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Brachyericinae is a subfamily of Erinaceidae (hedgehogs and moonrats) with a very short history and limited distribution. Fossil records of brachyericines, with rare materials, were confined to the...

Background: Streptococci are Gram-positive cocci comprising multiple bacterial species. Lancefield Group A Streptococcus is recognized as a human pathogen. Group A Streptococcal infection in Erinaceidae species has only been previously reported in a wild European hedgehog (Erinaceus europaeus), which died of a disseminated S. pyogenes infection. Case Description: A 1-year-old sexually intact female African pygmy hedgehog (Atelerix albiventris) presented with bilateral cutaneous wounds on both forelimbs. Diagnostic tests showed septic suppurative inflammation and isolation of Lancefield Group A Streptococcus on aerobic bacterial culture. Based on the clinical findings, a diagnosis of Lancefield Group A Streptococcus dermatitis was made. Animal responded well to antibiotic therapy and clinical signs resolved. No reoccurrence was reported in the following 6 months after resolution. Patient was lost to follow-up. Conclusions and Case Relevance: Lancefield Group A Streptococcus is pathogenic to humans and does not usually cause disease in veterinary species. The source of the bacteria in this case was unclear. Further research is necessary to document the normal microflora of hedgehogs and determine if hedgehogs may be carriers of Lancefield Group A Streptococcus.

Background: African pygmy hedgehogs (Atelerix albiventris) belong to the order Insectivora and the Erinaceidae family. In the wild they can be found in the steppes, grasslands and agricultural fields of central Africa. They are becoming more popular as pets and so clinicians need to be familiar with their general care, husbandry and health issues. Aim of the article: This article discusses the general husbandry and care requirements of African pygmy hedgehogs, as well as how to deal with sick hedgehogs.

The South Indian hedgehog (Paraechinus nudiventris) is a lesser known, highly exploited small mammal native to Tamil Nadu, Kerala and Andhra Pradesh in India. This species initially has a broader distribution history, due to ongoing threats, their population is decreased. Apart from distribution range the all other details such as ontology and morphology is still lacking. This study aims to investigate the skull and appendicular skeleton of P. nudiventris. Results revealed the head and body length of hedgehogs was measured as 140–200 mm, and their body weight ranges from 160 to 288 g. The male hedgehogs are larger in compared with females. The additional and more detailed data of the skull and skeletal material of Indian endemic mammal P. nudiventris (Madras hedgehog) would be useful towards its preservation and protection and disease’s management.

Due to the urbanization and human invasion of the natural environments, great changes have been occurred on the food composition and feeding ecology of several animals especially those are sharing human his habitat in fields, wadis and gardens. The desert hedgehogs Paraechinus aethiopicus populations inhabiting different localities in Saudi Arabia were studied by using stomach contents analysis between February 2015 and October 2019. Precise analysis of stomach contents of 55 hedgehogs showed that the food of P. aethiopicus is highly diverse and highly influenced with effect of human on the environment including cooked rice, insects, plant materials, eggshells, worms, garbage and remnants of mammals and birds. Diet composition showed seasonal variations that are apparently associated with changes in the availability of different food items. The present results clearly showed that P. aethiopicus is an omnivorous mammal, capable of adapting to a great variety of dietary compositions in the study sites. Resumo Devido à urbanização e invasão humana dos ambientes naturais, grandes mudanças têm ocorrido na composição alimentar e ecologia alimentar de vários animais, especialmente aqueles que estão compartilhando seu hábitat humano em campos, wadis e jardins. As populações de ouriços-do-deserto Paraechinus aethiopicus que habitam diferentes localidades na Arábia Saudita foram estudadas usando análise de conteúdo estomacal entre fevereiro de 2015 e outubro de 2019. A análise precisa do conteúdo estomacal de 55 ouriços mostrou que a alimentação de P. aethiopicus é altamente diversa e altamente influenciada com efeito de humanos no meio ambiente, incluindo arroz cozido, insetos, materiais vegetais, cascas de ovo, vermes, lixo e restos de mamíferos e pássaros. A composição da dieta apresentou variações sazonais que aparentemente estão associadas a mudanças na disponibilidade de diferentes itens alimentares. Os presentes resultados mostraram claramente que P. aethiopicus é um mamífero onívoro, capaz de se adaptar a uma grande variedade de composições dietéticas nos locais de estudo.

Insectivores (Mammalia: Eulipotyphla) are today a rather successful mammalian order, living almost worldwide in a large variety of habitats. The present chapter focuses on the review of the fossil record of Eulipotyphla in Greece, which starts in the late Oligocene. The fossil remains are isolated dental elements (more rarely postcranial elements), revealed in 47 localities, belonging to the three extant eulipotyphlan families present in Greece also today, Erinaceidae (five genera), Talpidae (six genera) and Soricidae (13 genera), and also the extinct families Dimylidae (one genus), Heterosoricidae (two genera), and Plesiosoricidae (one genus). Eight species which are still recognized have been described from Greek Neogene localities (the erinaceids Galerix symeonidisi, Parasorex kostakii, Schizogalerix macedonica, the talpids Myxomygale engesseri, Desmanella dubia, and the soricids Heterosorex ruemkeae, Amblycoptus jessiae, Deinsdorfia kerkhoffi), while three others are now considered junior synonyms of taxa described from elsewhere (Desmanodon meuleni, Galerix atticus, Dibolia dekkersi).

