restriction enzyme cleavage sites are relatively far away from the mutation, while digests that transform with low frequency indicate that the sites are close to the mutation. The transformation data are compared computationally to the genome restriction map to identify the regions that best fit the data. Transformations with PCR amplicons encompassing candidate regions identify the resistance locus and enable identification of the mutation. REMOTE was developed using Haemophilus influenzae strains with mutations in gyrA, gyrB, and rpsE that confer resistance to ciprofloxacin, novobiocin, and spectinomycin, respectively. We applied REMOTE to identify mutations that confer resistance to two novel antibacterial compounds. The resistance mutations were found in genes that can decrease the intracellular concentration of compounds: acrB, which encodes a subunit of the AcrAB-TolC efflux pump; and fadL, which encodes a long-chain fatty acid transporter.

Anti-Bacterial Agents↗

Evidence of participation of McrB(S) in McrBC restriction in Escherichia coli K-12.

The McrBC restriction system has the ability to restrict DNA containing 5-hydroxymethylcytosine, N4-methylcytosine, and 5-methylcytosine at specific sequences. The mcrB gene produces two gene products. The complete mcrB open reading frame produces a 51-kDa protein (McrB(L)) and a 33-kDa protein (McrB(S)). The smaller McrB polypeptide is produced from an in-frame, internal translational start site in the mcrB gene. The McrB(S) sequence is identical to that of McrB(L) except that it lacks 161 amino acids present at the N-terminal end of the latter protein. It has been suggested that McrB(L) is the DNA binding restriction subunit. The function of McrB(S) is unknown, although there has been speculation that it plays some role in the modulation of McrBC restriction. Studies of the function of McrB(S) have been challenging since it is produced in frame with McrB(L). In this study, we tested the effects of underproduction (via antisense RNA) and overproduction (via gene dosage) of mcrBC gene products on restriction levels of the mcrBC+ strain JM107. Among the parameters monitored was the induction of SOS responses, which indicate of DNA damage. Evidence from this study suggests that McrB(S) is necessary for stabilization of the McrBC restriction complex in vivo.

Bacterial Proteins↗

Restriction endonuclease analysis of the vp7 genes of human and animal rotaviruses.

The vp7 genes of 194 strains of group A rotaviruses representing all known G types were analyzed with three restriction enzymes by direct digestion of amplified cDNA copies or by deduction of the restriction patterns from known sequences. Mammalian rotavirus strains were classified into 28 restriction patterns consisting of combinations of the 6 profiles (s1 to s6) obtained by digestion with Sau96I endonuclease, 9 profiles (h1 to h9) obtained with HaeIII, and 15 profiles (b1 to b15) obtained with BstYI. Digestion with Sau96I and HaeIII identified restriction sites common to all, or almost all, rotavirus strains studied, whereas BstYI was the most discriminating among rotavirus strains. A clear correlation between some restriction patterns or individual profiles and G type and/or host species of origin was found. Several discriminatory restriction sites consisted of type-specific nucleic acid sequences that encoded conserved amino acid residues. Although not directly involved in antigenic diversity, these sites appear to indicate the G type of the isolate. The technique permits rapid comparison of a large number of virus isolates directly from fecal specimens and provides useful markers for investigating the evolution of rotavirus vp7 genes and tracing vaccine virus and interspecies transmission.

Animals↗

Protein restriction for diabetic renal disease.

OBJECTIVES: To determine whether protein restriction slows or prevents progression of diabetic nephropathy towards renal failure. SEARCH STRATEGY: Computerised databases MEDLINE (1976-1996) and EMBASE (1974-1996) were searched using keywords diabetes mellitus, diabetic nephropathy, dietary proteins, diet, protein restricted and uremia. Recent issues of selected journals (Diabetic Medicine, Diabetologia, Diabetes Care, Kidney International, Nephrology Dialysis and Transplantation) were handsearched for papers not yet in the computerised databases. Reference lists of papers were also checked. SELECTION CRITERIA: This review was not limited to randomised controlled trials. All trials involving people with insulin-dependent diabetes following a lower protein diet for at least 4 months were considered since the straight line nature of progression as reflected by GFR means that patients can act as their own controls in a before and after comparison. DATA COLLECTION AND ANALYSIS: Data were extracted for length of follow up, level of protein restriction, renal function and dietary compliance. No studies of the impact of protein restriction on outcomes such as the need for dialysis or transplantation were found. The trials reported only the effect on short-term indicators such as creatinine clearance. MAIN RESULTS: Overall a protein restricted diet (0.3-0. 8g/kg) does appear to slow the progression of diabetic nephropathy towards renal failure. REVIEWER'S CONCLUSIONS: The results show that reducing protein intake appears to slow progression to renal failure, but some questions remain unanswered. The first is what level of protein restriction we should be used? The trials aimed for a daily intake of between 0.3 to 0.8g/kg of protein. The second concerns compliance in routine care - what level would be acceptable to patients? The third concerns long term outcomes -the present trials use proxy indicators such as creatinine clearance rather than outcomes such as time to dialysis or prevention of ESRF. All trials were carried out in subjects with insulin-dependent diabetes. It remains to be seen if a lower protein intake would slow the progression of nephropathy affecting the non-insulin dependent diabetic population.

