Recent progress in hair follicle stem cell markers and their regulatory roles

Hair follicle stem cells(HFSCs)in the bulge are a multipotent adult stem cell population.They can periodically give rise to new HFs and even regenerate the epidermis and sebaceous glands during wound healing.An increasing number of biomarkers have been used to isolate,label,and trace HFSCs in recent years.Considering more detailed data from single-cell transcriptomics technology,we mainly focus on the important HFSC molecular markers and their regulatory roles in this review.

Bhlhe40 protects cochlear hair cell-like HEI-OC1 cells against H_(2)O_(2) ‑triggered oxidative injury

Background:Cochlear hair cell injury is a common pathological feature of hearing loss.The basic helix-loop-helix family,member e40(Bhlhe40),a gene belonging to the basic helix-loop-helix(bHLH)family,exhibits strong transcriptional repression activity.Methods:Oxidative damage,in House Ear Institute-Organ of Corti 1(HEI-OC1)cells,was caused using hydrogen peroxide(H2O2).The Ad-Bhlhe40 particles were constructed to overexpress Bhlhe40 in HEI-OC1 cells.Various assays including cell counting kit-8(CCK-8),terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay(TUNEL),flow cytometry,immunofluorescence,and corresponding commercial kits were employed to investigate the impacts of Bhlhe40 on cell viability,apoptosis,oxidative stress levels,mitochondrial membrane potential and cellular senescence.Additionally,a dual-luciferase reporter assay was performed to confirm the targeting of the histone deacetylases 2(Hdac2)by Bhlhe40.Results:The results revealed that Bhlhe40 was downregulated in H_(2)O_(2)-treated HEI-OC1 cells,but its overexpression improved cell viability and mitigated H_(2)O_(2)-induced oxidative injury in HEI-OC1 cells with increase of superoxide dismutase(SOD),catalase(CAT)and glutathione peroxidase(GPx)activities and decrease of reactive oxygen species(ROS)levels.Besides,overexpression of Bhlhe40 suppressed H_(2)O_(2)-triggered cell senescence,as evidenced by the fact that the upregulation of P53,P21,and P16 in HEI-OC1 cells treated with H2O2 were all alleviated by Bhlhe40 overexpression.And we further verified that overexpression of Bhlhe40 could inhibit the expression of Hdac2,which may be related to the repression of Hdac2 transcription.Conclusion:This study suggests that Bhlhe40 plays a protective role against senescence and oxidative damage in cochlear hair cells exposed to H2O2.

Determinants of Occipital Involvement in Males and Females with Pattern Hair Loss: A Retrospective Study

Background: Pattern hair loss (PHL) is the most common form of hair loss affecting both men and women. The occipital region, located at the back of the scalp, has been considered resistant to hair loss in PHL. It is often used as a donor site for hair transplantation procedures. However, evidence suggests that the occipital region may also be affected by PHL, although to a lesser extent compared to the frontal and vertex regions. Objective: To assess the levels and determinants of occipital involvement in PHL, focusing on gender and disease severity. Such data would enhance the comprehensive understanding of PHL progression and inform development of improved treatment strategies. Methods: This retrospective study involved 1993 adults (1000 males, 993 females) following for PHL at a specialized hair clinic in Jeddah, Saudi Arabia. Any patient who had hair transplantation in the past and any male who had balding areas (Hamilton-Norwood scales 4 to 7) at the initial consultation was excluded. The primary outcome was occipital involvement, defined as >10% thin hairs in the trichometry assessments of the occipital region. Additional data included patients age, treatment status, disease severity, and other trichometry parameters. Results: The prevalence of occipital involvement was found to be 23.8% overall, significantly more frequent in females (35.6%) than males with early PHL (Hamilton-Norwood scales 2 and 3) (12.1%) (p Conclusion: This study underscored the relevance of gender and disease severity in occipital involvement in PHL. Females had significantly higher rates of occipital involvement, suggesting that gender differences are critical in understanding PHL progression. Future research should aim to validate these findings, with an aim to refine therapeutic and surgical approaches to improve patient outcomes.

