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A novel TGFβ modulator that uncouples R-Smad/I-Smad-mediated negative feedback from R-Smad/ligand-driven positive feedback.

As some of the most widely utilised intercellular signalling molecules, transforming growth factor β (TGFβ) superfamily members play critical roles in normal development and become disrupted in human disease. Establishing appropriate levels of TGFβ signalling involves positive and negative feedback, which are coupled and driven by the same signal transduction components (R-Smad transcription factor complexes), but whether and how the regulation of the two can be distinguished are unknown. Genome-wide comparison of published ChIP-seq datasets suggests that LIM domain binding proteins (Ldbs) co-localise with R-Smads at a substantial subset of R-Smad target genes including the locus of inhibitory Smad7 (I-Smad7), which mediates negative feedback for TGFβ signalling. We present evidence suggesting that zebrafish Ldb2a binds and directly activates the I-Smad7 gene, whereas it binds and represses the ligand gene, Squint (Sqt), which drives positive feedback. Thus, the fine tuning of TGFβ signalling derives from positive and negative control by Ldb2a. Expression of ldb2a is itself activated by TGFβ signals, suggesting potential feed-forward loops that might delay the negative input of Ldb2a to the positive feedback, as well as the positive input of Ldb2a to the negative feedback. In this way, precise gene expression control by Ldb2a enables an initial build-up of signalling via a fully active positive feedback in the absence of buffering by the negative feedback. In Ldb2a-deficient zebrafish embryos, homeostasis of TGFβ signalling is perturbed and signalling is stably enhanced, giving rise to excess mesoderm and endoderm, an effect that can be rescued by reducing signalling by the TGFβ family members, Nodal and BMP. Thus, Ldb2a is critical to the homeostatic control of TGFβ signalling and thereby embryonic patterning.

FGF signalling restricts haematopoietic stem cell specification via modulation of the BMP pathway.

Haematopoietic stem cells (HSCs) are produced during embryogenesis from the floor of the dorsal aorta. The localization of HSCs is dependent on the presence of instructive signals on the ventral side of the vessel. The nature of the extrinsic molecular signals that control the aortic haematopoietic niche is currently poorly understood. Here we demonstrate a novel requirement for FGF signalling in the specification of aortic haemogenic endothelium. Our results demonstrate that FGF signalling normally acts to repress BMP activity in the subaortic mesenchyme through transcriptional inhibition of bmp4, as well as through activation of two BMP antagonists, noggin2 and gremlin1a. Taken together, these findings demonstrate a key role for FGF signalling in establishment of the developmental HSC niche via its regulation of BMP activity in the subaortic mesenchyme. These results should help inform strategies to recapitulate the development of HSCs in vitro from pluripotent precursors.

A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis.

Limited clinical benefits derived from anti-VEGF therapy have driven the identification of new targets involved in tumor angiogenesis. Here, we report an integrative meta-analysis to define the transcriptional program underlying angiogenesis in human cancer. This approach identified ELTD1, an orphan G-protein-coupled receptor whose expression is induced by VEGF/bFGF and repressed by DLL4 signaling. Extensive analysis of multiple cancer types demonstrates significant upregulation of ELTD1 in tumor-associated endothelial cells, with a higher expression correlating with favorable prognosis. Importantly, ELTD1 silencing impairs endothelial sprouting and vessel formation in vitro and in vivo, drastically reducing tumor growth and greatly improving survival. Collectively, these results provide insight into the regulation of tumor angiogenesis and highlight ELTD1 as key player in blood vessel formation.

Fgf differentially controls cross-antagonism between cardiac and haemangioblast regulators.

Fibroblast growth factor (Fgf) has been implicated in the control of heart size during development, although whether this is by controlling cell fate, survival or proliferation has not been clear. Here, we show that Fgf, without affecting survival or proliferation, acts during gastrulation to drive cardiac fate and restrict anterior haemangioblast fate in zebrafish embryos. The haemangioblast programme was thought to be activated before the cardiac programme and is repressive towards it, suggesting that activation by Fgf of the cardiac programme might be via suppression of the haemangioblast programme. However, we show that the cardiac regulator nkx2.5 can also repress the haemangioblast programme and, furthermore, that cardiac specification still requires Fgf signalling even when haemangioblast regulators are independently suppressed. We further show that nkx2.5 and the cloche candidate gene lycat are expressed during gastrulation and regulated by Fgf, and that nkx2.5 overexpression, together with loss of the lycat targets etsrp and scl can stably induce expansion of the heart. We conclude that Fgf controls cardiac and haemangioblast fates by the simultaneous regulation of haemangioblast and cardiac regulators. We propose that elevation of Fgf signalling in the anterior haemangioblast territory could have led to its recruitment into the heart field during evolution, increasing the size of the heart.

