Biology subjects

Lang, H.

Publications and source records attributed to Lang, H..

8 recordsLinked to original sources

bioRxiv2022

Peripheral Auditory Nerve Impairment in a Mouse Model of Syndromic Autism

Dysfunction of the peripheral auditory nerve (AN) contributes to dynamic changes throughout the central auditory system, resulting in abnormal auditory processing, including hypersensitivity. Altered sound sensitivity is frequently observed in autism spectrum disorder (ASD), suggesting that AN deficits and changes in auditory information processing may contribute to ASD-associated symptoms, including social communication deficits and hyperacusis. The MEF2C transcription factor is associated with risk for several neurodevelopmental disorders, and mutations or deletions of MEF2C produce a haploinsufficiency syndrome characterized by ASD, language and cognitive deficits. A mouse model of this syndromic ASD (i.e., Mef2c+/- or Mef2c-Het) recapitulates many of the MEF2C Haploinsufficiency syndrome-linked behaviors including communication deficits. We show here that Mef2c-Het mice exhibit functional impairment of the peripheral AN and a modest reduction in hearing sensitivity. We find that MEF2C is expressed during development in multiple AN and cochlear cell types, and in Mef2c-Het mice, we observe multiple cellular and molecular alterations associated with the AN, including abnormal myelination, neuronal degeneration, neuronal mitochondria dysfunction, and increased macrophage activation and cochlear inflammation. These results reveal the importance of MEF2C function in inner ear development and function and the engagement of immune cells and other non-neuronal cells, which suggests that microglia/macrophages and other non-neuronal cells might contribute, directly or indirectly, to AN dysfunction and ASD-related phenotypes. Finally, our study establishes a comprehensive approach for characterizing AN function at the physiological, cellular, and molecular levels in mice, which can be applied to animal models with a wide range of human auditory processing impairments. Significance StatementThis is the first report of peripheral auditory nerve (AN) impairment in a mouse model of human MEF2C haploinsufficiency syndrome that has well-characterized ASD related behaviors including communication deficits, hyperactivity, repetitive behavior, and social deficits. We identify multiple underlying cellular, sub-cellular, and molecular abnormalities that may contribute to peripheral AN impairment. Our findings also highlight the important roles of immune cells (e.g., cochlear macrophages) and other non-neuronal elements (e.g., glial cells and cells in the stria vascularis) in auditory impairment in ASD. The methodological significance of the study is the establishment of a comprehensive approach for evaluating peripheral AN function and impact of peripheral AN deficits with minimal hearing loss.

neuroscience↗

bioRxiv2022

Integrated molecular and pharmacological characterization of patient-derived xenografts from bladder and ureteral cancers identifies new potential therapies.

BackgroundMuscle-invasive bladder cancer (MIBC) and upper urinary tract urothelial carcinoma (UTUC) are molecularly heterogeneous. Despite chemotherapies, immunotherapies or anti-FGFR treatments, these tumors are still of poor outcome. Our objective was to develop a bank of patient-derived xenografts (PDXs) recapitulating molecular heterogeneity of MIBC and UTUC, to facilitate preclinical identification of therapies. MethodsFresh tumors were obtained from patients and subcutaneously engrafted into immune-compromised mice. Patient tumors and matched PDXs were compared regarding histopathology, transcriptomic (microarrays) and genomic profiles (targeted-NGS). Several PDXs were treated with chemotherapy (cisplatin/gemcitabine) or targeted therapies (FGFR and EGFR inhibitors). Results31 PDXs were established from 1 non-MIBC, 25 MIBC, 5 upper urinary tract tumors, including 28 urothelial (UCC) and 3 squamous-cell carcinomas (SCC). Integrated genomic and transcriptomic profiling identified PDXs of 3 different consensus molecular subtypes (Basal/Squamous, Luminal papillary and Luminal unstable), and included FGFR3-mutated PDXs. High histological and genomic concordance was found between matched patient tumor/PDX. Discordance in molecular subtypes, such as a basal/squamous patient tumor giving rise to a luminal papillary PDX, was observed (n=5) at molecular and histological levels. Ten models were treated with cisplatin-based chemotherapy and we did not observe association between subtypes and response. Of the 3 basal/squamous models treated with anti-EGFR therapy, two models were sensitive and one model, of sarcomatoid variant, was resistant. Treatment of 3 FGFR3-mutant PDXs with combined FGFR/EGFR inhibitors was more efficient than anti-FGFR3 treatment alone. ConclusionsWe developed preclinical PDX models that recapitulate the molecular heterogeneity of MIBCs and UTUC, including actionable mutations, which will represent an essential tool in therapy development. Pharmacological characterization of the PDXs suggested that upper urinary tract and MIBCs, UCC but also SCC, with similar molecular characteristics could benefit from the same treatments including anti-FGFR for FGFR3-mutated tumors and anti-EGFR for basal ones and showed a benefit for combined FGFR/EGFR inhibition in FGFR3-mutant PDXs, compared to FGFR inhibition alone.

