Comparative analysis of specificity in protein-protein interactions: Part I.: A theoretical and mathematical approach to specificity in protein-protein interactions

The definition of informational complementarity (IC) is introduced and a comparative computer method is described to analyse the possible sources of the specificity in some protein-protein (P-P) interactions. The essence of this method is the step-by-step comparation of the primary structures of the proteins regarding the frequency and sequence (distribution) of one or more selected amino acids. The calculation of the probability of finding two different amino acids in two different protein parts by the same frequency and distribution (Random Pair Building, RPB) and it's checking with the number of actually found pairs (Concrete Pair Building, CPB) and with the number of maximal available pair forming (Maximal Pair Building, MPB) may give the chance to find IC sequences and to understand the nature of specific P-P interactions. The usefulness of this method for analysing intramolecular structures and intermolecular interactions is discussed and an example is presented how it may be used.     

Noroviral P particle: structure, function and applications in virus-host interaction

Noroviruses are an important cause of epidemic acute gastroenteritis and the viruses recognize human histo-blood group antigens (HBGAs) as receptors. The protruding (P) domain of noroviral capsid, the receptor-binding domain, forms subviral particles in vitro that retain the receptor-binding function. In this study we characterized the structure and HBGA-binding function of the P particle. Structure reconstruction using cryo-EM showed that the P particles are comprised of 12 P dimers that are organized in octahedral symmetry. The dimeric packing of the proteins in the P particles is similar to that in the norovirus capsid, in which the P2 subdomain with the receptor-binding interface is located at the outermost surface of the P particle. The P particles are immunogenic and reveal similar antigenic and HBGA-binding profiles with their parental virus-like particle, further confirming the shared surface structures between the two types of particles. The P particles are easily produced in E. coli and yeast and are stable, which are potentially useful for a broad application including vaccine development against noroviruses.     

Methods of synthesis,properties and biomedical applications of polyhydroxyalkanoates: a review

This study aims to provide an overview of the main polyhydroxyalkanoates (PHAs) used in medical applications. In this review, it has been demonstrated that the properties of PHAs can be controlled both by varying the concentration of units in the copolymer and the substrate for PHA production.

Another way of controlling the mechanical properties of PHAs is varying the 3HV content, such as the case of P(3HB-co-3HV). A higher 3HV content in the structure of this polyester will lead to a lower cristallinity and, therefore, to greater flexibility, strength and elongation at break.

PHAs are biocompatible, completely biodegradable, and non-toxic. Considering the state of the art technologies and their ideal properties, PHAs (especially the short-chain-length PHA polymers) can be tailored for specific medical applications, such as surgical suture, scaffolds, grafts and heart valves or drug delivery systems. Nowaday, random copolyesters of 3HB and 4HB (P(3HB-co-4HB)) are used for the development of biodegradable implants loaded with antibiotics for therapeutic treatment of chronic osteomyelitis.

It is also believed that these biodegradable materials can be efficient alternatives for reducing the pollution produced by the medical waste consisting of replacing plastic handles, packs, syringes or tubes that are trashed into the homes, clinics and hospitals around the world.     

Iron/iron oxide nanoparticles: advances in microbial fabrication,mechanism study,biomedical, and environmental applications

Abstract

Microbially synthesized iron oxide nanoparticles (FeONPs) hold great potential for biomedical, clinical, and environmental applications owing to their several unique features. Biomineralization, a process that exists in almost every living organism playing a significant role in the fabrication of FeONPs through the involvement of 5–100 nm sized protein compartments such as dodecameric (Dps), ferritin, and encapsulin with their diameters 9, 12, and ～32 nm, respectively. This contribution provides a detailed overview of the green synthesis of FeONPs by microbes and their applications in biomedical and environmental fields. The first part describes our understanding in the biological fabrication of zero-valent FeONPs with special emphasis on ferroxidase (FO) mediated series of steps involving in the translocation, oxidation, nucleation, and storage of iron in Dps, ferritin, and encapsulin protein nano-compartments. Secondly, this review elaborates the significance of biologically synthesized FeONPs in biomedical science for the detection, treatment, and prevention of various diseases. Thirdly, we tried to provide the recent advances of using FeONPs in the environmental process, e.g. detection, degradation, remediation and treatment of toxic pesticides, dyes, metals, and wastewater.     