Cardiopoietic factors: extracellular signals for cardiac lineage commitment.

Cardiac muscle creation during embryogenesis requires extracellular instructive signals that are regulated precisely in time and space, intersecting with intracellular genetic programs that confer or fashion the ability of the cells to respond. Unmasking the essential signals for cardiac lineage decisions has paramount importance for cardiac development and regenerative medicine, including the directed differentiation of progenitor and stem cells to a cardiac muscle fate.

Functional heterogeneity within the developing zebrafish epicardium

The epicardium is essential during cardiac development, homeostasis and repair and yet fundamental insights into its underlying cell biology, notably epicardium formation, lineage heterogeneity and functional cross-talk with other cell types in the heart, are currently lacking. In this study, we investigated epicardial heterogeneity and the functional diversity of discrete epicardial subpopulations in the developing zebrafish heart. Single-cell RNA-sequencing uncovered three epicardial subpopulations with specific genetic programmes and distinctive spatial distribution within the developing heart. Perturbation of unique gene signatures uncovered distinct functions associated with each subpopulation and established novel epicardial roles in cell adhesion, migration, and chemotaxis as a mechanism for recruitment of leukocytes into the heart. This work elucidates the mutual spatiotemporal relationships between different epicardial subpopulations and assigns unique function to each during cardiac development. Understanding which mechanisms cells employ to establish a functional epicardium and to communicate with other cardiovascular cell types during development will bring us closer to repairing cellular relationships that are disrupted during cardiovascular disease.

The ontogeny, activation and function of the epicardium during heart development and regeneration.

The epicardium plays a key role during cardiac development, homeostasis and repair, and has thus emerged as a potential target in the treatment of cardiovascular disease. However, therapeutically manipulating the epicardium and epicardium-derived cells (EPDCs) requires insights into their developmental origin and the mechanisms driving their activation, recruitment and contribution to both the embryonic and adult injured heart. In recent years, studies of various model systems have provided us with a deeper understanding of the microenvironment in which EPDCs reside and emerge into, of the crosstalk between the multitude of cardiovascular cell types that influence the epicardium, and of the genetic programmes that orchestrate epicardial cell behaviour. Here, we review these discoveries and discuss how technological advances could further enhance our knowledge of epicardium-based repair mechanisms and ultimately influence potential therapeutic outcomes in cardiovascular regenerative medicine.

Immune cells in cardiac repair and regeneration.

The immune system is fundamental to tissue homeostasis and is the first line of defense following infection, injury or disease. In the damaged heart, large numbers of immune cells are recruited to the site of injury. These cells play an integral part in both repair by scar formation and the initiation of tissue regeneration. They initially assume inflammatory phenotypes, releasing pro-inflammatory cytokines and removing dead and dying tissue, before entering a reparative stage, replacing dead muscle tissue with a non-contractile scar. In this Review, we present an overview of the innate and adaptive immune response to heart injury. We explore the kinetics of immune cell mobilization following cardiac injury and how the different innate and adaptive immune cells interact with one another and with the damaged tissue. We draw on key findings from regenerative models, providing insight into how to support a robust immune response permissible for cardiac regeneration. Finally, we consider how the latest technological developments can offer opportunities for a deeper and unbiased functional understanding of the immune response to heart disease, highlighting the importance of such knowledge as the basis for promoting regeneration following cardiac injury in human patients.

Perceptual constancy for an odor is acquired through changes in primary sensory neurons.

The ability to consistently recognize an object despite variable sensory input is termed perceptual constancy. This ability is not innate; rather, it develops with experience early in life. We show that, when mice are naïve to an odor object, perceptual constancy is absent across increasing concentrations. The perceptual change coincides with a rapid reduction in activity from a single olfactory receptor channel that is most sensitive to the odor. This drop in activity is not a property of circuit interactions within the olfactory bulb; instead, it is due to a sensitivity mismatch of olfactory receptor neurons within the nose. We show that, after forming an association of this odor with food, the sensitivity of the receptor channel is matched to the odor object, preventing transmission failure and promoting perceptual stability. These data show that plasticity of the primary sensory organ enables learning of perceptual constancy.