A large-sized species of Parasorex is common in the MN 13 mammal assemblages from the uppermost Messinian sandy-marly fissure fillings within the Gessoso Solfifera Formation at Brisighella (Northern Apennine). This erinaceid has been classified as Galerix sp. in the first papers on the Brisighella fauna. Later, it was described in detail in an unpublished Ph.D. dissertation by Fanfani (1999), who referred it to Galerix depereti. Van den Hoek Ostende (2001) included G. depereti in the genus Parasorex, Parasorex depereti has been described by Crochet (1986) on scarce material from a few Early Pliocene (MN 14–15) localities of southern France and Spain. Parasorex cf. depereti has been reported from the Early Pliocene fauna of Capo Mannu (Mandriola, Sardinia; Furió and Angelone 2010). The species seems actually distributed in south-western Europe, where it represents the youngest occurrence of the genus Parasorex. The very abundant sample of P. depereti from fissure filling BRS 25 enables a more accurate and comprehensive description of the species. It also permits inspection of the mesial elements of the dentition, which were lacking in the material examined by Crochet (1986). The systematic position of the species has been revisited and compared with those of other Galericini of the Parasorex group.

Iran is home to three genera and four species of hedgehogs in the family Erinaceidae. One of these, Paraechinus hypomelas, is known to occur in Fars Province. In the present study, we report two new distribution records of the Long-eared Hedgehog, Hemiechinus auritus from the southwestern region of Fars Province (Varavi Mountain in Mohr and Lamerd Townships in the southern Zagros Mountains), marking a range extension for this species in southern Iran.

Simple Summary Hedgehogs have a sensitive olfaction, but little is known about their vomeronasal organ, which detects specific chemicals such as pheromones. This is the first study to reveal the morphological and histological features of the vomeronasal organ in the African pygmy hedgehog. Notably, unlike other mammals, the hedgehog has a large, well-developed serous gland in the vomeronasal organ. This gland seems to allow flushing out odorous substances from the vomeronasal organ and might be favorable for subsequent stimulus reception. Abstract The vomeronasal organ (VNO) detects specific chemicals such as pheromones and kairomones. Hedgehogs (Eulipotyphla: Erinaceidae) have a well-developed accessory olfactory bulb that receives projections from the VNO, but little is known about the hedgehog VNO. Here, we studied the histological features of the VNO in five individual African pygmy hedgehogs by hematoxylin-eosin, periodic acid-Schiff, and Alcian blue stains. The hedgehog VNO comprises a hyaline cartilage capsule, soft tissue and epithelial lumen, and it branches from the site just before the incisive duct opening into the nasal cavity. The soft tissues contain several small mucous (or mucoserous) glands and a large serous gland, and many venous sinuses all around the lumen. The VNO lumen is round to oval throughout the hedgehog VNO, and the sensory epithelium lines almost the entire rostral part and medial wall of the middle part. These findings indicate that the VNO is functional and plays an important role in the hedgehog. Notably, the VNO apparently has a characteristic flushing mechanism with serous secretions like those of gustatory glands, which the hedgehog might frequently use to recognize the external environment.

Skulls, jaws and teeth of wild terrestrial small mammals (Sciuridae, Soricidae, Erinaceidae, Talpidae, Gliridae, Arvicolidae, Muridae) are occasionally affected by anomalies and pathologies. The present study documents a total of 362 anomalies and 122 pathological changes across 20 different species. These are all based on data published in Germany, supplemented by our own records. Cases were classified into 14 different categories, according to bone and dental anomalies, fractures and inclusions, bone proliferation, dental disease and extreme wear of teeth. An additional category to specifically account for bone proliferation of the skull was not needed, but such findings are to be expected. The most frequent finding was abnormal tooth growth, particularly the elongation of the upper incisors. In individual cases, there was evidence that small mammals are able to recover even from serious injuries to the skull.

Classifying fossil teeth of Erinaceinae (spiny hedgehogs) is a challenging task, because of their scanty record and systematic treatment that heavily relies on skull characteristics. In this paper we describe the complete set of isolated dental elements of Erinaceinae from the upper Miocene sediments of the Teruel Basin (eastern Central Spain). Four different species were recognized: Postpalerinaceus cf. vireti, Atelerix aff. depereti, Atelerix steensmai nov. sp., and a form classified as Erinaceinae genus and species indet. All four are relatively derived in showing multi-purpose dentitions, not showing only adaptations to insectivory, but also to carnivory, herbivory and possibly durophagy/malacophagy. The temporal occurrence of spiny hedgehogs during the middle to late Miocene in the Teruel Basin and neighboring Calatayud-Montalban Basin peaks within periods of relative aridity, a correlation consistent with modern geographic distribution. Messinian cooling is the best candidate for explaining a remarkable demise of Erinaceinae at 7 Ma.

Ereberix erebericulus gen. et sp. nov., the smallest representative of the Asian Brachyericinae (Erinaceidae, Erinaceomorpha), a peculiar extinct group of short-faced hedgehogs with predatory adaptations, is described from the Lower Miocene Loo Formation of the Taatsiin Gol locality (Valley of Lakes, Mongolia). The description of the new form expands the knowledge on the taxonomic and morphological diversity of the Asian Brachyericinae.

Background/aim Resistance to chemotherapeutic agents is the main cause of reduced survival in non-small cell lung cancer (NSCLC) patients. The Hedgehog (HH) pathway has been shown to be crucial in cell development and survival. Activated in several types of cancer it might be a potent bypass mechanism mediating chemotherapy resistance. Materials and methods HCC827 NSCLC cells were treated with sub-lethal doses of pemetrexed to produce pemetrexed resistance. RT-qPCR was performed to measure gene expression of HH pathway proteins. A cell growth assay was used to measure the impact of the HH-inhibitor Gant61 in naive and chemoresistant cell lines. Results Pemetrexed resistant cells showed significantly increased expression of HH signaling genes (GLI1, GLI2, GLI3, PTCH1, SHH). Supporting these results, pemetrexed resistant cells treated with the HH inhibitor Gant61 showed reduced proliferation compared to naive cells. Conclusion HH pathway may play an important role in mediating pemetrexed resistance in NSCLC cells. Blocking the HH pathway may be a potential option to overcome this resistance.

