EBF1 nuclear repositioning instructs chromatin refolding to promote therapy resistance in T leukemic cells.

Chromatin misfolding has been implicated in cancer pathogenesis; yet, its role in therapy resistance remains unclear. Here, we systematically integrated sequencing and imaging data to examine the spatial and linear chromatin structures in targeted therapy-sensitive and -resistant human T cell acute lymphoblastic leukemia (T-ALL). We found widespread alterations in successive layers of chromatin organization including spatial compartments, contact domain boundaries, and enhancer positioning upon the emergence of targeted therapy resistance. The reorganization of genome folding structures closely coincides with the restructuring of chromatin activity and redistribution of architectural proteins. Mechanistically, the derepression and repositioning of the B-lineage-determining transcription factor EBF1 from the heterochromatic nuclear envelope to the euchromatic interior instructs widespread genome refolding and promotes therapy resistance in leukemic T cells. Together, our findings suggest that lineage-determining transcription factors can instruct changes in genome topology as a driving force for epigenetic adaptations in targeted therapy resistance.

Genetic Variation in Type 1 Diabetes Reconfigures the 3D Chromatin Organization of T Cells and Alters Gene Expression.

Genetics is a major determinant of susceptibility to autoimmune disorders. Here, we examined whether genome organization provides resilience or susceptibility to sequence variations, and how this would contribute to the molecular etiology of an autoimmune disease. We generated high-resolution maps of linear and 3D genome organization in thymocytes of NOD mice, a model of type 1 diabetes (T1D), and the diabetes-resistant C57BL/6 mice. Multi-enhancer interactions formed at genomic regions harboring genes with prominent roles in T cell development in both strains. However, diabetes risk-conferring loci coalesced enhancers and promoters in NOD, but not C57BL/6 thymocytes. 3D genome mapping of NODxC57BL/6 F1 thymocytes revealed that genomic misfolding in NOD mice is mediated in cis. Moreover, immune cells infiltrating the pancreas of humans with T1D exhibited increased expression of genes located on misfolded loci in mice. Thus, genetic variation leads to altered 3D chromatin architecture and associated changes in gene expression that may underlie autoimmune pathology.

Lineage-Determining Transcription Factor TCF-1 Initiates the Epigenetic Identity of T Cells.

T cell development is orchestrated by transcription factors that regulate the expression of genes initially buried within inaccessible chromatin, but the transcription factors that establish the regulatory landscape of the T cell lineage remain unknown. Profiling chromatin accessibility at eight stages of T cell development revealed the selective enrichment of TCF-1 at genomic regions that became accessible at the earliest stages of development. TCF-1 was further required for the accessibility of these regulatory elements and at the single-cell level, it dictated a coordinate opening of chromatin in T cells. TCF-1 expression in fibroblasts generated de novo chromatin accessibility even at chromatin regions with repressive marks, inducing the expression of T cell-restricted genes. These results indicate that a mechanism by which TCF-1 controls T cell fate is through its widespread ability to target silent chromatin and establish the epigenetic identity of T cells.

Oncogenic Notch Promotes Long-Range Regulatory Interactions within Hyperconnected 3D Cliques.

Chromatin loops enable transcription-factor-bound distal enhancers to interact with their target promoters to regulate transcriptional programs. Although developmental transcription factors such as active forms of Notch can directly stimulate transcription by activating enhancers, the effect of their oncogenic subversion on the 3D organization of cancer genomes is largely undetermined. By mapping chromatin looping genome-wide in Notch-dependent triple-negative breast cancer and B cell lymphoma, we show that beyond the well-characterized role of Notch as an activator of distal enhancers, Notch regulates its direct target genes by instructing enhancer repositioning. Moreover, a large fraction of Notch-instructed regulatory loops form highly interacting enhancer and promoter spatial clusters termed "3D cliques." Loss- and gain-of-function experiments show that Notch preferentially targets hyperconnected 3D cliques that regulate the expression of crucial proto-oncogenes. Our observations suggest that oncogenic hijacking of developmental transcription factors can dysregulate transcription through widespread effects on the spatial organization of cancer genomes.

Poly(ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization.

In amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD), cytoplasmic aggregates of hyperphosphorylated TDP-43 accumulate and colocalize with some stress granule components, but how pathological TDP-43 aggregation is nucleated remains unknown. In Drosophila, we establish that downregulation of tankyrase, a poly(ADP-ribose) (PAR) polymerase, reduces TDP-43 accumulation in the cytoplasm and potently mitigates neurodegeneration. We establish that TDP-43 non-covalently binds to PAR via PAR-binding motifs embedded within its nuclear localization sequence. PAR binding promotes liquid-liquid phase separation of TDP-43 in vitro and is required for TDP-43 accumulation in stress granules in mammalian cells and neurons. Stress granule localization initially protects TDP-43 from disease-associated phosphorylation, but upon long-term stress, stress granules resolve, leaving behind aggregates of phosphorylated TDP-43. Finally, small-molecule inhibition of Tankyrase-1/2 in mammalian cells inhibits formation of cytoplasmic TDP-43 foci without affecting stress granule assembly. Thus, Tankyrase inhibition antagonizes TDP-43-associated pathology and neurodegeneration and could have therapeutic utility for ALS and FTD.

The nuclear ubiquitin ligase adaptor SPOP is a conserved regulator of C9orf72 dipeptide toxicity.

A hexanucleotide repeat expansion in the C9orf72 gene is the most common cause of inherited amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Unconventional translation of the C9orf72 repeat produces dipeptide repeat proteins (DPRs). Previously, we showed that the DPRs PR50 and GR50 are highly toxic when expressed in Caenorhabditis elegans, and this toxicity depends on nuclear localization of the DPR. In an unbiased genome-wide RNA interference (RNAi) screen for suppressors of PR50 toxicity, we identified 12 genes that consistently suppressed either the developmental arrest and/or paralysis phenotype evoked by PR50 expression. All of these genes have vertebrate homologs, and 7 of 12 contain predicted nuclear localization signals. One of these genes was spop-1, the C. elegans homolog of SPOP, a nuclear localized E3 ubiquitin ligase adaptor only found in metazoans. SPOP is also required for GR50 toxicity and functions in a genetic pathway that includes cul-3, which is the canonical E3 ligase partner for SPOP Genetic or pharmacological inhibition of SPOP in mammalian primary spinal cord motor neurons suppressed DPR toxicity without affecting DPR expression levels. Finally, we find that knockdown of bromodomain proteins in both C. elegans and mammalian neurons, which are known SPOP ubiquitination targets, suppresses the protective effect of SPOP inhibition. Together, these data suggest a model in which SPOP promotes the DPR-dependent ubiquitination and degradation of BRD proteins. We speculate the pharmacological manipulation of this pathway, which is currently underway for multiple cancer subtypes, could also represent an entry point for therapeutic intervention to treat C9orf72 FTD/ALS.

Correlation between Radiological Characteristics, PET-CT and Histological Subtypes of Primary Lung Adenocarcinoma-A 102 Case Series Analysis.

Background and Objectives: Lung cancer is the second most common form of cancer in the world for both men and women as well as the most common cause of cancer-related deaths worldwide. The aim of this study is to summarize the radiological characteristics between primary lung adenocarcinoma subtypes and to correlate them with FDG uptake on PET-CT. Materials and Methods: This retrospective study included 102 patients with pathohistologically confirmed lung adenocarcinoma. A PET-CT examination was performed on some of the patients and the values of SUVmax were also correlated with the histological and morphological characteristics of the masses in the lungs. Results: The results of this analysis showed that the mean size of AIS-MIA (adenocarcinoma in situ and minimally invasive adenocarcinoma) cancer was significantly lower than for all other cancer types, while the mean size of the acinar cancer was smaller than in the solid type of cancer. Metastases were significantly more frequent in solid adenocarcinoma than in acinar, lepidic, and AIS-MIA cancer subtypes. The maximum standardized FDG uptake was significantly lower in AIS-MIA than in all other cancer types and in the acinar predominant subtype compared to solid cancer. Papillary predominant adenocarcinoma had higher odds of developing contralateral lymph node involvement compared to other types. Solid adenocarcinoma was associated with higher odds of having metastases and with higher SUVmax. AIS-MIA was associated with lower odds of one unit increase in tumor size and ipsilateral lymph node involvement. Conclusions: The correlation between histopathological and radiological findings is crucial for accurate diagnosis and staging. By integrating both sets of data, clinicians can enhance diagnostic accuracy and determine the optimal treatment plan.

TooManyCells identifies and visualizes relationships of single-cell clades.