Nitrogen metabolism in cyanobacteria: metabolic and molecular control,growth consequences and biotechnological applications

Cyanobacteria are one of the earliest branching groups of organisms on the planet, and during their evolutionary history were submitted to varying selective pressures. Nowadays, cyanobacteria can grow in a variety of conditions, using a large number of nitrogen sources. The control of the nitrogen metabolism in cyanobacteria depends on a fine-tuning regulatory network involving 2-oxoglutarate (2-OG), PII, PipX, and NtcA. This network answers to the cellular 2-OG levels, which reflects the cellular carbon/nitrogen balance, and as an output regulates gene expression, translation, protein activities and thus metabolic pathways. Hence, the diurnal regulation of growth may be directly dependent of this network, as it coordinates the use of photoassimilates towards either growth or the accumulation of reserves, based on the environmental conditions. Therefore, analysis of the nitrogen control network is not only important to comprehend the metabolic control of growth in cyanobacteria, but is also a target to improve cyanobacterial biotechnological potential. In this review, we discuss the mechanisms involved in the control of nitrogen metabolism and its potential role in the diurnal regulation of growth. Then, we highlight why a better understanding of the mechanisms involved in the partitioning of carbon and nitrogen towards growth or storage would increase the biotechnological potential of these organisms.     

Physician gaze shifts in patient-physician interactions: functions,accounts and responses

ObjectivesPhysician gaze towards patients is fundamental for medical consultations. Physicians’ use of Electronic Health Records (EHR) affects their gaze towards patients, and may negatively influence this interaction. We aimed to study conversation patterns during gaze shifts of physicians from the patient towards the EHR.MethodsOutpatient consultations (N = 8) were eye-tracked. Interactions around physician gaze shifts towards the computer were transcribed.ResultsWe found that physician gaze shifts have different interactional functions, e.g., introducing a topic switch or entering data into the EHR. Furthermore, physicians differ in how they account for their gaze shifts, i.e., both implicitly and explicitly. Third, patients vary in treating the gaze shift as an indication to continue their turn or not.ConclusionsOur results suggest that physician gaze shifts vary in function, in how physicians account for them, and in how they influence the conversation. Future research should take into account distinctions when relating gaze to patient outcomes.Practice implicationsPhysicians may be aware of the interactional context of their gaze behaviour. Patients respond differently to various types of gaze shifts. How physicians handle gaze shifts can therefore have different consequences for the interaction.     

IL1β, IL18, NFKB1 and IFNG gene interactions are associated with severity of rheumatoid arthritis: A pilot study

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease which can lead to progressive and functional disability. Literature data suggest that some inflammatory proteins are dysregulated in RA patients and its genetic polymorphisms may contribute to the aetiology and pathogenesis of disease in different ethnic groups. Polymorphisms in IL1β, IL18, NFKB1 and IFNG genes were studied in different populations with RA, but the analysis indicated contradictory results. Thereby, we hypothesised that polymorphisms in these genes could have a combined effect on susceptibility to and severity of disease. We evaluated the +3953?C/T IL1β (rs1143634), –137?G/C IL18 (rs187238), –94 ins/del ATTG NFKB1 (rs28362491) and +874?T/A IFNG (rs2430561) polymorphisms in the northeastern Brazilian population. Peripheral blood samples were collected and DNA extraction was conducted. The polymorphisms were evaluated by RFLP and ARMS–PCR. An association was observed in rs1143634 which showed a protective effect against development of RA in carriers of the T allele (OR?=?0.58; 95% CI 0.36–0.92; p?=?.020). In addition, we found an association among genotypes of the rs1143634 with the HAQ index (p?=?.021) and rs2430561 with DAS28 (p?=?.029) and CDAI (p?=?.029). In relation to combined effects of these SNPs (C/C to rs1143634, G/G to rs187238, I/I to rs28362491 and AA to rs2430561) we found a significant association with decreased functional disability (HAQ index p?<?.001) and ESR (p?=?.034), indicating a lower disease activity in carriers of these genotypes. GLM analysis confirmed these associations (HAQ (F?=?5.497; p?<?.001) and ESR (F?=?2.727; p?=?.032)). Our analysis indicated that in the studied population +3953?C/T IL-1β (rs1143634), –137?G/C IL-18 (rs187238), –94 ins/del ATTG NFKB1 (rs28362491) and +874?T/A IFNG (rs2430561) polymorphisms can together contribute to RA severity although they do not individually influence the disease.     