Gymnures are an ancient group of small insectivorous mammals and are characterized by a controversial taxonomic status and the lack of a description of karyotypes for certain species. In this study, conventional cytogenetic techniques (Giemsa, CBG- and GTG-banding, Ag-NOR), CMA3-DAPI staining, and fluorescent in situ hybridization (FISH) with telomeric DNA probes were used to examine for the first time the karyotypes of lesser gymnures of group Hylomyssuillus Müller, 1840 from northern and southern Vietnam. All studied specimens had karyotypes with 2n=48, NFa=64. C-positive heterochromatic blocks existed in centromeric regions of 7 bi-armed autosomes and the submetacentric X chromosome. The Y chromosome is a C-positive and dot-like. The nucleolus organizer regions resided terminally on the short arms of 2 small bi-armed pairs. Positive signals at the telomeres of all chromosomes were revealed by FISH. CMA3-positive blocks were localized on the telomeric and pericentric regions of most bi-armed and acrocentric chromosomes. Despite the large genetic distances between Hylomys Müller, 1840, lesser gymnures from H.suillus-group from northern and southern Vietnam have similar karyotypic characteristics.

In this issue of Blood , Ghia et al observe that a proportion of patients with chronic lymphocytic leukemia (CLL) harbor mutations in genes involved in the Hedgehog (Hh) pathway resulting in expression of glioma-associated oncogene homolog 1 (GLI1). They also find that GLI1 is expressed in CLL cells without evidence of Hh mutations and that the high GLI1 levels correlate with disease progression. 1

A 3.5-year-old, spayed female, African pygmy hedgehog (Atelerix albiventris) presented with neurologic signs. The tentative clinical diagnosis was wobbly hedgehog syndrome. After 3 months, the patient exhibited the following clinical disease signs, anorexia, weight loss, horizontal nystagmus, exophthalmos, and seizures. The patient's clinical condition gradually became more severe over the next 6 months, without response to any treatment, and subsequently died. Necropsy revealed no gross abnormalities of any internal organs other than the brain. On cross section of the fixed right cerebrum, an 8 × 5 × 5 mm, tan to gray mass was evident within the parenchyma. Histologically, the cerebral mass comprised polygonal to spindle-shaped cells arranged in interlacing bundles, whorls and sheets, consistent with meningioma. To the best of the authors’ knowledge this report represents the first description of meningioma in an African pygmy hedgehog, as also in the Erinaceidae family. Neoplasia should be included among the differential diagnoses when neurologic signs are observed in hedgehogs.

Up to 80% of meningiomas are classified as clinically low-grade, however, a subset of these ‘benign’ cases will ultimately recur and require additional treatment. The role of molecular subgroup in meningioma recurrence has not been thoroughly investigated, despite correlations of this variable with other clinical features. Indeed, epigenetic and transcriptional evidence supports involvement of distinct oncogenic processes within each subgroup, and as shown in other brain tumors, this may result in divergent clinical courses. In the present study, we classified 429 meningiomas into six established molecular subgroups based on genomic driver, and investigated associations of each subgroup with tumor recurrence. At two years of follow-up, we observed differences in progression free survival curves among relatively aggressive (NF2-loss, PI3K-activated, Hedgehog-activated) and quiescent (KLF4-mutant, SMARCB1-mutant, POLR2A-mutant) subgroups (log rank p = 4.3 x 10-2), with the former group recurring at a rate 14x higher. We found PI3K-activated meningiomas recurred significantly earlier than other subgroups (average time to recurrence of 19.2 months; p = 2.2 x 10-2), though we observed an intermediate long-term outcome relative to the Hedgehog and NF2 lesions. Overall, Hedgehog tumors recurred significantly more frequently than other low-grade meningiomas (adj. p = 3.1 x 10-2), and this subgroup was found to be an independent predictor of progression free survival using cox proportional hazards modelling (HR = 3.1; p = 2.4 x 10-2). By contrast, the aggressiveness of NF2 meningiomas was found to depend upon gender, WHO grade, and elevated Ki-67 index, and this subgroup was not an independent prognostic predictor. Our results suggest molecular subgroup is predictive of recurrence in low-grade meningiomas, and thus is an important consideration in post-operative management decisions. Routine genotyping to detect Hedgehog and PI3K mutant lesions may identify patients that would benefit from closer follow-up and consideration of adjuvant therapies.

BACKGROUND Medulloblastoma is an aggressive pediatric brain tumor that is associated with misactivation of the Hedgehog (HH) pathway. Our lab has shown that CDK6, a critical activator of the cell cycle, is a direct transcriptional target of oncogenic HH signaling, and that inhibiting CDK6 blocks the growth of HH-associated medulloblastoma in mice. A clinical trial exploring the efficacy of CDK6 inhibition in medulloblastoma patients is underway, but prior attempts to target the HH pathway in medulloblastoma have been encumbered by resistance to molecular monotherapy. Thus, we sought to identify mechanisms of resistance to CDK6 inhibition in HH-associated medulloblastoma. METHODS We performed orthogonal CRISPR and CRISPR interference screens in HH-associated medulloblastoma cells treated with pharmacologic inhibitors of CDK6 in vitro, and RNA-sequencing of HH-associated medulloblastomas with genetic deletion of CDK6 in vivo. Mechanistic and functional validation of resistance pathways was performed using CRISPR interference, immunoblotting, immunofluorescence, genetics, and pharmacology. Lipid quantification was carried out by ultra-high performance liquid chromatography-tandem mass spectrometry. RESULTS Our results reveal that decreased ribosomal protein expression underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, leading to endoplasmic reticular (ER) stress and activation of the unfolded protein response (UPR). We show that ER stress and the UPR increase the activity of enzymes producing Smoothened-activating sterol lipids that sustain oncogenic HH signaling in medulloblastoma despite CDK6 inhibition. These discoveries suggest that combination molecular therapy against CDK6 and HSD11ß2, an enzyme producing Smoothened-activating lipids, may be an effective treatment for HH-associated medulloblastoma. In support of this hypothesis, we demonstrate that concurrent genetic deletion or pharmacological inhibition of CDK6 and HSD11ß2 additively blocks the growth of multiple models of HH-associated medulloblastoma in mice. CONCLUSIONS Smoothened-activating lipid biosynthesis underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, revealing a novel combination therapy to treat the most common malignant brain tumor in children.