Melatonin promotes the development of the secondary hair follicles by regulating circMPP5

Background The quality and yield of cashmere fibre are closely related to the differentiation and development of secondary hair follicles in the skin of cashmere goats.The higher the density of secondary hair follicles,the higher the quality and yield of cashmere from the fleece.Development of secondary hair follicles commences in the embryonic stage of life and is completed 6 months after birth.Preliminary experimental results from our laboratory showed that melatonin(MT)treatment of goat kids after their birth could increase the density of secondary hair follicles and,thus,improve the subsequent yield and quality of cashmere.These changes in the secondary hair follicles resulted from increases in levels of antioxidant and expression of anti-apoptotic protein,and from a reduction in apoptosis.The present study was conducted to explore the molecular mechanism of MT-induced secondary hair follicle differentiation and development by using whole-genome analysis.Results MT had no adverse effect on the growth performance of cashmere kids but significantly improved the character of the secondary hair follicles and the quality of cashmere,and this dominant effect continued to the second year.Melatonin promotes the proliferation of secondary hair follicle cells at an early age.The formation of secondary hair follicles in the MT group was earlier than that in the control group in the second year.The genome-wide data results involved KEGG analysis of 1044 DEmRNAs,91 DElncRNAs,1054 DEcircRNAs,and 61 DEmiRNAs which revealed that the mitogen-activated protein kinase(MAPK)signaling pathway is involved in the development of secondary hair follicles,with key genes(FGF2,FGF21,FGFR3,MAPK3(ERK1))being up-regulated and expressed.We also found that the circMPP5 could sponged miR-211 and regulate the expression of MAPK3.Conclusions We conclude that MT achieves its effects by regulating the MAPK pathway through the circMPP5 sponged the miR-211,regulating the expression of MAPK3,to induce the differentiation and proliferation of secondary hair follicle cells.In addition there is up-regulation of expression of the anti-apoptotic protein causing reduced apoptosis of hair follicle cells.Collectively,these events increase the numbers of secondary hair follicles,thus improving the production of cashmere from these goats.

Artificial nerve graft constructed by coculture of activated Schwann cells and human hair keratin for repair of peripheral nerve defects

Studies have shown that human hair keratin(HHK) has no antigenicity and excellent mechanical properties. Schwann cells, as unique glial cells in the peripheral nervous system, can be induced by interleukin-1β to secrete nerve growth factor, which promotes neural regeneration. Therefore, HHK with Schwann cells may be a more effective approach to repair nerve defects than HHK without Schwann cells. In this study, we established an artificial nerve graft by loading an HHK skeleton with activated Schwann cells. We found that the longitudinal HHK microfilament structure provided adhesion medium, space and direction for Schwann cells, and promoted Schwann cell growth and nerve fiber regeneration. In addition, interleukin-1β not only activates Schwann cells, but also strengthens their activity and increases the expression of nerve growth factors. Activated Schwann cells activate macrophages, and activated macrophages secrete interleukin-1β, which maintains the activity of Schwann cells. Thus, a beneficial cycle forms and promotes nerve repair. Furthermore, our studies have found that the newly constructed artificial nerve graft promotes the improvements in nerve conduction function and motor function in rats with sciatic nerve injury, and increases the expression of nerve injury repair factors fibroblast growth factor 2 and human transforming growth factor B receptor 2. These findings suggest that this artificial nerve graft effectively repairs peripheral nerve injury.

Hair growth-promotion effects and antioxidant activity of the banana flower extract HappyAngel^(■):double-blind, placebo-controlled trial

Banana flowers contain various bioactive components, including several antioxidants with anti-inflammatory effects. However, it is unclear whether they can reduce and prevent hair loss. This study examines the effect of banana flower extracts on preventing hair loss and strengthening hair roots. The banana flower extract(HappyAngel^(■))was used to treat human hair follicle dermal papilla cells(HFDPCs)and the expression of reactive oxygen species(ROS), dihydrotestosterone(DHT), and hair-related genes(SRD5A1, SRD5A2, AR, and KROX20)were monitored. Fifty subjects were divided into a placebo group and a banana flower group. The experimental group consumed banana flower extract daily for twelve weeks and then underwent hair testing, hair-related genes analysis, collection of hair loss, and questionnaires. The results showed that the banana flower extract significantly increased hair cell growth and decreased the expression of ROS, DHT, and hair follicle growth inhibition-related SRD5A1, SRD5A2, and AR genes, and significantly increased the expression of hair growth-related KROX20 gene in HFDPCs. Consuming banana flower extract for twelve weeks increased the hair root diameter and reduced hair loss and scalp redness compared to the placebo group. Thus, banana flower extract(HappyAngel^(■))can stimulate hair growth and inhibit the activation of hair loss genes.