cancer biology↗

bioRxiv2022

The CIpP activator, TR-57, is highly effective as a single agent and in combination with venetoclax against CLL cells in vitro.

Despite advances in treatment, a significant proportion of patients with chronic lymphocytic leukaemia (CLL) will relapse with drug-resistant disease. Recent studies demonstrate that the imipridones ONC-201 and ONC-212 and the more potent TR-compounds are effective against a range of different cancers, including acute myeloid leukaemia and tumours of the brain, breast, and prostate. These drugs induce cell death through inhibition of mitochondrial function and activation of the mitochondrial protease, caseinolytic protease (CIpP), and the unfolded protein response (UPR). Here we demonstrate that a drug in this class, TR-57, has efficacy as a single agent and is synergistic with venetoclax against CLL cells cultured under in vitro conditions that mimic the tumour microenvironment. The inhibitory effects of TR-57 on cell survival, proliferation and migration were irrespective of poor-risk features, including aberrations of TP53. Changes in protein expression suggest the mechanisms of action of TR-57 and its synergy with venetoclax involve activation of the UPR, inhibition of the AKT and ERK1/2 pathways and a pro-apoptotic shift in expression of proteins of the BCL-2 family. The study suggests TR-57, as a single agent and in combination with venetoclax, may represent an effective treatment option for CLL, including for patients with poor-risk disease.

cancer biology↗

bioRxiv2022

Age-Related Central Gain with Degraded Neural Synchrony in the Auditory Brainstem of Mice and Humans

Aging is associated with auditory nerve (AN) functional deficits and decreased inhibition in the central auditory system, amplifying central responses in a process known as central gain. Although central gain enhances response amplitudes, central gain may not restore disrupted response timing. In this translational study, we measured responses from the AN and auditory midbrain in younger and older mice and humans. We hypothesized that older mice and humans exhibit central gain without an improvement in inter-trial synchrony in the midbrain. Our data demonstrated greater age-related deficits in AN response amplitudes than auditory midbrain response amplitudes, as shown by significant interactions between neural generator and age group, indicating central gain in auditory midbrain. However, synchrony decreases with age in both the AN and midbrain responses. These results reveal age-related central gain without concomitant improvements in synchrony, consistent with those predictions based on decreases in inhibition. Persistent decreases in synchrony may contribute to auditory processing deficits in older mice and humans.

neuroscience↗

bioRxiv2022

Characterization of TR-107, a Novel Chemical Activator of the Human Mitochondrial Protease ClpP

We recently described the identification of a new class of small molecule activators of the mitochondrial protease ClpP. These compounds synthesized by Madera Therapeutics showed increased potency of cancer growth inhibition over the related compound ONC201. In this study, we describe chemical optimization and characterization of the next generation of highly potent and selective small molecule ClpP activators (TR compounds) and demonstrate their efficacy against breast cancer models in vitro and in vivo. One of these compounds (TR-107) with excellent potency, specificity and drug-like properties was selected for further evaluation. Examination of TR-107 effects in triple-negative breast cancer (TNBC) cell models showed growth inhibition in the low nanomolar range, equipotent to paclitaxel, in a ClpP-dependent manner. TR-107 reduced specific mitochondrial proteins including OXPHOS and TCA cycle components, in a time, dose and ClpP-dependent manner. Seahorse XF analysis and glucose deprivation experiments confirmed inactivation of OXPHOS and demonstrated an increased dependence on glycolysis following TR-107 exposure. The pharmacokinetic properties of TR-107 were compared to other known ClpP activators including ONC201 and ONC212. TR-107 displayed excellent exposure and serum t1/2 after oral administration. The antitumor response to TR-107 was investigated using human TNBC MDA-MB-231 cell line-induced xenograft tumors. Oral administration of TR-107 resulted in reduction in tumor volume and extension of survival in the treated compared with vehicle control mice. In summary, we describe the identification of highly potent new ClpP agonists with improved efficacy against TNBC, through targeted inactivation of OXPHOS and disruption of mitochondrial metabolism.

pharmacology and toxicology↗

bioRxiv2021

Integrative genomics uncover mechanisms of renal medullary carcinoma transformation, microenvironment landscape and therapeutic vulnerabilities.