Background: Zoonotic cutaneous leishmaniasis caused by Leishmania major is endemic in 17 of 31 Iranian provinces. Various species of rodents have been introduced as the main reservoirs of the disease. This study was conducted to de­termine the natural infection of hedgehogs with Leishmania spp. in an endemic area of the disease, northern Iran. Methods: Fifteen long-eared hedgehogs were captured alive during 18 months study period, from Apr 2015 to Sep 2016, in Damghan City, Semnan Province, Iran. The animals were identified using apparent characteristics and to de­termine the Leishmania infection, impression smears were prepared from their ear lobes, hind feet, livers, and spleens. Micro­scopic examination and semi-nested PCR were applied to determine the infection and to identify the parasites species respectively. Results: All examined animals were identified as Hemiechinus auritus (Family: Erinaceidae). In microscopic examina­tion, 8 (53.3%) samples were shown to be infected with Leishmania parasites. The higher and lower rate of the infection was observed in the ears as well as the feet and in the liver specimens, 53.3%, and 33.3% respectively. Forty percent (6/ 15) of the samples were molecularly positive and all were identified as L. major parasites. All the examined animals in au­tumn and 50% of them in summer were shown to be infected with Leishmania parasites. Conclusion: This study demonstrated the natural infection of H. auritus with L. major for the first time in Damghan City and introduced these mammals as new potential reservoirs of ZCL in the study area.

Aberrant activation of the sonic hedgehog (SHH) pathway is one of the key drivers of tumorigenesis in aggressive pediatric brain tumors. However, SHH pathway inhibitors for the treatment of brain tumors demonstrated only limited responses in clinical trials indicating that a better understanding of the human SHH pathway is needed. Using an integrative transcriptomic analysis of several thousand normal and neoplastic tissues with and without SHH activation, we identified HHIP-AS1 as an important long non-coding RNA that is strongly associated with SHH signaling in pediatric brain tumors. HHIP-AS1 expression was significantly up- and downregulated upon SHH activation or inhibition, respectively. We also revealed that HHIP-AS1 shares a bidirectional promoter with HHIP and that common transcription factors control both expressions. Transient and stable HHIP-AS1 knockdown (KD) led to a significant less aggressive phenotype of medulloblastoma and ATRT in vitro and in vivo (in cell lines, patient-derived primary cultures and in orthotopic mouse models). In detail, we observed a significant reduction of proliferation, cell viability, clonogenicity, and an induction of cell cycle arrest with a mitotic arrest upon HHIP-AS1 KD. Additionally, RNA sequencing and proteomic analysis unraveled cytoplasmic dynein complex 1 intermediate chain 2 (DYNC1I2), which is a key mitosis regulator, as a target of HHIP-AS1. Further investigations revealed that HHIP-AS1 stabilizes DYNC1I2 via RNA–RNA interaction and that DYNC1I2 overexpression rescued the observed phenotypes. Taken together, our analysis demonstrates that HHIP-AS1 promotes tumorigenesis in SHH-driven brain tumors and identify a novel lncRNA as a component in the human SHH signaling pathway. STEM CELLS

BACKGROUND Medulloblastoma is an aggressive pediatric brain tumor that is associated with misactivation of the Hedgehog (HH) pathway. Our lab has shown that CDK6, a critical activator of the cell cycle, is a direct transcriptional target of oncogenic HH signaling, and that inhibiting CDK6 blocks the growth of HH-associated medulloblastoma in mice. A clinical trial exploring the efficacy of CDK6 inhibition in medulloblastoma patients is underway, but prior attempts to target the HH pathway in medulloblastoma have been encumbered by resistance to molecular monotherapy. Thus, we sought to identify mechanisms of resistance to CDK6 inhibition in HH-associated medulloblastoma. METHODS We performed orthogonal CRISPR and CRISPR interference screens in HH-associated medulloblastoma cells treated with pharmacologic inhibitors of CDK6 in vitro, and RNA-sequencing of HH-associated medulloblastomas with genetic deletion of CDK6 in vivo. Mechanistic and functional validation of resistance pathways was performed using CRISPR interference, immunoblotting, immunofluorescence, genetics, and pharmacology. Lipid quantification was carried out by ultra-high performance liquid chromatography-tandem mass spectrometry. RESULTS Our results reveal that decreased ribosomal protein expression underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, leading to endoplasmic reticular (ER) stress and activation of the unfolded protein response (UPR). We show that ER stress and the UPR increase the activity of enzymes producing Smoothened-activating sterol lipids that sustain oncogenic HH signaling in medulloblastoma despite CDK6 inhibition. These discoveries suggest that combination molecular therapy against CDK6 and HSD11ß2, an enzyme producing Smoothened-activating lipids, may be an effective treatment for HH-associated medulloblastoma. In support of this hypothesis, we demonstrate that concurrent genetic deletion or pharmacological inhibition of CDK6 and HSD11ß2 additively blocks the growth of multiple models of HH-associated medulloblastoma in mice. CONCLUSIONS Smoothened-activating lipid biosynthesis underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, revealing a novel combination therapy to treat the most common malignant brain tumor in children.