Evaluation of Effectiveness of Diode Laser System (808 nm) versus Intense Pulse Light (IPL) in the Management of Unwanted Hair: A Split Face Comparative Study

We have evaluated and compared the effectiveness of diode laser system (808 nm) and Intense Pulse Light (IPL) system (690 - 1200 nm) by studying the change in hair density, and the time of regrowth the hair. A total of 26 have completed three months’ treatment, aged 16 - 50 years. Patients were treated by diode laser 808 nm and IPL 690 - 1200 nm devices. Pulse repetition rate for both was 1 Hz and short pulse width for diode laser and the IPL pulse width was 15 ms. The fluence was (33 - 41 and 30 - 41) J/cm2 respectively. A split face treatment method was used. The treatment was carried out on monthly bases for three months. Hair density and regrowth duration were recorded before and after each session. After the third session, the hair density was decreased by (58%) for diode laser versus (49%) for IPL p = 0.366. The time of hair regrowth was increased to (327%) for diode laser versus IPL (339%) p = 0.821. Pain appeared more during the treatment with IPL than with diode laser. Post treatment side effects such as erythema, hyper pigmentation, and burn appeared on patients treated with diode laser more than those treated with IPL. In conclusion both diode laser and IPL were effective in reduction of hair density, and prolongation of the time of hair regrowth.

The role of Rho GTPase family in cochlear hair cells and hearing

Rho GTPases are essential regulators of the actin cytoskeleton.They are involved in various physiological and biochemical processes such as the regulation of cytoskeleton dynamics,development,proliferation,survival,and regeneration.During the development of cochlear hair cells,Rho GTPases are activated by various extracellular signals through membrane receptors to further stimulate multiple downstream effectors.Specifically,RhoA,Cdc42,and Rac1,members of the classical subfamily of the Rho GTPase family,regulate the development and maintenance of cilia by inducing the polymerization of actin monomers and stabilizing actin filaments.In addition,they also regulate the normal morphology orientation of ciliary bundles in auditory hair cells,which is an important element of cell polarity regulation.Moreover,the actin-related pathways mediated by RhoA,Cdc42,and Rac1 also play a role in the motility of outer hair cells,indicating that the function of Rho GTPases is crucial in the highly polar auditory sensory system.In this review,we focus on the expression of RhoA,Cdc42,and Rac1 in cochlear hair cells and how these small molecules participate in ciliary bundle morphogenesis and cochlear hair cell movement.We also discuss the progress of current research investigating the use of these small molecules as drug targets for deafness treatment.

Natural product rhynchophylline prevents stress-induced hair graying by preserving melanocyte stem cells via theβ2 adrenergic pathway suppression

Norepinephrine(NA),a stress hormone,can accelerate hair graying by binding toβ2 adrenergic receptors(β_(2)AR)on melanocyte stem cells(McSCs).From this,NA-β_(2)AR axis could be a potential target for preventing the stress effect.However,identifying selective blockers forβ_(2)AR has been a key challenge.Therefore,in this study,advanced computer-aided drug design(CADD)techniques were harnessed to screen natural molecules,leading to the discovery of rhynchophylline as a promising compound.Rhynchophylline exhibited strong and stable binding within the active site ofβ_(2)AR,as verified by molecular docking and dynamic simulation assays.When administered to cells,rhyncho-phylline effectively inhibited NA-β_(2)AR signaling.This intervention resulted in a significant reduction of hair graying in a stress-induced mouse model,from 28.5%to 8.2%.To gain a deeper understanding of the underlying mechanisms,transcriptome sequencing was employed,which revealed that NA might disrupt melanogenesis by affecting intracellular calcium balance and promoting cell apoptosis.Importantly,rhynchophylline acted as a potent inhibitor of these downstream pathways.In conclusion,the study demonstrated that rhynchophylline has the potential to mitigate the negative impact of NA on melanogenesis by targetingβ_(2)AR,thus offering a promising solution for preventing stress-induced hair graying.

