Mammalian organ regeneration in spiny mice.

Fibrosis-driven solid organ failure is a major world-wide health burden with few therapeutic options. Spiny mice (genus: Acomys) are terrestrial mammals that regenerate severe skin wounds without fibrotic scars to evade predators. Recent studies have shown that spiny mice also regenerate acute ischemic and traumatic injuries to kidney, heart, spinal cord, and skeletal muscle. A common feature of this evolved wound healing response is a lack of formation of fibrotic scar tissue that degrades organ function, inhibits regeneration, and leads to organ failure. Complex tissue regeneration is an extremely rare property among mammalian species. In this article, we discuss the evidence that Acomys represents an emerging model organism that offers a unique opportunity for the biomedical community to investigate and clinically translate molecular mechanisms of scarless wound healing and regeneration of organ function in a mammalian species.

A conserved acetylation switch enables pharmacological control of tubby-like protein stability.

Tubby-like proteins (TULPs) are characterized by a conserved C-terminal domain that binds phosphoinositides. Collectively, mammalian TULP1-4 proteins play essential roles in intracellular transport, cell differentiation, signaling, and motility. Yet, little is known about how the function of these proteins is regulated in cells. Here, we present the protein-protein interaction network of TULP3, a protein that is responsible for the trafficking of G-protein-coupled receptors to cilia and whose aberrant expression is associated with severe developmental disorders and polycystic kidney disease. We identify several protein interaction nodes linked to TULP3 that include enzymes involved in acetylation and ubiquitination. We show that acetylation of two key lysine residues on TULP3 by p300 increases TULP3 protein abundance and that deacetylation of these sites by HDAC1 decreases protein levels. Furthermore, we show that one of these sites is ubiquitinated in the absence of acetylation and that acetylation inversely correlates with ubiquitination of TULP3. This mechanism is evidently conserved across species and is active in zebrafish during development. Finally, we identify this same regulatory module in TULP1, TULP2, and TULP4 and demonstrate that the stability of these proteins is similarly modulated by an acetylation switch. This study unveils a signaling pathway that links nuclear enzymes to ciliary membrane receptors via TULP3, describes a dynamic mechanism for the regulation of all tubby-like proteins, and explores how to exploit it pharmacologically using drugs.

Development and evolution of the vestibular apparatuses of the inner ear.

The vertebrate inner ear is a labyrinthine sensory organ responsible for perceiving sound and body motion. While a great deal of research has been invested in understanding the auditory system, a growing body of work has begun to delineate the complex developmental program behind the apparatuses of the inner ear involved with vestibular function. These animal studies have helped identify genes involved in inner ear development and model syndromes known to include vestibular dysfunction, paving the way for generating treatments for people suffering from these disorders. This review will provide an overview of known inner ear anatomy and function and summarize the exciting discoveries behind inner ear development and the evolution of its vestibular apparatuses.

Morphogenetic defects underlie Superior Coloboma, a newly identified closure disorder of the dorsal eye.

The eye primordium arises as a lateral outgrowth of the forebrain, with a transient fissure on the inferior side of the optic cup providing an entry point for developing blood vessels. Incomplete closure of the inferior ocular fissure results in coloboma, a disease characterized by gaps in the inferior eye and recognized as a significant cause of pediatric blindness. Here, we identify eight patients with defects in tissues of the superior eye, a congenital disorder that we term superior coloboma. The embryonic origin of superior coloboma could not be explained by conventional models of eye development, leading us to reanalyze morphogenesis of the dorsal eye. Our studies revealed the presence of the superior ocular sulcus (SOS), a transient division of the dorsal eye conserved across fish, chick, and mouse. Exome sequencing of superior coloboma patients identified rare variants in a Bone Morphogenetic Protein (Bmp) receptor (BMPR1A) and T-box transcription factor (TBX2). Consistent with this, we find sulcus closure defects in zebrafish lacking Bmp signaling or Tbx2b. In addition, loss of dorsal ocular Bmp is rescued by concomitant suppression of the ventral-specific Hedgehog pathway, arguing that sulcus closure is dependent on dorsal-ventral eye patterning cues. The superior ocular sulcus acts as a conduit for blood vessels, with altered sulcus closure resulting in inappropriate connections between the hyaloid and superficial vascular systems. Together, our findings explain the existence of superior coloboma, a congenital ocular anomaly resulting from aberrant morphogenesis of a developmental structure.