The morphology and histological structure of two adult Brandt’s hedgehog, Paraechinus hypomelas, (Brandt, 1836) tongue were examined by light and scanning electron microscopy. On the dorsal surface of the tongue, three types of papillae were observed: filiform, fungiform and vallate papillae. Apex and corpus of the tongue as well as the lateral surface of the corpus were covered with numerous filiform papillae with bifurcated tip, while the epithelium lining the ventral lingual surface was free from papillae. Discoid shape fungiform papillae were scattered over the entire surface of the lingual apex, corpus and lateral surface uniformly between the filiform ones without regional variation in number and size. Three elliptical or oval vallate papillae in an inverted triangle form were found on the root of the tongue. Each papilla had a lobulated and very irregular dorsal surface. Both fungiform and vallate papillae contain taste buds. The foliate papillae was absent. Overall, the present findings reveal that despite some similarities, the lingual papillae of the Brandt’s hedgehog as an omnivore animal has spices-specific characteristics compare to the Erinaceous auritus as an insectivore species. This finding provides a set of basic data about the morphology of tongue and its lingual papillae in Brandt’s hedgehog.

Twenty-one species of small mammals are recognized from the Observation Quarry fauna including four new species: the lipotyphlans Lanthanotherium observatum (Erinaceidae), Antesorex wilsoni (Soricidae), and Scalopoides hutchisoni (Talpidae), and the rodent Mioheteromys subterior (Heteromyidae). Due to more complete material, emended diagnoses are provided for the plesiosoricid Plesiosorex greeni Martin and Lim, 2004, and cricetid rodent Copemys lindsayi Sutton and Korth, 1995. Of the 21 species recognized, seven are unique to this faunal assemblage, six are restricted to the Hemingfordian, seven are known elsewhere only from the Barstovian or later, and one is known from both the Hemingfordian and Barstovian. The small mammals suggest that the Observation Quarry contains a transitional Hemingfordian-Barstovian fauna with a greater number of species from the latter, supporting an early Barstovian age.

Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment. Pro-inflammatory macrophages can suppress while anti-inflammatory macrophages can promote tumor growth. Despite their abundance in many tumors, the origins and diversity of TAMs are not well understood, especially in pediatric brain tumors. Using single-cell RNA sequencing in a genetically engineered mouse model (Ptch+/-:p53-/-) of SHH-MB, we identified the dual microglia and monocytic origin of macrophage and their transcriptomic heterogeneity. We demonstrate differential recruitment and function of macrophages under distinct modalities of tumor therapy of molecular targeted hedgehog inhibition versus radiation. We additionally identify a monocytic macrophage population recruited post-radiation that is immune suppressive, suggesting a mechanism for radiation treatment failure. These insights uncover potential strategies for immunomodulation as adjunctive therapy for radiation.

Breast cancer is the second leading cause of brain metastases in women; patients with breast cancer brain metastasis (BCBM) survive an average of 6–18 months following diagnosis. Cancer stem cells are thought to be one of the driving forces behind distant metastasis, treatment resistance, and late-stage recurrence. The hedgehog-smoothened pathway has been identified as an important mediator of breast cancer stem cells (BCSC); however, FDA-approved therapies targeting smoothened have demonstrated limited clinical efficacy in breast cancer. Despite advances made in understanding BCSC, it is still challenging to effectively target BCSC underscoring the need to identify and inhibit novel mediators of BCSC for treating BCBM patients. Our laboratory recently reported that truncated glioma-associated oncogene homolog 1 (tGLI1) promotes preferential metastasis to the brain in breast cancer by activating BCSC and astrocytes in the tumor microenvironment (Oncogene 39:64–78, 2020). tGLI1 was discovered in our laboratory as an alternatively spliced GLI1 that functions as a tumor-specific gain-of-function transcription factor and terminal effector of the hedgehog pathway. We found that tGLI1 knockdown abrogated BCBM, providing the rationale to therapeutically target tGLI1. Cell-based chemical screens followed by validations demonstrated that ketoconazole, an FDA-approved azole antifungal, specifically inhibits tGLI1 leading to suppression of BCSC in vitro and BCBM in vivo. Based on these data, we opened a window-of-opportunity study in patients with BCBM to determine if ketoconazole penetrates the blood-brain barrier (BBB) and alters tGLI1 signaling in humans (NCT03796273). Preliminary sample analysis has confirmed tGLI1 expression in collected BCBM samples. To help identify more effective tGLI1 inhibitors, we screened 63 azole compounds for tGLI1-selectivity and identified four additional compounds as potential tGLI1 inhibitors. Animal studies were performed to compare the efficacy of these four compounds with ketoconazole in suppressing BCBM. Collectively, these data establish tGLI1 as an actionable target for BCBM.

The Galericinae are a group of Erinaceidae that are currently distributed in Southeast and Eastern Asia. Although galericines have an Asian origin, their fossil record in this region is scarce, whi...

The Korean Peninsula and its associated Pacific islands have a distinctive, yet poorly studied mammalian fauna. Korea was a land of invasions and wars for many centuries. The loss of large mammals per unit area that has occurred in Korea may have been greater than in any other country. The peninsula has a depauperate rodent community. The forests are mostly harvested, replaced by intensive agriculture. Unfortunately, the dissemination of information about the mammals of Korea and their taxonomy has been limited because most publications were written in Japanese or Korean. We provide an updated checklist of all the species of Korean mammals, including a review of their taxonomy, distribution, and conservation status based on information extracted from international museum collections, local survey databases (Wildlife Survey and National Nature-Environmental Survey, South Korea) and a literature review. We identify 84 species of terrestrial mammals and 43 species of marine mammals that occur, or once occurred, in Korea. Due to previous, erroneous identifications, we delisted three soricids, two vespertilionids, one phocid, one sciurid and one murid. In total, we confirm the presence in Korea of 127 species of mammals distributed in eight Orders and 32 Families. We provide dichotomous keys for the identification of all the Korean species of mammals together with updated distribution maps.