Isolation and Identification of Fungi That Cause Hair Loss (Alopecia)

Due to the crowded number of female students in a very narrow place, the fact that the college is for females only, and the fact that some of the female students live in the internal sections of the student residence, as well as the crowded number there, and as a result of the presence of the head covering or what is known as the Islamic veil on the head, which covers the hair of the head, which provides a suitable hot humid atmosphere 100% of fungal growth in the scalp of female students. Therefore, it is necessary to know the widespread fungal species that contaminate the scalp. In other research, we learn about the antifungals that should be used to reduce fungal infections in college employees. The study was carried out to identify the presence and spread of fungi that cause hair loss. The study was conducted on some students of the College of Education for Girls/University of Shatra for the period from 1/11/2021 to 1/12/2021, where 100 hundred hair samples were collected from (the scalp) from different ages in different educational stages, as random samples were taken after asking the student whether she suffers from hair loss or not, and studying the presence and spread of fungi in terms of density and type, after transferring them to the microbiology laboratory-College of Education for Girls using sterile sample collection bags. The current results showed that the fungal species E. flocculosum is the most common among them, followed by the fungal species C. carrionii, then the rest of the genera are as follows: E. flocculosum, Basisdioplus, Aspergillus terreud Hormderndrum Rhodotorula, Bipolaris, Aspergillus, Phoma, Rhizopus, Blastomyces, Microsporum, Sporothrix, Exophiala jeanselmei, Neoscytalidium Aeremonium Cladophialophora carrionii, Paecilomyces, Exophiala dermatitidis, Geotrichum, Volvariella, Rhizomucor, Saksmaea vassiformis, Candida albicans, Chrysosporium, Dimiatum.

Efficacy and Safety of Alexandrite and Nd:YAG Laser Combination in Permanent Hair Removal

Background and Objective: Unwanted hair growth is a discomforting issue affecting both genders. People have tried various methods to get rid of this situation. This study aims to evaluate the efficacy and safety of a combined Alexandrite and Nd:YAG laser treatment for permanent hair removal, drawing insights from existing literature. Materials and Methods:This study included a total of 2127 patients (302 males, 1825 females) aged 18 - 65, with complete data, who underwent hair removal treatment between December 2018 and April 2021. These patients were treated using the Duetta laser system (Quanta system, Samarate, Italy), combining Alexandrite 755 nm and Nd:YAG 1064 nm wavelengths. The patients’ skin types were classified according to the Fitzpatrick classification scale. Target area/areas for laser hair removal was/were determined. Laser parameters, pulse counts, pain levels assessed through the Visual Pain Scale (VPS), and patient satisfaction were documented based on skin types. Findings: Across various skin types, Types I - II exhibited the highest treatment success rates (87%), with the axillary region achieving the highest rate (83%) and the face region achieving the lowest rate (75%). Pain scale analysis indicated that 98% of patients tolerated the procedure well. Patient satisfaction levels exceeded 90%. Evaluation of complication rates revealed minimal occurrences. Conclusion: The combined Alexandrite and Nd:YAG laser system demonstrates both efficacy and safety across diverse skin types, attributed to its notable success rates, minimal adverse effects, and high patient tolerance.

The Haircare Efficacy Research of Prinsepia Utilis OilPrinsepia Oil

To research the hair-care efficacy of prinsepia utilis oil.We evaluated the haircare efficacies of prinsepia utilis oil through methods such as differential scanning calorimetry(DSC),measuring difficulty level and mechanical resistance against combing of wet and dry hair,scanning electron microscopy(SEM).According to the analysis of differential scanning calorimetry(DSC),the testing sample has repairing effect on the hairα-keratin damage induced by heated blowing.According to the pictures of scanning electron microscopy(SEM),The test results indicate the repairing or resisting thermal damage effects induced by hair drier of prinsepia utilis oil.By comparison with the blank control group,the strength and work of dry comb and wet comb were significantly reduced in the samples tested with 2%prinsepia utilis oil concentration(P﹤0.05).This indicates the testing sample has the efficacy to improve the easiness of combing and anti-tangle.And friction work is significantly reduced This indicates the smoothing efficacy of the testing sample.and the hair scales status is better;this indicates hair scales repairing efficacy of testing sample.Conclusion:PRINSEPIA UTILIS OIL has the effect of repairing hair scales,resisting thermal damage caused by hair dryer,easy to comb,anti-tangle,smoothing.