Ocular coloboma: Genetic variants reveal a dynamic model of eye development.

Ocular coloboma is a congenital disorder of the eye where a gap exists in the inferior retina, lens, iris, or optic nerve tissue. With a prevalence of 2-19 per 100,000 live births, coloboma, and microphthalmia, an associated ocular disorder, represent up to 10% of childhood blindness. It manifests due to the failure of choroid fissure closure during eye development, and it is a part of a spectrum of ocular disorders that include microphthalmia and anophthalmia. Use of genetic approaches from classical pedigree analyses to next generation sequencing has identified more than 40 loci that are associated with the causality of ocular coloboma. As we have expanded studies to include singleton cases, hereditability has been very challenging to prove. As such, researchers over the past 20 years, have unraveled the complex interrelationship amongst these 40 genes using vertebrate model organisms. Such research has greatly increased our understanding of eye development. These genes function to regulate initial specification of the eye field, migration of retinal precursors, patterning of the retina, neural crest cell biology, and activity of head mesoderm. This review will discuss the discovery of loci using patient data, their investigations in animal models, and the recent advances stemming from animal models that shed new light in patient diagnosis.

Chemogenetic ablation of dopaminergic neurons leads to transient locomotor impairments in zebrafish larvae.

To determine the impact of a controlled loss of dopaminergic neurons on locomotor function, we generated transgenic zebrafish, Tg(dat:CFP-NTR), expressing a cyan fluorescent protein-nitroreductase fusion protein (CFP-NTR) under the control of dopamine transporter (dat) cis-regulatory elements. Embryonic and larval zebrafish express the transgene in several groups of dopaminergic neurons, notably in the olfactory bulb, telencephalon, diencephalon and caudal hypothalamus. Administration of the pro-drug metronidazole (Mtz) resulted in activation of caspase 3 in CFP-positive neurons and in a reduction in dat-positive cells by 5 days post-fertilization (dpf). Loss of neurons coincided with impairments in global locomotor parameters such as swimming distance, percentage of time spent moving, as well as changes in tail bend parameters such as time to maximal bend and angular velocity. Dopamine levels were transiently decreased following Mtz administration. Recovery of some of the locomotor parameters was observed by 7 dpf. However, the total numbers of dat-expressing neurons were still decreased at 7, 12, or 14 dpf, even though there was evidence for production of new dat-expressing cells. Tg(dat:CFP-NTR) zebrafish provide a model to correlate altered dopaminergic neuron numbers with locomotor function and to investigate factors influencing regeneration of dopaminergic neurons.

Hemophagocytic Lymphohistiocytosis Induced by Brucellosis: A Case Report.

Hemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory condition triggered by infections, malignancies, or autoimmune conditions. Brucellosis is a zoonotic disease contracted through exposure to infected animals or consumption of unpasteurized dairy products. The complications of both pathologies may be fatal. This report presents a rare instance of HLH induced by Brucellosis, highlighting the need for increased recognition of this life-threatening association.

A narrative review of combining radiation and immunotherapy in gastroesophageal cancers.

Despite advances in chemotherapy, radiation, and surgery, prognosis in gastroesophageal cancers (GEC) remains poor. Recent studies have demonstrated that immune checkpoint inhibitors specific to the PD-1/PD-L1 axis can improve survival with dramatic durability for a subset of patients with GEC. Radiation therapy (RT) has been shown to enhance priming and anti-tumor immunogenicity. The combination of these two treatments has shown promising results acting synergistically in pre-clinical and clinical models. Much of this synergy appears linked to in-field radiation responses, but also the abscopal response where out-of-field tumors demonstrate regression. In this review, we summarize the current role of immunotherapy and radiation in GEC. We also highlight progress from preclinical studies and translational biomarker analyses that provide rationale for ongoing efforts combining immune checkpoint inhibition and radiotherapy specifically in GECs. Questions that remain unanswered in the clinic are the optimal radiation dosing, timing, and fractionation strategies to augment abscopal immune responses. Increasing recognition of the heterogeneity of immunosuppressive mechanisms that can arise in response to radiation indicates the need for novel immune checkpoint inhibitors that target beyond the PD-1/PD-L1 axis. Smartly designed prospective trials incorporating these two approaches with ongoing translational analyses will be critical in increasing the success of combinatorial radiation and immunotherapy strategies in this disease.