Hedgehog (Hh) signalling plays conserved roles in controlling embryonic development; its dysregulation causes many diseases including cancers. The G protein-coupled receptor Smoothened (Smo) is the key signal transducer of the Hh pathway, whose posttranslational regulation has been shown to be critical for its accumulation and activation. Ubiquitination has been reported an essential posttranslational regulation of Smo. Here, we identify a novel E3 ligase of Smo, Herc4, which binds to Smo, and regulates Hh signalling by controlling Smo ubiquitination and degradation. Interestingly, our data suggest that Herc4-mediated Smo degradation is regulated by Hh in PKA-primed phosphorylation-dependent and independent manners.

Moniliformis cryptosaudi n. sp. (Moniliformidae) is an acanthocephalan described from the long-eared hedgehog Hemiechinus auritus (Gmelin) (Erinaceidae) in Iraq as an incipient cryptic species of Moniliformis saudi Amin, Heckmann, Mohammed, Evans, 2016 described from the desert hedgehog Paraechinus aethiopicus (Ehrenberg) (Erinaceidae) in Saudi Arabia. Microscopical studies demonstrate that the two species are morphologically indistinguishable with practically identical measurements and counts but differed significantly in their energy dispersive X-ray analysis (EDXA) of metal composition of hooks. Hooks of specimens of the new species appeared to be of collagen material with very low levels of phosphorus and calcium unlike those of M. saudi and Moniliformis kalahariensis Meyer, 1931 that had high levels of calcium and phosphorus. Using 18S rDNA and cox1 genes, M. Saudi and M. kalahariensis were shown to be molecularly distinct but the molecular profiles of M. saudi and M. cryptosaudi were more similar. The molecular profile of M. kalahariensis collected from the South African hedgehog Atelerix frontalis Smith (Erinaceidae) in South Africa is reported for the first time and is studied only for comparative purposes. Moniliformis saudi and M. kalahariensis had comparable EDXA metal analysis that was distinct from that of M. cryptosaudi.

Medulloblastoma, the most common pediatric malignant brain tumor, is divided into at least four molecular subtypes. The Sonic Hedgehog (SHH) subtype, accounts for approximately 30% of all cases and has an intermediate prognosis (5-year overall survival of 60%). Current treatments involve surgery, adjuvant radiotherapy for older children, and chemotherapy, however, lead to devastating morbidity, including decline in cognition and intellect, endocrine deficiencies, and secondary malignancies. More recently, targeted treatment options that inhibit the Hedgehog pathway have demonstrated clinical efficacy, including the Smoothened inhibitor, Vismodegib, however result studies have also shown secondary toxicities including effects on bone development. Here we investigated the efficacy of Vismodegib packaged in a fucoidan-based nanoparticle (Fi-Vis) that targets P-selectin, a protein overexpressed on vascular endothelial cells and is induced by 2Gy ionizing radiation (XRT) in a time- and dose-dependent manner. This p-selectin targeting nanoparticle drug delivery system shows selectivity toward tumor vasculature and not normal brain vasculature in a genetically relevant SHH-driven medulloblastoma mouse model as assessed by ex vivo infrared imaging. Quantitative RT-PCR analysis on SHH medulloblastoma tumor tissue following 2Gy XRT and Fi-Vis single dose treatment (as low as 10mg/kg) showed a synergistic inhibition of Gli1 expression (up to ~90% target inhibition). Furthermore, we demonstrate that lower single fraction XRT doses as low as 1Gy also induce P-selectin expression within medulloblastoma tumor vasculature. These data suggest applicability of combined XRT and tumor vasculature-targeted nanotherapeutic dose de-escalation strategies for medulloblastoma and potentially other pediatric brain tumors.

The classic locality of Hasznos (Middle Miocene, Mid Badenian, Hungary) has yielded a diverse assemblage of insectivores that is dominated by Erinaceidae and Soricidae, with three species each. The Talpidae are represented by one species, Desmanodon aff. crocheti. Prior to this record of D. crocheti in Hasznos, this species has only been recorded in the Late Badenian of the North Alpine Foreland Basin. The high similarity of the assemblage to that of Samsonhaza 3 confirms that Hasznos and Samsonhaza are very close in age. The new data are discussed in their biostratigraphical and biogeographical contexts.

Hedgehogs (erinaceid insectivores) are a common element in Miocene small mammal faunas of Pakistan, but little material has been formally described. Here, we report on extensive collections from numerous localities across Pakistan, most from the Potwar Plateau, Punjab, and the Sehwan area in Sindh. The dominant erinaceid is Galerix, which is also known from Europe, Turkey, and East Africa. We document a new early species of Galerix, Galerix wesselsae, in sites from Sehwan, the Zinda Pir Dome, the Potwar Plateau, and Banda Daud Shah ranging in age from about 19 to 14 Ma. This species briefly co-occurs with and is then replaced by the smaller Galerix rutlandae, previously based on a few teeth from Daud Khel. G. rutlandae is a common element of Chinji Formation faunas through about 11.5 Ma. Scanty material of an apparently new species of Schizogalerix succeeds Galerix. After 10.2 Ma, no galericines occur in Pakistan, but rare erinaceines are later faunal components.

In the Early Pleistocene locality of Cueva Victoria, the insectivores are represented by several fossil teeth, mandibles and skull fragments. In the present work, we describe and provide measurements of these fossils for the first time. Insectivores show a rather low taxonomic diversity in Cueva Victoria, with only two different species. Considering the environmental requirements for their extant relatives, the presence of only one hedgehog (Erinaceus cf. praeglacialis Brunner, 1933), and one shrew (Crocidura kornfeldi Kormos, 1934) points to the existence of dry and warm conditions in the surrounding area of Cueva Victoria, unfavourable to other contemporary species of insectivores.