Therapeutic Approach for Hair Growth and Regeneration Using Bioactive Formulation Containing Mesenchymal Stromal Cell-Derived Conditioned Medium

Background and Aims: Androgenetic alopecia (AGA) is a common form of hair loss in both men and women. Despite its high prevalence and associated patient morbidity, the approved therapeutic options are limited to finasteride and minoxidil. The present study is aimed at assessing the efficacy of hair serum formulation, Trichosera®containing Bone marrow-derived mesenchymal stromal cells conditioned media as an active ingredient, for hair fall control and hair regrowth in healthy Indian human volunteers. Methods: The product was made using a 20% concentration of 10X Conditioned Media along with excipients. The final product was tested for physicochemical parameters, biomarkers, total protein content and microbial limits as per our in-house specifications. Results: The primary irritation patch test showed that the product is non-irritant and dermatologically safe. A clinical study on 40 subjects was conducted to evaluate the effectiveness of the bioactive formulation in hair fall control and hair regrowth in healthy volunteers. Phototrichogram measurement showed hair density and hair growth rate increased significantly by 11.54% and 18.66% at week 24. Hair tensile strength also increased significantly by 41.10% at 12 weeks follow-up. Hair pull test, to see a reduction in pulled hair and comb’s test to show a decrease in hair fall significantly improved from week 4 onwards. There were no significant adverse events in response to the product application. Conclusion: It is concluded that the hair serum product is completely safe on direct application to the scalp and showed significant improvement in the hair growth rate, hair density, scalp condition and reduction in hair fall. .

Comparison between the Medullary Indexes of Hairs from Apodemus orestes and A.draco,with Discussion about the Taxonomic Status of A.orestes

The taxonomic status of long-tailed field mouse (Apodemus orestes) is still uncertain up to now.Some scholars regarded it as a subspecies or a synonym of dragon field mouse (A.draco),while other scholars considered it a valid species.In the study,five specimens of adult long-tailed field mouse,dragon field mouse and Chevrier's field mouse (A.chevrieri) (as a contrast) were chosen respectively.After treated,with the eyepiece micrometer in the inverted microscope,we made measurements of the widths of hairs and medullas and then calculated the medullary indexes of straight guard hairs from around the mouth,head,back,abdomen and forelimb of each species.The results indicate that,viewing at each of the five parts and the mixture of the five parts,there are no significant differences between A.orestes and A.draco,Significant differences can be found between A.orestes & A.chevrieri and A.draco & A.chevrieri though.The standpoint that A.orestes was listed as a valid species is not supported by this study.

Effects of Different Culture Condition in vitro on Growth of Cashmere Goat Primary Hair Follicles

[Objective] The aim of this study is to lay a foundation for illustrating the biological characteristics and growth regulation mechanism of hair follicles.[Method]Cashmere goat primary hair follicles were separated under aseptic condition and cultured in serum-free DMEM and serum-free Williams E media respectively;subsequently,the growth rate and morphological changes were observed under the inverted microscope.[Result]Hair follicles cultured in serum-free DMEM media showed a growth rate of 0.034 mm/d during the first 3 days,whose structure and morphological characteristics could maintian a stable status for a long time in the growth process.Hair follicles grew much faster in the serum-free Williams E media with a growth rate of 0.077 mm/d during the first 3 days.[Conclusion]There were significant differences(P<0.05)between the growth of cashmere goat hair follicles cultured in the 2 kinds of media.Serum-free Williams E medium was superior to serum-free DMEM medium.

Mechanical upper bowel obstruction caused by a large trichobezoar in a young woman: A very unusual case report

BACKGROUND Bezoars usually compile human fibers and debris.A special form of bezoar in case of psychologically altered individuals is the trichobezoar.It consists of voluntarily swallowed hair bulks and is normally removed via gastroscopy.Trichobezoars leading to ileus have rarely been reported.CASE SUMMARY A 24-year-old female patient presented to the emergency room with abdominal pain,nausea,and vomiting for 3 d.Her previous medical and psychiatric history was unremarkable.Laboratory analysis showed iron deficiency anemia,leukocytosis,and elevated liver enzymes.An abdominal CT scan revealed a dense structure in the patients’stomach which turned out to be a huge trichobezoar completely obstructing the pylorus.The trichobezoar had to be removed surgi-cally.During her postoperative course,a subcutaneous seroma formed.After a single puncture,the rest of the recovery process was unremarkable,and the patient recovered fully.CONCLUSION A mechanical bowel obstruction is a potentially life-threatening event for every patient.In our case a young female was suffering from severe symptoms of an obstruction which might have resulted in serious harm without successful surgical management.