Sarcoma of the Breast: Clinical Characteristics and Outcomes of 991 Patients from the National Cancer Database.

BACKGROUND: Sarcoma of the breast is a rare malignancy with heterogeneous histology. Angiosarcoma, including secondary angiosarcoma from previous radiation, is the most common type of sarcoma of the breast. Other types of sarcomas of the breast have limited clinical and survival information. METHODS: We obtained clinicopathological data and survival outcomes from the patients with sarcoma of the breast, excluding angiosarcoma, that were registered in the National Cancer Database (NCDB) from 2004 to 2016. The treatment patterns and prognostic factors were analyzed. RESULTS: A total of 991 patients had sarcoma of the breast other than angiosarcoma. The most common histology was spindle cell sarcoma (13.4%), followed by leiomyosarcoma (11.7%) and giant cell sarcoma (10.1%). Surgical resection was performed in 894 out of 991 patients (90.2%), including R0 resection achieved in 781 (87.4%). The patients who received surgery showed better survival than the patients without surgery regardless of radiation therapy. When radiation was added to the surgical management, the OS (overall survival) benefit was marginally significant (hazard ratio 1.30 (CI 1.01-1.67), p=0.044). Adding chemotherapy did not improve OS. CONCLUSIONS: Surgical resection seems to be the most important treatment modality in sarcoma of the breast from the analysis of a large database. Radiation therapy added a minor survival benefit to the patients who received surgical resection. Systemic chemotherapy did not play a clear role in sarcoma of the breast.

Visualization of the Superior Ocular Sulcus during Danio rerio Embryogenesis.

Congenital ocular coloboma is a genetic disorder that is typically observed as a cleft in the inferior aspect of the eye resulting from incomplete choroid fissure closure. Recently, the identification of individuals with coloboma in the superior aspect of the iris, retina, and lens led to the discovery of a novel structure, referred to as the superior fissure or superior ocular sulcus (SOS), that is transiently present on the dorsal aspect of the optic cup during vertebrate eye development. Although this structure is conserved across mice, chick, fish, and newt, our current understanding of the SOS is limited. In order to elucidate factors that contribute to its formation and closure, it is imperative to be able to observe it and identify abnormalities, such as delay in the closure of the SOS. Here, we set out to create a standardized series of protocols that can be used to efficiently visualize the SOS by combining widely available microscopy techniques with common molecular biology techniques such as immunofluorescent staining and mRNA overexpression. While this set of protocols focuses on the ability to observe SOS closure delay, it is adaptable to the experimenter's needs and can be easily modified. Overall, we hope to create an approachable method through which our understanding of the SOS can be advanced to expand the current knowledge of vertebrate eye development.

The mechanism of morphogenesis in a phase-separating concentrated multicomponent alloy.

What determines the morphology of a decomposing alloy? Besides the well-established effect of the nucleation barrier, we demonstrate that, in a concentrated multicomponent Ni(Al,Cr) alloy, the details of the diffusion mechanism strongly affect the kinetic pathway of precipitation. Our argument is based on the combined use of atomic-scale observations, using three-dimensional atom-probe tomography (3D APT), lattice kinetic Monte Carlo simulations and the theory of diffusion. By an optimized choice of thermodynamic and kinetic parameters, we first reproduce the 3D APT observations, in particular the early-stage transient occurrence of coagulated precipitates. We then modify the kinetic correlations among the atomic fluxes in the simulation, without altering the thermodynamic driving force for phase separation, by changing the vacancy-solute interactions, resulting in a suppression of coagulation. Such changes can only be quantitatively accounted for with non-zero values for the off-diagonal terms of the Onsager matrix, at variance with classical models.