Renal medullary carcinoma (RMC) is an aggressive desmoplastic tumour driven by bi-allelic loss of SMARCB1, however the cell-of-origin, the oncogenic mechanism and the features of its microenvironment remain poorly understood. Using single-cell and multi-region sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into at least three RMC cell states along an epithelial-mesenchymal gradient through a transcriptional switch involving loss of renal transcription factor TFCP2L1 and gain of a NFE2L2-associated ferroptosis resistance program. SMARCB1 re-expression in cultured RMC cells reactivates TFCP2L1 that relocates SWI/SNF from the promoters of the MYC-driven oncogenic program to the enhancers of TAL identity genes followed by ferroptotic cell death. We further show that RMC is associated with abundant M2-type macrophages and cancer-associated fibroblasts (CAFs) and we identify key regulatory cross-talks that shape this immunosuppressive microenvironment. Together our data describe the molecular events of RMC transformation and identify novel therapeutically targetable vulnerabilities. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC="FIGDIR/small/462391v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@152fa6eorg.highwire.dtl.DTLVardef@b76f50org.highwire.dtl.DTLVardef@ed1382org.highwire.dtl.DTLVardef@9be54f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Two distinct types of nodes of Ranvier support auditory nerve function in the mouse cochlea

Glial cells of the auditory nerve regulate formation of the nodes of Ranvier that are needed for regeneration of action potentials and proper hearing function. Here we identify and describe the distinct features of two novel types of Ranvier nodes--the axonal node and the ganglion node--in the mouse auditory nerve that change across the lifespan, including during myelination and postnatal development, and degenerate during aging. Cellular, molecular, and structure-function correlation evaluations revealed that nodal types are critical for different aspects of auditory nerve function. Specifically, the length of the axonal node is associated with neural processing speed and neural synchrony, whereas ganglion node development is associated with amplitude growth of the action potential. Moreover, our data indicate that dysregulation of glial cells and associated degeneration of the ganglion node structure are an important and new mechanism of auditory nerve dysfunction in age-related hearing loss.

neuroscience↗

bioRxiv2020

Honeybee genetics shape the strain-level structure of gut microbiota in social transmission

Honeybee gut microbiota transmitted via social interactions are beneficial to the host health. Although the microbial community is relatively stable, individual variations and high strain-level diversity have been detected across honeybees. Although the bee gut microbiota structure is influenced by environmental factors, the heritability of the gut members and the contribution of the host genetics remains elusive. Considering bees within a colony are not readily genetically identical due to the polyandry of queen, we hypothesize that the microbiota structure can be shaped by host genetics. We used shotgun metagenomics to simultaneously profile the microbiota and host genotypes of individuals from hives of four different subspecies. Gut composition is more distant between genetically different bees at both phylotype- and "sequence-discrete population"-level. We then performed a successive passaging experiment within colonies of hybrid bees generated by artificial insemination, which revealed that the microbial composition dramatically shifts across batches of bees during the social transmission. Specifically, different strains from the phylotype of Snodgrassella alvi are preferentially selected by genetically varied hosts, and strains from different hosts show a remarkably biased distribution of single-nucleotide polymorphism in the Type IV pili loci. A genome-wide association analysis identified that the relative abundance of a cluster of Bifidobacterium strains is associated with the host glutamate receptor gene that is specifically expressed in the bee brain. Finally, mono-colonization of Bifidobacterium with a specific polysaccharide utilization locus impacts the expression and alternative splicing of the gluR-B gene, which is associated with an altered circulating metabolomic profile. Our results indicated that host genetics influence the bee gut composition, and suggest a gut-brain connection implicated in the gut bacterial strain preference. Honeybees have been used extensively as a model organism for social behaviors, genetics, and gut microbiome. Further identification of host genetic function as shaping force of microbial structure will advance our understanding of the host-microbe interactions.

microbiology↗