Effects of Estradiol on Cashmere Goat Primary Hair Follicles Cultured in vitro

[Objective] The aim of this study was to preliminarily explore the effects of estradiol on morphology and growth of cashmere goat primary hair follicles. [Method] Cashmere goat primary hair follicles were cultured in serum-free Williams E media supplemented with different doses of 17 β-E2 (0, 0.1, 1.0, 10.0, 100.0 nmol/L), and their growth rates and morphological changes were observed. [Result] The growth rate of 0.1 nmol/L 17 β-E2 group was quite comparable with that of the control group(0 nmol/L), but the 17 β-E2 with concentrations of 1.0, 10.0 and 100.0 nmol/L displayed different degrees of inhibition on the growth of hair follicles. Different morphological changes of hair follicles could also be discovered in different concentration treatments. [Conclusion] The study laid a certain foundation for exploring the regulation mechanism of estrogen on growth of cashmere goat hair follicles.

1-苯基2-硫脲通过p53调控自噬活性来保护斑马鱼神经丘毛细胞

为了确定细胞自噬与毛细胞存活的关系,通过溶酶体标记物Lyso Tracker对神经丘的细胞自噬进行活体染色发现,斑马鱼(Danio rerio)经过苯基硫脲(PTU)处理后,其神经丘毛细胞Lyso Tracker信号强度增加,并伴随毛细胞数量增多和肿瘤抑制蛋白p53基因(Tumor protein p53 gene,tp53)上调。为了阐明毛细胞的存活和保护机制,通过CRISPR/Cas9技术构建了tp53突变体斑马鱼,发现该基因突变后不会影响斑马鱼神经丘毛细胞的数量,但抑制了PTU对神经丘毛细胞自噬的促进,神经丘毛细胞不再增多。研究结果表明:PTU可以通过上调tp53基因的表达,促进斑马鱼侧线神经丘毛细胞的自噬活性,进而促进毛细胞的存活,为保护毛细胞奠定了重要基础。

Comparison on Several Methods for Extracting DNA from Raccoon Dog Hair Follicle

[Objective] This study aimed to investigate a reliable method for DNA ex- traction from Wusuli raccoon dog＇s hair. [Method] Several DNA extraction methods were used to extract DNA from Wusuli raccoon dog hair, including Chelex-100 method, PCR buffer method, organic phenol-chloroform method and centrifugal col- umn type kit method. The extracted DNA was analyzed by using PCR amplification and electrophoresis to compare these four DNA extraction methods. [Result] Accord- ing to the results of spectrophotometer detection and gel electrophoresis, nucleic acid extracted by Chetex-100 method had proteins and other impurities; nucleic acid ex- tracted by PCR buffer method was low in concentration; however, DNA extracted by organic phenol-chloroform method and centrifugal column type kit was high in con- centration with no impurity band. [Conclusion] This study had laid the strong founda- tion of scientific theory to further explore the efficient and simple method for extracting DNA from Wusuli raccoon dog hair follicle.

A dose-dependent bimodal switch by homologous Aux/IAA transcriptional repressors

Combinatorial interactions between different regulators diversify and enrich the chance of transcriptional regulation in eukaryotic cells.However,a dose-dependent functional switch of homologous transcriptional repressors has rarely been reported.Here,we show that SHY2,an auxin/indole-3-acetic acid(Aux/IAA)repressor,exhibits a dose-dependent bimodal role in auxin-sensitive root-hair growth and gene transcrip-tion in Arabidopsis,whereas other Aux/lAA homologs consistently repress the auxin responses.The co-repressor(TOPLESS[TPL])-binding affinity of a bimodal Aux/IAA was lower than that of a consistently re-pressing Aux/IAA.The switch of a single amino acid residue in the TPL-binding motif between the bimodal form and the consistently repressing form switched their TPL-binding affinity and transcriptional and bio-logical roles in auxin responses.Based on these data,we propose a model whereby competition between homologous repressors with different co-repressor-binding affinities could generate a bimodal output at thetranscriptional anddevelopmental levels.