Fasudil,a Rho-kinase inhibitor,attenuates induction and progression of cerebral aneurysms: Experimental study in rats using vascular corrosion casts

Fasudil (a Rho-kinase inhibitor) has been shown to attenuate abdominal aortic aneurysm development, but any preventive effect against development of cerebral aneurysms is unclear. The effect of fasudil on the development of cerebral aneurysms was investigated in 55 female Sprague-Dawley rats divided into 4 groups: Group 1 (n = 10) was the control group without treatment. Groups 2–4 (n = 15 each) were subjected to cerebral aneurysm induction procedures plus 1% NaCl in the drinking water. Groups 3 and 4 were also treated with 0.5 or 1.0 mg/mL of fasudil in the drinking water, respectively. Vascular corrosion casts of the cerebral arteries were prepared and examined using a scanning electron microscope after 2 months. No significant differences were observed in the degree of induced hypertension between Groups 2, 3 and 4. No aneurysms were found in Group 1. Examination of the left anterior cerebral–olfactory artery junction, which is the most susceptible site for aneurysm development, found significantly fewer aneurysmal lesions in Groups 3 (60%) and 4 (53%) compared to Group 2 (100%) (P < 0.02). This study suggests that fasudil attenuated induction of cerebral aneurysms in the rat model.     

COVID-2019: The role of the nsp2 and nsp3 in its pathogenesis

Last December 2019, a new virus, named novel Coronavirus (COVID-2019) causing many cases of severe pneumonia was reported in Wuhan, China. The virus knowledge is limited and especially about COVID-2019 pathogenesis. The Open Reading Frame 1ab (ORF1ab) of COVID-2019 has been analyzed to evidence the presence of mutation caused by selective pressure on the virus. For selective pressure analysis fast-unconstrained Bayesian approximation (FUBAR) was used. Homology modelling has been performed by SwissModel and HHPred servers. The presence of transmembrane helical segments in Coronavirus ORF1ab non structural protein 2 (nsp2) and nsp3 was tested by TMHMM, MEMSAT, and MEMPACK tools. Three-dimensional structures have been analyzed and displayed using PyMOL. FUBAR analysis revealed the presence of potential sites under positive selective pressure (P < .05). Position 723 in the COVID-2019 has a serine instead a glycine residue, while at aminoacidic position 1010 a proline instead an isoleucine. Significant (P < .05) pervasive negative selection in 2416 sites (55%) was found. The positive selective pressure could account for some clinical features of this virus compared with severe acute respiratory syndrome (SARS) and Bat SARS-like CoV. The stabilizing mutation falling in the endosome-associated-protein-like domain of the nsp2 protein could account for COVID-2019 high ability of contagious, while the destabilizing mutation in nsp3 proteins could suggest a potential mechanism differentiating COVID-2019 from SARS. These data could be helpful for further investigation aimed to identify potential therapeutic targets or vaccine strategy, especially in the actual moment when the epidemic is ongoing and the scientific community is trying to enrich knowledge about this new viral pathogen.     

Measuring single-cell protein secretion in immunology: Technologies,advances, and applications

The dynamics, nature, strength, and ultimately protective capabilities of an active immune response are determined by the extracellular constitution and concentration of various soluble factors. Generated effector cells secrete such mediators, including antibodies, chemo- and cytokines to achieve functionality. These secreted factors organize the individual immune cells into functional tissues, initiate, orchestrate, and regulate the immune response. Therefore, a single-cell resolved analysis of protein secretion is a valuable tool for studying the heterogeneity and functionality of immune cells. This review aims to provide a comparative overview of various methods to characterize immune reactions by measuring single-cell protein secretion. Spot-based and cytometry-based assays, such as ELISpot and flow cytometry, respectively, are well-established methods applied in basic research and clinical settings. Emerging novel technologies, such as microfluidic platforms, offer new ways to measure and exploit protein secretion in immune reactions. Further technological advances will allow the deciphering of protein secretion in immunological responses with unprecedented detail, linking secretion to functionality. Here, we summarize the development and recent advances of tools that allow the analysis of protein secretion at the single-cell level, and discuss and contrast their applications within immunology.     