Identifying and visualizing transcriptionally similar cells is instrumental for accurate exploration of the cellular diversity revealed by single-cell transcriptomics. However, widely used clustering and visualization algorithms produce a fixed number of cell clusters. A fixed clustering 'resolution' hampers our ability to identify and visualize echelons of cell states. We developed TooManyCells, a suite of graph-based algorithms for efficient and unbiased identification and visualization of cell clades. TooManyCells introduces a visualization model built on a concept intentionally orthogonal to dimensionality-reduction methods. TooManyCells is also equipped with an efficient matrix-free divisive hierarchical spectral clustering different from prevalent single-resolution clustering methods. TooManyCells enables multiresolution and multifaceted exploration of single-cell clades. An advantage of this paradigm is the immediate detection of rare and common populations that outperforms popular clustering and visualization algorithms, as demonstrated using existing single-cell transcriptomic data sets and new data modeling drug-resistance acquisition in leukemic T cells.

Determining the Impact of the COVID-19 Pandemic on Dental Care in the Serbian Adult Population: An Online Questionnaire-Based Study.

BACKGROUND Emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus) could lead to an increase in dental anxiety, avoidance of dental visits, and general neglect of oral health. This online questionnaire-based study conducted in April and May of 2021 in Serbia aimed to determine the impact of the coronavirus disease 2019 (COVID-19) pandemic on dental care. MATERIAL AND METHODS The study included 2060 adult citizens of the Republic of Serbia who participated in an anonymous online questionnaire based on a 5-point Likert scale. Data were collected on dental care routine prior to and during the pandemic, and the fear of negative consequences for oral health. The results were statistically analyzed using descriptive statistics, Pearson's correlation coefficient, ANOVA, and the paired t test. RESULTS Approximately one-fifth of the respondents postponed dental visits during the pandemic. Concern about postponing dental treatment was expressed by more than one-half of the respondents (57.1%), while 21.4% thought that they were already experiencing the consequences. Avoidance of preventive examinations and improvement of oral hygiene are more common among the elderly compared to younger respondents (P=.000). CONCLUSIONS The COVID-19 pandemic did not significantly affect the habit of avoiding dental interventions due to fear, but it did lead to part of the population completely avoiding even urgent dental interventions during the peak of the pandemic, and opting for tooth extraction rather than treatment. The strongest impact on dental care in the pandemic was among people over 64 years old.

Different Alterations of Hippocampal and Reticulo-Thalamic GABAergic Parvalbumin-Expressing Interneurons Underlie Different States of Unconsciousness.

We traced the changes in GABAergic parvalbumin (PV)-expressing interneurons of the hippocampus and reticulo-thalamic nucleus (RT) as possible underlying mechanisms of the different local cortical and hippocampal electroencephalographic (EEG) microstructures during the non-rapid-eye movement (NREM) sleep compared with anesthesia-induced unconsciousness by two anesthetics with different main mechanisms of action (ketamine/diazepam versus propofol). After 3 h of recording their sleep, the rats were divided into two experimental groups: one half received ketamine/diazepam anesthesia and the other half received propofol anesthesia. We simultaneously recorded the EEG of the motor cortex and hippocampus during sleep and during 1 h of surgical anesthesia. We performed immunohistochemistry and analyzed the PV and postsynaptic density protein 95 (PSD-95) expression. PV suppression in the hippocampus and at RT underlies the global theta amplitude attenuation and hippocampal gamma augmentation that is a unique feature of ketamine-induced versus propofol-induced unconsciousness and NREM sleep. While PV suppression resulted in an increase in hippocampal PSD-95 expression, there was no imbalance between inhibition and excitation during ketamine/diazepam anesthesia compared with propofol anesthesia in RT. This increased excitation could be a consequence of a lower GABA interneuronal activity and an additional mechanism underlying the unique local EEG microstructure in the hippocampus during ketamine/diazepam anesthesia.

COVID-19: Another Cause of Dental Anxiety?

BACKGROUND Fear has always been closely linked to dentistry but it could be intensified by the objective risks imposed by the pandemic. The objective of this study was to determine the profile of the frightened dental patient during the COVID-19 pandemic and determine measures taken by dentists to reduce fear and increase security among their patients. MATERIAL AND METHODS An anonymous online survey was conducted between March 15 and April 15, 2021. The respondents were 2060 adult citizens of the Republic of Serbia. In addition to demographic data, data related to the COVID-19 pandemic, dental fear, and attitudes and fear of dental interventions during the ongoing pandemic were compiled. The data were analyzed using descriptive statistics: the chi-square test and Pearson's coefficient. RESULTS Seventy percent of the respondents felt some level of fear of the ongoing pandemic, 50% felt fear of going to a dentist during the pandemic, 20% considered a dental office a hotspot for the transmission of SARS-CoV-2, and 43% would visit their dentist only in the case of emergency. CONCLUSIONS The COVID-19 pandemic has affected the attitudes and behavior of people pertaining to visits to dental offices. Identifying frightened patients and their opinions and fears at this challenging time would make it easier for dentists to include protocols in their everyday practice to increase a sense of security among their patients, such as implementing preventive measures in front of the patients, ensuring an empty waiting room, and providing telephone consultations.