International audience; Background: In Europe, hard ticks of the subgenus Pholeoixodes (Ixodidae: Ixodes) are usually associated with burrow-dwelling mammals and terrestrial birds. Reports of Pholeoixodes spp. from carnivores are frequently contradictory, and their identification is not based on key diagnostic characters. Therefore, the aims of the present study were to identify ticks collected from dogs, foxes and badgers in several European countries, and to reassess their systematic status with molecular analyses using two mitochondrial markers. Results: Between 2003 and 2017, 144 Pholeoixodes spp. ticks were collected in nine European countries. From accurate descriptions and comparison with type-materials, a simple illustrated identification key was compiled for adult females, by focusing on the shape of the anterior surface of basis capituli. Based on this key, 71 female ticks were identified as I. canisuga, 21 as I. kaiseri and 21 as I. hexagonus. DNA was extracted from these 113 female ticks, and from further 31 specimens. Fragments of two mitochondrial genes, cox1 (cytochrome c oxidase subunit 1) and 16S rRNA, were amplified and sequenced. Ixodes kaiseri had nine unique cox1 haplotypes, which showed 99.2-100% sequence identity, whereas I. canisuga and I. hexagonus had eleven and five cox1 haplotypes, respectively, with 99.5-100% sequence identity. The distribution of cox1 haplotypes reflected a geographical pattern. Pholeoixodes spp. ticks had fewer 16S rRNA haplotypes, with a lower degree of intraspecific divergence (99.5-100% sequence identity) and no geographical clustering. Phylogenetic analyses were in agreement with morphology: I. kaiseri and I. hexagonus (with the similar shape of the anterior surface of basis capituli) were genetically more closely related to each other than to I. canisuga. Phylogenetic analyses also showed that the subgenus Eschatocephalus (bat ticks) clustered within the subgenus Pholeoixodes. Conclusions: A simple, illustrated identification key is provided for female Pholeoixodes ticks of carnivores (including I. hexagonus and I. rugicollis) to prevent future misidentification of these species. It is also shown that I. kaiseri is more widespread in Europe than previously thought. Phylogenetic analyses suggest that the subgenus Pholeoixodes is not monophyletic: either the subgenus Eschatocephalus should be included in Pholeoixodes, or the latter subgenus should be divided, which is a task for future studies.

The Late Miocene giant erinaceid Deinogalerix from Scontrone and Gargano (Italy) is associated with many other vertebrates in deposits of a past island, the “Abruzzo-Apulia Platform”. At Gargano, Deinogalerix is accompanied by the moderately endemized Galericini Apulogalerix. This first extensive cladistic analysis is aimed at defining the relationships of Deinogalerix with characteristic members of the tribe Galericini. The analysis was performed on a matrix of 30 characters and 19 taxa and identified some smaller clades, nested within three major ones. The latter include: (i) a pentatomy of Galerix species, (ii) a polytomy of “transitional” Galerix–Parasorex species and (iii) a large clade with Parasorex, Schizogalerix and Gargano representatives. Galerix and Parasorex proved to be paraphyletic and Schizogalerix monophyletic. Based on the results of the analysis, Deinogalerix and Apulogalerix have distinct origins, which supports an asynchronous colonization of the island. The line of Deinogalerix possibly stemmed from some eastern species transitional between Galerix and Parasorex around Mammal Neogene (MN) zone 2. Conversely, the line of Apulogalerix originated from a primitive Parasorex ibericus, or a close relative, around MN 9–10. Another important result was detecting an impressive early Miocene (MN 2?) radiation of Galericini. Moreover, Schizogalerix and Parasorex originated from eastern Galericini morphologically transitional between Galerix and Parasorex.

We sequenced and characterized the complete mitogenome (KX964606) of the Amur hedgehog Erinaceus amurensis to provide more data for comparative mitogenomics of the genus Erinaceus (Erinaceidae). The mitogenome of E. amurensis is a circular molecule 16,941 bp long, consisting of a control region and a conserved set of 37 genes containing 13 protein-coding genes, 22 tRNA genes, and two rRNA genes (12S rRNA and 16S rRNA). The mitogenome of E. amurensis is AT-biased, with a nucleotide composition of 33.9% A, 21.1% C, 32.6% T, and 12.4% G. The mitogenomes of E. amurensis and the closely related hedgehog species E. europaeus, excluding the control region (66.7%), share over 90% sequence similarity. According to the inter-generic relationship based on six mitogenomes described from five genera of Erinaceidae, the subfamilies Erinaceinae and Galericinae are strongly supported as monophyletic groups, with each genus well placed within its own subfamily. Within the subfamily Erinaceinae, E. amurensis is a sister species to E. europaeus, and the relationship between Hemiechinus and Erinaceus is strongly supported. Within the subfamily Galericinae, the clade of Hylomys + Neotetracus was sister to that of Echinosorex, with clades supported by high values. Our findings will help to understand the codon usage pattern and molecular evolution of E. amurensis, and provide insight into inter-generic relationships within the family Erinaceidae. In future studies, the inclusion of mitogenomes from other genera would greatly enhance our understanding of higher phylogeny within the Erinaceidae.

In the present study, light and scanning electron microscopy (SEM) were used to further study the detailed morphology of Physaloptera clausa Rudolphi, 1819, based on the material collected from the Amur hedgehog E. amurensis Schrenk in China. The results revealed a few previously unreported morphological features and some morphological and morphometric variability between our specimens and the previous studies. The present supplementary morphological characters and morphometric data could help us to recognize this species more accurately.