Impact of an Arthritis Self-Management Programme with an added exercise component for osteoarthritic knee sufferers on improving pain, functional outcomes, and use of health care services: An experimental study

OBJECTIVE: The aim of this study was to assess the effect of an adopted Arthritis Self-Management Programme (ASMP) with an added exercise component among osteoarthritic knee sufferers in Hong Kong. METHODS: An experimental study with 88 participants assigned to an intervention group and 94 participants to a control group. One hundred and forty-nine participants (81.9%) completed the 1 week and 120 participants (65.6%) the 16 week post-intervention assessments. Participants in the intervention group received a 6-week ASMP with an added exercise component. Outcome measures included arthritic pain and fatigue rating, practice of light exercise routines, functional status, and number of unplanned arthritis-related medical consultations. To assess the programme's effect on outcome measures, the between-groups and within-group mean changes were compared using Mann-Whitney U-test and Friedman test. RESULTS: At 16 weeks, there were significant mean changes between groups in four outcome measures: reduction in arthritis pain (p=0.0001) and fatigue (p=0.008), and increased duration of weekly light exercise practice (p=0.0001) and knee flexion (p=0.004). The ability to perform daily activities and the number of unplanned arthritis-related medical consultations show statistically significant improvements between three time-points within the intervention group only (p=0.0001 and p=0.005, respectively), but not between-groups (p=0.14 and p=0.86, respectively). Both groups apparently had no changes in muscle strength. CONCLUSION: Our findings suggest that the intervention had a positive effect in reducing pain, fatigue, knee range of motion, the practice of exercise routines, the number of medical consultations and in improving functional status and over a 16-week period. PRACTICE IMPLICATIONS: The self-management programme we applied took into account the local context and the ethnicity of the group. This process is worth further exploration and testing in different groups.     

Mapping Power Law Distributions in Digital Health Social Networks: Methods,Interpretations, and Practical Implications

Background

Social networks are common in digital health. A new stream of research is beginning to investigate the mechanisms of digital health social networks (DHSNs), how they are structured, how they function, and how their growth can be nurtured and managed. DHSNs increase in value when additional content is added, and the structure of networks may resemble the characteristics of power laws. Power laws are contrary to traditional Gaussian averages in that they demonstrate correlated phenomena.

Objectives

The objective of this study is to investigate whether the distribution frequency in four DHSNs can be characterized as following a power law. A second objective is to describe the method used to determine the comparison.

Methods

Data from four DHSNs—Alcohol Help Center (AHC), Depression Center (DC), Panic Center (PC), and Stop Smoking Center (SSC)—were compared to power law distributions. To assist future researchers and managers, the 5-step methodology used to analyze and compare datasets is described.

Results

All four DHSNs were found to have right-skewed distributions, indicating the data were not normally distributed. When power trend lines were added to each frequency distribution, R ² values indicated that, to a very high degree, the variance in post frequencies can be explained by actor rank (AHC .962, DC .975, PC .969, SSC .95). Spearman correlations provided further indication of the strength and statistical significance of the relationship (AHC .987. DC .967, PC .983, SSC .993, P<.001).

Conclusions

This is the first study to investigate power distributions across multiple DHSNs, each addressing a unique condition. Results indicate that despite vast differences in theme, content, and length of existence, DHSNs follow properties of power laws. The structure of DHSNs is important as it gives insight to researchers and managers into the nature and mechanisms of network functionality. The 5-step process undertaken to compare actor contribution patterns can be replicated in networks that are managed by other organizations, and we conjecture that patterns observed in this study could be found in other DHSNs. Future research should analyze network growth over time and examine the characteristics and survival rates of superusers.     

Involving the patient: a prospective study on use, appreciation and effectiveness of an information system in head and neck cancer care