Antidepressant Activity of Agarwood Essential Oil: A Mechanistic Study on Inflammatory and Neuroprotective Signaling Pathways

Background: Depression ranks among the most severe mental health conditions, and poses a burden on global health. Agarwood, an aromatic medicinal plant, has shown potential for improving mental symptoms. As a common folk medicine, agarwood has been applied as an alternative method for mental disorders such as depression through aromatherapy. Previous studies have found that the therapeutic effects of agarwood aromatherapy are primarily related to its volatile components. This study aimed to examine the antidepressant properties and underlying mechanisms of agarwood essential oil (AEO), a collection of the volatile components of agarwood utilized through aromatherapy inhalation and injection administration in mice. Methods: A lipopolysaccharide (LPS)-induced inflammatory depression model was used to evaluate the effects of AEO inhalation and injection on depression-like symptoms. Behavioral assessments included the open-field, tail suspension, and forced swimming tests. Western blot (WB) and ELISA techniques were used to further verify the mechanistic insights. Results: In the LPS-induced depression-like model, AEO inhalation and injection significantly improved depression-like symptoms, decreased immobility duration in both the tail suspension and forced swimming tests in model mice, and reduced the levels of inflammatory cytokines IL-1β, IL-6, and TNF-α. WB experiments demonstrated that AEO inhibited the NF-κB/IκB-α inflammatory pathway and activated the BDNF/TrkB/CREB pathway in the hippocampus of the LPS-depression model mice. Notably, AEO extracted by hydrodistillation was more effective in alleviating LPS-induced depressive-like behaviors than using supercritical CO2 fluid extraction. Conclusions: Both the inhalation and the injection administration of AEO exerted notable antidepressant effects, potentially associated with reducing inflammation levels in the brain, downregulating inflammatory NF-κB/IκB-α, and upregulating the neuroprotective BDNF/TrkB/CREB signaling pathway. In the future, it is necessary to further determine the pharmacodynamic components, key targets and specific molecular mechanisms of AEO’s antidepressant effects so as to provide more support for the neuroprotective research of medicinal plants.

Metabolic regulation of insulin secretion in health and disease

Despite the current media focus, Covid-19 is not the only current pandemic. There is also a global pandemic of diabetes. It is caused by an insufficiency of the hormone insulin, which lowers blood glucose levels. Here we highlight recent work that addresses the question of how insulin is normally secreted from the β-cells of the pancreas and what goes wrong with this process in diabetes. We focus on the metabolic regulation of the ATP-sensitive potassium channel, an ATP-gated membrane pore that regulates insulin secretion. We show that when this pore is shut, insulin is released, and when it is open, insulin release is prevented. As may be expected, genetic mutations that impair the ability of ATP to close the channel cause neonatal diabetes. We also consider if a failure of β-cell metabolism to generate enough ATP to close the channel may lead to the progressive decline in β-cell function in type 2 diabetes.

Beta bursts in the parkinsonian cortico-basal ganglia network form spatially discrete ensembles.

Defining spatial synchronisation of pathological beta oscillations is important, given that many theories linking them to parkinsonian symptoms propose a reduction in the dimensionality of the coding space within and/or across cortico-basal ganglia structures. Such spatial synchronisation could arise from a single process, with widespread entrainment of neurons to the same oscillation. Alternatively, the partially segregated structure of cortico-basal ganglia loops could provide a substrate for multiple ensembles that are independently synchronized at beta frequencies. Addressing this question requires an analytical approach that identifies groups of signals with a statistical tendency for beta synchronisation, which is unachievable using standard pairwise measures. Here, we utilized such an approach on multichannel recordings of background unit activity (BUA) in the external globus pallidus (GP) and subthalamic nucleus (STN) in parkinsonian rats. We employed an adapted version of a principle and independent component analysis-based method commonly used to define assemblies of single neurons (i.e., neurons that are synchronized over short timescales). This analysis enabled us to define whether changes in the power of beta oscillations in local ensembles of neurons (i.e., the BUA recorded from single contacts) consistently covaried over time, forming a "beta ensemble". Multiple beta ensembles were often present in single recordings and could span brain structures. Membership of a beta ensemble predicted significantly higher levels of short latency (<5 ms) synchrony in the raw BUA signal and phase synchronisation with cortical beta oscillations, suggesting that they comprised clusters of neurons that are functionally connected at multiple levels, despite sometimes being non-contiguous in space. Overall, these findings suggest that beta oscillations do not comprise of a single synchronisation process, but rather multiple independent activities that can bind both spatially contiguous and non-contiguous pools of neurons within and across structures. As previously proposed, such ensembles provide a substrate for beta oscillations to constrain the coding space of cortico-basal ganglia circuits.