Diabetic Nephropathies↗

Membrane-mediated ultrafast restriction digestion and subsequent rapid gel microchip electrophoresis of DNA.

Ultrafast, membrane-mediated restriction digestion of DNA molecules followed by rapid gel microchip electrophoresis of the resulting fragments is described. Combination of restriction endonuclease digestion on small pore-size microfibrous membranes with sample loading and electrophoresis analysis in a multilane (up to 96) format resulted in very fast restriction digest based microscale DNA analysis. Complete digestion of several nanogram target DNA was accomplished on the microporous membrane at room temperature just in a few minutes with a single or a combination of various restriction enzymes, using only submicroliter quantities of samples and reagents. The reaction mixture containing membrane also served as sample loading device for the subsequent gel microchip electrophoresis based analysis. This work establishes methods for high-speed, high-throughput DNA analysis, featuring extremely low sample and reagent consumption, and fast restriction digestion in combination with sample loading and rapid gel microchip analysis of the resulting fragments. The entire restriction digestion, sample loading and electrophoresis analysis process required less than 20 min.

Bacteriophage phi X 174↗

Physical activity and low-fat diet: is it enough to maintain weight stability in the reduced-obese individual following weight loss by drug therapy and energy restriction?

OBJECTIVE: The anthropometric and physiological effects of a physical activity (PA) and a mildly energy-restricted low-fat diet (LFD) follow-up program after a long-term dietary restriction were studied in 12 men and 8 women. RESEARCH METHODS AND PROCEDURES: The dietary restriction (approximately 700 kcal/day) was accompanied by a fenfluramine (60 mg/day) or placebo treatment for 15 weeks, whereas the mean duration of the PA-LFD follow-up was 18 weeks. RESULTS: The long-term dietary restriction reduced body weight (-11.9 and -7.6 kg, p<.001), fat mass (FM) (-10.6 and -5.8 kg, p<0.01), resting metabolic rate (RMR) (-304 kcal/day, p<0.01 and -148 kcal/day, NS) in men and women, respectively. A decrease in fat-free mass (FFM) was also observed in women (-1.8 kg, p<0.05). The PA-LFD follow-up preserved weight stability at a reduced body weight and caused an additional significant decrease in FM for men (-3.4 kg, p<0.05). This part of the intervention also caused an increase in daily RMR for men (134 kcal/day, NS) to the point where this value no longer differed from the pre-energy restriction value. In contrast, RMR was further reduced in women (-200 kcal/day) to the point where it significantly differed from initial values (p<0.01). Resting seated heart rate was reduced by the PA-LFD follow-up in men leading it to differ significantly from both pre- and post-energy restriction values (-8.5 and -5.5 bpm, p<0.01). DISCUSSION: In conclusion, these results suggest that a PA-LFD follow-up has the potential to permit body weight stability and may even accentuate fat loss in the reduced-obese state. Moreover, resting energy expenditure is increased under such conditions in men. These stimulating effects seem to be specific to energy metabolism since seated heart rate was either further reduced or remained stable in response to the PA-LFD follow-up.

Adult↗

Studies on the genomic heterogeneity of Micrococcus luteus strains by macro-restriction analysis using pulsed-field gel electrophoresis.

Macro-restriction analysis by means of double digestion using DraI and VspI demonstrated that they cleaved the genomic DNAs from Micrococcus luteus JCM1464(T), JCM3347, and JCM3348 into four to five fragments in a distinguishable manner by pulsed-field gel electrophoresis (PFGE). Separate digestion with DraI and VspI cleaved the genomic DNA from M. luteus ATCC9341 into a relatively limited number of restriction fragments (six pieces). SspI and XbaI cleaved the genomic DNA from each of the four strains into restriction fragments in a distinctly different and distinguishable manner.Thus, PFGE profiles after digestion with these four restriction enzymes that recognize six specific base sequences demonstrated the heterogeneity at the whole genomic DNA level among the four strains of M. luteus. The size of the genomic DNA of M. luteus ATCC9341 was estimated to be approximately 2.3 Mb by the summing the lengths of the restriction fragments generated by each three restriction enzymes (DraI, SspI, and VspI) and averaging the results.