OBJECTIVE: To determine use, appreciation and effectiveness of an electronic health information support system in head and neck (H&N) cancer care. DESIGN: A prospective evaluation study. The evaluated system has four different functions: (1) communication amongst health care providers and between health care providers and patients, (2) information for health care providers and patients, (3) contact with fellow sufferers and (4) monitoring of discharged patients by means of electronic questionnaires. Evaluation of the system was done both objectively using automatically created log files and stored messages, and subjectively by using paper questionnaires from patients and general practitioners (GPs). SETTING: Department of Otorhinolaryngology and Head and Neck Surgery of a tertiary health care centre in the Netherlands. The system was put at patients' disposal for a period of 6 weeks following discharge from the hospital after surgery for H&N cancer, and was additional to standard care. PARTICIPANTS: Head and neck cancer patients, hospital physicians, members of a hospital-based support team, GPs, district nurses and speech therapists. MAIN OUTCOME MEASURES: Actual use of the system by patients and health care providers. Patients' appreciation for each of the system's four different functions. GPs' appreciation for the system. Capability to detect potential patient problems with the system. RESULTS: The system was used by 36 H&N cancer patients, 10 hospital physicians, 2 members of the support team, 8 GPs, 2 district nurses and 2 speech therapists. The total number of patient-sessions was 982: an average of 27.3 sessions per patient during the 6 weeks study period. In total, 456 monitoring questionnaires were completed. The support team in hospital responded with 231 actions. In 16 cases, an extra appointment was made for a patient with the hospital physician. Out of these cases, immediate action was considered necessary eight times. Patients appreciated the system highly, rating it with an average score of 8.0 on a 10-point scale. All patients used the monitoring function, and rated 'monitoring' with a mean score of 8.0 on a 10-point scale. Least used and appreciated was the 'contact with fellow sufferers' function. Only 8 out of possible 36 GPs used the system, rating it with an average of 5.6 on a 10-point scale. CONCLUSIONS: The electronic health information support system was used intensively and highly appreciated by H&N cancer patients. The system enabled the early detection of occurring health problems that required direct intervention. ICT can play an additional role in the management of patients, also in a relatively elderly and computer illiterate patient population.     

Refined modelling of the short‐T2 signal component and ensuing detection of glutamate and glutamine in short‐TE,localised, 1H MR spectra of human glioma measured at 3 T

Short‐TE ¹H MRS has great potential for brain cancer diagnostics. A major difficulty in the analysis of the spectra is the contribution from short‐T₂ signal components, mainly coming from mobile lipids. This complicates the accurate estimation of the spectral parameters of the resonance lines from metabolites, so that a qualitative to semi‐quantitative interpretation of the spectra dominates in practice. One solution to overcome this difficulty is to measure and estimate the short‐T₂ signal component and to subtract it from the total signal, thus leaving only the metabolite signals. The technique works well when applied to spectra obtained from healthy individuals, but requires some optimisation during data acquisition. In the clinical setting, time constraints hardly allow this. Here, we propose an iterative estimation of the short‐T₂ signal component, acquired in a single acquisition after measurement of the full spectrum. The method is based on QUEST (quantitation based on quantum estimation) and allows the refinement of the estimate of the short‐T₂ signal component after measurement. Thus, acquisition protocols used on healthy volunteers can also be used on patients without further optimisation. The aim is to improve metabolite detection and, ultimately, to enable the estimation of the glutamine and glutamate signals distinctly. These two metabolites are of great interest in the characterisation of brain cancer, gliomas in particular. When applied to spectra from healthy volunteers, the new algorithm yields similar results to QUEST and direct subtraction of the short‐T₂ signal component. With patients, up to 12 metabolites and, at least, seven can be quantified in each individual brain tumour spectrum, depending on the metabolic state of the tumour. The refinement of the short‐T₂ signal component significantly improves the fitting procedure and produces a separate short‐T₂ signal component that can be used for the analysis of mobile lipid resonances. Thus, in brain tumour spectra, distinct estimates of signals from glutamate and glutamine are possible. Copyright © 2016 John Wiley & Sons, Ltd.     

Course of spinocerebellar axons in the ventral and lateral funiculi of the spinal cord with projections to the posterior cerebellar termination area: an experimental anatomical study in the cat,using a retrograde tracing technique

The course of retrogradely labeled spinocerebellar fibers in the ventral and lateral funiculi of the spinal cord was studied following injections of wheat germ agglutinin-conjugated horseradish peroxidase into the posterior spinocerebellar termination area in the cat. Fibers labeled from unilateral injections into the paramedian lobule were found on the same side in the dorsal part of the lateral funiculus (DLF), corresponding to the dorsal spinocerebellar tract (DSCT), but contralaterally in the ventral part of the lateral funiculus (VLF) and in the ventral funiculus (VF), corresponding to the ventral spinocerebellar tract (VSCT). Following injections into the posterior vermis, labeled fibers were less numerous. Most of them were found in the DSCT and only very few in the VSCT. Previously identified cells of origin of these spinocerebellar tracts were labeled in these experiments and counted. They correlated well with the extents and the locations of the injections that had been made into the two termination sites. These results represent novel detailed information on the location of axons projecting to the two main posterior spinocerebellar termination sites in the spinal white matter in the cat.     