Direct specification of lymphatic endothelium from mesenchymal progenitors.

During embryogenesis, endothelial cells (ECs) are generally described to arise from a common pool of progenitors termed angioblasts, which diversify through iterative steps of differentiation to form functionally distinct subtypes of ECs. A key example is the formation of lymphatic ECs (LECs), which are thought to arise largely through transdifferentiation from venous endothelium. Opposing this model, here we show that the initial expansion of mammalian LECs is primarily driven by the in situ differentiation of mesenchymal progenitors and does not require transition through an intermediate venous state. Single-cell genomics and lineage-tracing experiments revealed a population of paraxial mesoderm-derived Etv2+Prox1+ progenitors that directly give rise to LECs. Morphometric analyses of early LEC proliferation and migration, and mutants that disrupt lymphatic development supported these findings. Collectively, this work establishes a cellular blueprint for LEC specification and indicates that discrete pools of mesenchymal progenitors can give rise to specialized subtypes of ECs.

Correction: Multi-modal characterisation of early-stage, subclinical cardiac deterioration in patients with type 2 diabetes.

Nimesulide induced histopathological changes in the vas deferens of mice.

AIM: Nimesulide, a preferential COX-2 inhibitor has 20 times more selectivity towards COX-2 than that of COX-1. COX-2 selective inhibitors cause frequent nephrotoxicity and hepatotoxicity following their usage. This proposes a physiological role of COX-2 in kidney and liver. Not much attention has been focused on the role of COX-2 with respect to reproduction especially in male reproduction, and the available information is scanty. AIMs and Objectives: The present study aims to investigate the adverse effects of nimesulide in the vas deferens thereby indirectly assess the role of COX-2 in male reproductive tract. MATERIAL AND METHODS: Nimesulide was administered orally and the animals were maintained for different time periods prior to sacrifice. RESULTS: The vas deferens of nimesulide treated mice showed extensive histopathological changes such as vacoulation and exfoliation of cells in the epithelial layer. CONCLUSION: Nimesulide administration leads to cytotoxic effects suggestive of apoptosis in the vas deferens of mice.

Foramen of civinini: a new anatomical guide for maxillofacial surgeons.

INTRODUCTION: Study on Morphometric and radiological aspect on existence of foramen of civinini. Sphenoid bone comprises of some rare ossified ligaments, may encounter difficulty in surgical procedures. Incidence of Pterygospinous bars various with different racial groups and they are genetically controlled. Complete ossification of pterygospinous ligament form foramen of civinini. Entrapments of vessels or nerves may occur due to existence of pterygospinous bar. The bar may locate medially or inferiorly to formen ovale as seen in Hawaiian and lemurs. Co - existence of bar with the wide lateral pterygoid plate exhibits development of the bar from herbivore, carnivore and old world monkeys. Comparatively absence or small spine of civinini noted in new world monkeys, rodents and platyrrhines. Pterygospinousbar represents the phylogenetic remnant of Human beings. MATERIAL AND METHODS: By using digital vernier caliper, the measurements of length, width of the pterygospinous bar and area of foramen of civinini including the length and breadth of lateral pterygoid plate were measured. Using X rays the radiological view was determined. RESULTS: In this study from 160 cases of skull and sphenoid bones revealed that complete and incomplete foramen of civinini in 1.25% and 7.5% of cases respectively. Peculiarly accessory foramen of civinini noticed in 1.25% of cases. Maximum area of foramen of civinini was 94.2mm(2). The maximum width of lateral pterygoid was noted as 19.6mm respectively. Mentocoronal view of skiagram clearly shows the bar. CONCLUSION: During Anaesthesia for trigeminal neuralgia may encounter difficult to pass the needle. The bar compress the mandibular nerve branches can cause lingual numbness, pain and speech impairment. Conductive anaesthesia on the mandibular nerve through the lateral subzygomatic route may be difficult to approach. Exploring the anatomical and clinical updates of pterygospinous bar may guide the surgeons and radiologists to overcome any difficulties in infratemporal and para or retropharyngeal regions.