Base Sequence↗

[Protection of foreign DNA against host-controlled restriction in bacterial cells. II. Protection of pSF2124 plasmid by the gene function of bacteriophages T3 and T7].

When restriction-active Escherichia coli cells (R+P1m+P1) are transformed with the pSF2124 plasmid, a common vector in experimental gene transfer, the efficiency of transformation (e.o.t.) is lowered by 2 orders of magnitude compared with restriction-negative (r-P1m-P1 or r-P1m+P1) recipient cells due to restriction of the pSF2124 DNA by endoR.EcoP1. Preinfection of r+P1m+P1 cells with UV-inactivated ocr+ phages (T3, T7, T3sam-) still able to express their early genes protects the plasmid DNA against restriction by endoR.EcoP1: The e.o.t. of r+P1m+P1 recipient cells with pSF2124 attains the same high value as that of r-m- cells. The specific role of the ocr+ gene function was demonstrated by the use of ocr- mutants (T3/R7, T7/D111): Preinfection with such phage mutants does not increase the e.o.t. of r+P1m+P1 cells. An unspecific e.o.t. alteration of restriction-negative (r-m-) recipient cells by ocr+ or ocr- phages was excluded. The ocr+ gene function can be exploited to protect pSF2124 against DNA restriction. The recipient cells survive the process of phage preinfection and transformation and stably replicate themselves as well as the plasmid DNA.

DNA Restriction Enzymes↗

Remodeling of turkey adrenal steroidogenic tissue induced by dietary protein restriction: the potential role of cell death.

The present study focused on the cellular remodeling of steroidogenic tissue in the domestic turkey (Meleagris gallopavo) adrenal gland in response to dietary protein restriction stress. Immature male turkeys (1 week old) were fed isocaloric synthetic diets containing either 28% (control) or 8% (restriction) soy protein for 4 weeks. Adrenal glands were processed for the isolation of density- separable, visibly distinct adrenal steroidogenic cell subpopulations: three low-density subpopulations [LDAC-1 (rho = 1. 0350-1.0490 g/ml), LDAC-2 (rho = 1.0490-1.0570 g/ml), and LDAC-3 (rho = 1.0570-1.0585 g/ml)] and one high-density subpopulation [HDAC (rho = 1.0590-1.0720 g/ml)]. Dietary protein restriction increased the proportion of LDAC-3 and HDAC by 98 and 350%, respectively, and decreased LDAC-2 by 46%. LDAC-1 also showed signs of proportional decrement. To determine the role of cell death in this process, the potential for apoptosis was assessed in adrenal tissue and isolated adrenal steroidogenic cells using short-term culture followed by analysis of oligonucleosome formation. Basal, culture-triggered oligonucleosome formation of tissue and cells derived from protein-restricted birds was 80% greater than that of tissue and cells derived from control birds. This differential in apoptotic potential persisted with a variety of treatments, in vitro. Apoptotic potential was suppressed by human adrenocorticotropin and enhanced by angiotensin II (Ang II). The proapoptotic effect of Ang II (100 nM) with adrenal fragments was inhibited by the Ang II receptor antagonist [Sar(1), Ile(8)]ang II (10 microM) to below basal values (by about 60%), but the inhibition was surmountable by high concentrations (10 and 100 microM) of Ang II. The antagonist also attenuated basal, culture-triggered DNA fragmentation of tissue and cells, suggesting that at least part of the basal DNA fragmentation was due to intrinsically generated Ang II. Differences in apoptotic potential were also apparent with cell subpopulations. Compared to control subpopulations, protein restriction enhanced basal oligonucleosome formation in LDAC-1 and -2 by 38 and 122%, respectively, and reduced it in LDAC-3 and HDAC by 53 and 70%, respectively. These data suggest a role for apoptotic cell death in the remodeling of turkey adrenal steroidogenic tissue induced by dietary protein restriction. In addition, other data suggest that Ang II is an important regulator of adrenal steroidogenic cell turnover in the avian adrenal gland.

Adrenal Cortex Hormones↗