Onset,duration and unresolved symptoms,including smell and taste changes,in mild COVID-19 infection: a cohort study in Israeli patients

ObjectivesTo characterize longitudinal symptoms of mild coronavirus disease 2019 (COVID-19) patients for a period of 6 months, to potentially aid in disease management.MethodsPhone interviews were conducted with 103 patients with mild COVID-19 in Israel over a 6-month period (April 2020 to October 2020). Patients were recruited via social media and word to mouth and were interviewed up to 4 times, depending on reports of their unresolved symptoms. Inclusion criteria required participants to be residents of Israel aged 18 years or older, with positive COVID-19 real-time PCR results and nonsevere symptoms. The onset, duration, severity and resolution of symptoms were analysed.ResultsA total of 44% (45/103), 41% (42/103), 39% (40/103) and 38% (39/103) of patients experienced headache, fever, muscle ache and dry cough as the first symptom respectively. Smell and taste changes were experienced at 3.9 ± 5.4 and 4.6 ± 5.7 days (mean ± standard deviation (SD)) after disease onset respectively. Among prevalent symptoms, fever had the shortest duration (5.8 ± 8.6 days), and taste and smell changes were the longest-lasting symptoms (17.2 ± 17.6 and 18.9 ± 19.7 days; durations censored at 60 days). Longer recovery of the sense of smell correlated with the extent of smell change. At the 6-month follow-up, 46% (47/103) of the patients had at least one unresolved symptom, most commonly fatigue (22%, 23/103), smell and taste changes (15%, 15/103 and 8%, 8/103 respectively) and breathing difficulties (8%, 8/103).ConclusionsLong-lasting effects of mild COVID-19 manifested in almost half of the participants reporting at least one unresolved symptom after 6 months.     

Characteristics,risk factors and outcomes of community-acquired acute kidney injury in the elderly: a prospective tertiary hospital study,Egypt

BackgroundAcute Kidney Injury (AKI) is a public health problem. Elderly present a greater predisposition to the development of AKI, either due to kidney senility, or due to high prevalence of comorbidities and polypharmacy. Considering the scarcity of studies on AKI in the elderly particularly in developing countries, this study emphasizes on the pattern and outcome of AKI in the Egyptian elderly.ObjectiveTo analyze the demographics, risk factors and outcomes of Acute Kidney Injury (AKI) in the Egyptian elderly.MethodsA total of 199 patients were included over one year and were divided into two groups; group I (79 elderly patients) and group II (120 non-elderly patients). The two groups were compared regarding demographics, risk factors and major outcomes including patient and renal survival.ResultsElderly patients showed a higher prevalence of Diabetes Mellitus and chronic kidney disease (p=0.004 and 0.005 respectively). Pre-renal causes of AKI principally dehydration represented the major risk factor (p=0.003). Sepsis and hypertension predicted mortality in the elderly (p=0.001 and 0.035 respectively).ConclusionIn our locality; the elderly is highly vulnerable to AKI. Pre-renal causes principally dehydration represent the main triggers of AKI. Sepsis and hypertension contribute to mortality in this population. Preventive strategies are crucial not only in the hospital but also at home.     

Expression pattern of notch1, 2 and 3 and Jagged1 and 2 in lymphoid and stromal thymus components: distinct ligand-receptor interactions in intrathymic T cell development.

The suggested role of Notch1 or its mutants in thymocyte differentiation and T cell tumorigenesis raises the question of how the different members of the Notch family influence distinct steps in T cell development and the role played by Notch ligands in the thymus. We report here that different Notch receptor-ligand partnerships may occur inside the thymus, as we observed differential expression of Notch1, 2 and 3 receptors, their ligands Jagged1 and 2, and downstream intracellular effectors hairy and Enhancer of Split homolog 1 (HES-1) and hairy and Enhancer of Split homolog 5 (HES-5), depending on ontogenetic stage and thymic cell populations. Indeed, while Jagged2 is expressed in both stromal cells and thymocytes, Jagged1 expression is restricted to stromal cells. Moreover, a differential distribution of Notch3, with respect to Notch1, was observed in distinct age-related thymocyte subsets. Finally, Notch3 was preferentially up-regulated in thymocytes, following the induction of their differentiation by interaction with thymic epithelial cells expressing the cognate Jagged1 and 2 ligands, suggesting that, besides Notch1, Notch3 may also be involved in distinct steps of thymocyte development. Our results suggest that the Notch signaling pathway is involved in a complex interplay of T cell developmental stages, as a consequence of the heterogeneity and specific expression of members of the Notch receptor family and their cognate ligands, in distinct thymic cell compartments.