Variations in the posterior division branches of the mandibular nerve in human cadavers.

INTRODUCTION: The lingual, inferior alveolar and auriculotemporal nerves, being branches of the posterior division of the mandibular nerve, mainly innervate the mandibular teeth and all the major salivary glands. Anomalous communications among these branches are widely reported due to their significance to various treatment procedures undertaken in the region. This study was performed as detailed exploration of the functional perspectives of such communicating branches would further enhance the scope of these procedures. METHODS: A total of 36 specimens were dissected to examine the infratemporal region. The branches from the posterior division of the mandibular nerve--namely the lingual, inferior alveolar and auriculotemporal nerves--were carefully dissected, and their branches were studied and analysed for abnormal course. RESULTS: Communication between branches of the posterior division of the mandibular nerve was observed in four specimens. In two of the four specimens, communication between the mylohyoid and lingual nerves was observed. A rare and seldom reported type of communication between the auriculotemporal and inferior alveolar nerves is described in this study. This communicating nerve split into two to form a buttonhole for the passage of the mylohyoid nerve. CONCLUSION: Such communicating branches between nerves found in this study are developmental in origin and thought to maintain functional integrity through an alternative route.

Analysis of the arterial anatomical variations of thyroid gland: anatomic guide for surgical neck dissection.

PURPOSE: Aim of this study was to establish preliminary data on the variations of arterial supply of thyroid gland in Karnataka population. METHODS: The anterior triangles in the neck of formalin fixed cadavers were dissected. The length, branching pattern, number and length of branches of superior thyroid artery (STA) were noted. We measured the length of inferior thyroid artery (ITA) from its point of emergence from thyrocervical trunk (TCT) to lower pole of thyroid gland. The length of the external carotid artery (ECA), TCT from the point of its emergence to the point of its branching was noted. We noted the number of branches from ITA and TCT. Presence of any additional artery supplying the thyroid gland was searched for. Difference in the length of STA and ITA between the two sexes and sides were noted. Statistical analysis was done by Student's t-test. RESULTS: In our study the maximum length of STA was 5.34cm and that of ITA was 5.07cm and there were no statistically significant side-to-side differences in level of bifurcation. CONCLUSIONS: Observations of the present study on the course and branching pattern of arteries around thyroid gland will help in easier approach during thyroid surgeries and interventional techniques (Tab. 1, Fig. 3, Ref. 38).

Morphological and morphometric analysis of supraorbital foramen and supraorbital notch: a study on dry human skulls.

OBJECTIVES: A clear knowledge of the location of the maxillo-facial foramina is essential for clinicians while performing endoscopic surgeries and regional nerve blocks. In the present study, a detailed analysis of the supraorbital foramen (SOF) and supraorbital notch (SON) of South Indian skulls is reported and the data are compared with those from other races and regions. METHODS: Anatomical variation of SOF/SON was studied in 83 adult human skulls bilaterally, using "travelling Vernier's microscope". The skulls belonged to the cadavers of South Indian origin. The parameters used were distanced between the SON/SOF and the nasal midline; distance between the SON/SOF and the frontozygomatic suture (FZS); shape and height of the SOF; transverse diameter of the SON; the presence of accessory foramina (ACF) and their number; as well as the location and distance from the main SON/SOF. RESULTS: SON was more frequently found than the SOF. The mean distance of SON/SOF to the nasal midline was 22.24 mm on the right side and 22.2 mm on the left side. The mean distance of SON/SOF to the frontozygomatic suture was 29.34 mm on the right side and 28.7 mm on the left side. While the mean height of SOF was 3.5 mm on the right side and 3.04 mm on the left side. Also, the mean transverse diameter of SON was 5.17 mm on the right side and 5.58 mm on the left side. The accessory supraorbital foramina were observed in 66.25% of cases. CONCLUSION: There is a difference in the position and dimensions of SOF /SON between different races and people of different regions. Anatomical knowledge of SON /SOF is important in facilitating local anesthetic, forehead lifting, blepharoplasty and other craniofacial surgical procedures.

HIF2α: the interface between oxygen-sensing systems in physiology and pathology

More than 100 years after the original descriptions of altitude adaptation, it is now clear that many of these responses are mediated by a specific isoform of the transcription factor hypoxia-inducible factor (HIF-2α). Here, we review this work, including connectivity with the oxygen chemosensitive response itself, and with paraganglioma, a tumour often affecting chemosensitive tissues.