Methods of the diagnosis of pathophysiological processes in the skulls of hedgehogs are provided. They are based on the identification of functional relationships between the development of the individual parts of skull and evaluation of the potential danger for the changes. Swelling of frontal bones is not a diagnostic feature for diagnostics of the Eastern hedgehog, but a sign (indicator) of pathology. Swelling of frontal bones is not a diagnostic feature, but a sign (indicator) of pathology. Age changes of the hedgehogs skull arch’s inner surface are analyzed.

Recent advances in understanding the major bottlenecks in derivation of engraftable HSCs and lymphoid cells from pluripotent stem cells (PSC), have identified deficiencies in NOTCH and HOXA signaling as contributing factors to the observed functional deficits of PSC-derived hematopoietic progenitors. However, little is known about the mechanisms that are essential for establishing these pathways during PSC differentiation. Here, we revealed the critical role of SOX17 in linking HOXA and NOTCH-mediated arterial programs in hemogenic endothelium (HE) and specification of definitive lympho-myeloid hematopoiesis. Using SOX17-knockout (SOX17-/-) and SOX17 DOX-inducible (iSOX17) hESCs, we found that SOX17-deficiency substantially reduces formation of CD144+CD43-CD73-DLL4+CXCR4+/- arterial HE and definitive lympho-myeloid hematopoiesis, while SOX17 upregulation at mesodermal stage of development causes the opposite effect. Molecular profiling of HE generated from iSOX17 hESCs in DOX+ and DOX- conditions using RNAseq, SOX17 ChIPseq and ATACseq, revealed that SOX17 overexpression upregulates 522 genes enriched in NOTCH, TGFb, HEDGEHOG and WNT signaling, including DLL1, DLL4, NOTCH4, LFNG, WNT5a, WNT5b, GLI3, and genes associated with HSC development, CXCR4,KITLG and ALDH1A2. In addition, we noted significant upregulation of HOXA7,HOXA9, HOXA10, HOXB8, HOXC4 and CDX2 homeobox genes in SOX17-induced cultures, with no expression of HOXA genes observed in HE from SOX17-/- cells. ChIPSeq analysis revealed DOX+ specific SOX17 binding at transcriptional start sites (TSS) of 316 significantly upregulated genes, including ALDH1A2, CDX2, DLL1, DLL4, HEY1, HOXA7, HOXB8, HOXC4 and KITLG, suggesting that upregulation of these genes could be explained by their direct activation by SOX17. Since ALDH1A2 and CDX2 are known to play a role in the activation of HOXA genes, we investigated whether SOX17's effect on HOXA expression could also be mediated by ALDH1A2 and CDX2. We found that adding ALDH1 inhibitor to DOX+ cultures had no effect on arterial HE development and HOXA expression. In contrast, transfection of iSOX17 hPSCs cultures with CDX2 shRNA significantly decreased arterial HE formation and downregulated HOXA7, HOXA9, and HOXA10 expression. Overall, our studies indicate that SOX17 plays a critical role in the activation and integration of arterial and HOXA programs in HE, which is mediated by CDX2. These findings will be important for designing a strategy for direct HSC fate programming from hPSCs. Disclosures Uenishi: Casebia Therapeutics: Employment. Slukvin:Cynata Therapeutics: Consultancy, Other: Founder and Stockholder.

Sonic Hedgehog (SHH) medulloblastoma originates from the cerebellar granule neuron progenitor (CGNP) population that depends on Hedgehog signaling for its expansion. While SHH tumors are characterized by an overall deregulation of this pathway, they also exhibit aberrations that are specific for patient age. To investigate if the developmental stage of the tumor cell-of-origin can account for these age-specific lesions, we compared transcriptomes from developing mouse CGNPs and observed highly dynamic gene expression changes as function of age. Cross-species comparison with a cohort of SHH medulloblastoma showed partial maintenance of these patterns in the different medulloblastoma patient-age groups. In particular, we found low primary cilia expression in early CGNPs and infant medulloblastoma, which coincided with insensitivity to Smoothened manipulation. Together, these findings can explain the absence of SMOOTHENED mutations in infant patients and suggest that drugs targeting the SHH pathway downstream of SMOOTHENED will be most appropriate for infant patients.

The complete mitochondrial genome of the small-toothed forest hedgehog Mesechinus miodon (Eulipotyphla: Erinaceidae) has been reconstructed from Illumina sequencing data. The circular genome is 16 842 bp long, comprising 22 transfer RNAs (tRNAs), 13 protein-coding genes (PCGs), two ribosomal RNAs (rRNAs), and one control region. All PCGs are initiated with ATR (ATA/ATG) codons, except for nad4 with GTG as its initiation codon. Two PCGs (cox3 and nad4) harbor an incomplete termination codon T, while the others are terminated with TAA (atp6, cox1, cox2, nad1, nad2, nad3, nad4l, nad5, and nad6), TAG (atp8) or AGA (cytb). The base composition is highly biased (34.9% A, 19.7% C, 11.9% G, and 33.5% T for the light strand) with an overall A + T content of 68.4%. Phylogenetic analysis indicated that M. miodon is more closely related to the consubfamilial long-eared hedgehog Hemiechinus auritus than to those within the order Eulipotyphla.

Programs that control early lineage fate decisions and transitions from embryonic to adult human cell types during development are poorly understood. Using human pluripotent stem cells (hPSCs), in the present study, we reveal reduction of Hedgehog (Hh) signaling correlates to developmental progression of hematopoiesis throughout human ontogeny. Both chemical- and gene-targeting–mediated inactivation of Hh signaling augmented hematopoietic fate and initiated transitions from embryonic to adult hematopoiesis, as measured by globin regulation in hPSCs. Inhibition of the Hh pathway resulted in truncation of Gli3 to its repressor, Gli3R, and was shown to be necessary and sufficient for initiating this transition. Our results reveal an unprecedented role for Hh signaling in the regulation of adult hematopoietic specification, thereby demonstrating the ability to modulate the default embryonic programs of hPSCs.