18F-FDG PET/CT value in the detection of seminoma and correlation with CT and tumor marker levels - up to 8 years of follow-up.

OBJECTIVE: Positron emission tomography/computed tomography using fluorine-18 fluoro-deoxyglucose (18F-FDG PET/CT) is not routinely used for diagnosis of testicular carcinoma. Unlike CT which cannot confirm with certainty the nature of the lesions, especially in post-therapy setting, 18F-FDG PET/CT detects active disease by showing increased glucose metabolism within the lesions. AIM: Determination of 18F-FDG PET/CT usefulness in detection of seminoma, therapy response evaluation and comparison to CT findings and tumor marker levels. MATERIAL AND METHODS: Eighty-two men (age 39.8±10.1) after orchiectomy and histopathological confirmation of seminoma were included in this study. Indications for 18F-FDG PET/CT were initial staging, restaging after chemo/radiotherapy with positive/uncertain CT, suspected recurrence on CT, elevated tumor markers. All patients had clinical follow-up of up to 8 years (median 33.5) after the first 18F-FDG PET/CT examination. Degree of metabolic activity was analyzed visually and semi-quantitatively using maximum standardized uptake value(SUVmax). RESULTS: Fluorine-18-FDG PET/CT was true positive in 36 patients (43.9%) with average SUVmax of 7.9±4.8.Recurrence was mostly found in retroperitoneal lymph nodes and distant metastases in lungs, bones, liver. Six findings were false positive and 3 false negative. Sensitivity, specificity, accuracy of 18F-FDG PET/CT were 92.3%, 86.0%, 89.0% and of CT 60.8%, 66.6%, 63.4%. Pearson Chi-square test showed statistically significant difference between the results of 18F-FDG PET/CT and CT (P=0.016). Significant correlation was found between positive 18F-FDG PET/CT findings and levels of LDH (P=0.043), while non-significant between AFP, ß-hCG (P>0.05). CONCLUSION: Fluorine-18-FDG PET/CT was superior to CT in evaluation of therapy response, active disease in residual tissue and normal size lymph nodes, as well as when CT was negative and tumor markers were elevated. Elevated lactate dehydrogenase (LDH) contributes to positive 18F-FDG PET/CT findings.

Calcium-pyro-hydrochar derived from the spent mushroom substrate as a functional sorbent of Pb2+ and Cd2+ from aqueous solutions.

A calcium-pyro-hydrochar (Ca-PHC) can be distinguished as a novel sorbent of Pb2+ and Cd2+ from an aqueous solution. It was obtained using hydrothermal treatment of the spent mushroom substrate (SMS), followed by a CaCl2·5H2O activation and pyrolysis. The characterisation of chars before and after modifications was done by scanning electron microscope (SEM), Brunauer-Emmett-Teller (BET) and Fourier transform infrared (FTIR). Batch experiments were performed to examine Ca-PHC's sorption properties and binding mechanisms to selected metal ions. The maximum sorption capacities of Ca-PHC for Pb2+ and Cd2+ were 297 mg g-1, and 131 mg g-1, respectively. The obtained results demonstrated that the sorption of Pb2+ and Cd2+ by Ca-PHC follows a pseudo-second kinetic model and Freundlich isotherm. The binding of the selected metals onto Ca-PHC was enabled by the ion-exchange mechanism, surface complexation, mineral precipitation and cation-π interaction. Thermodynamic parameters indicate that metal ions binding by Ca-PHC are spontaneous and endothermic. Due to the high adsorption capacities, the obtained Ca-PHC has good potential for application in industrial wastewater treatment. In addition, the demonstrated use of SMS highlights another possibility of applying this specific biomass relevant to sustainable and economical waste management in the growing mushroom industry.

Diversity of simultaneous sleep in the motor cortex and hippocampus in rats.

We investigated the homogeneity/heterogeneity of spontaneous sleep, simultaneously recorded in the motor cortex and the hippocampus of control rats, and particularly analysed simultaneous and non-simultaneous motor cortical and hippocampal non-rapid eye movement (NREM)/rapid eye movement (REM) sleep. We demonstrate that the sleep architectures of the motor cortex and hippocampus are different in control rats. There was an increase of NREM duration and a decrease of REM duration in the hippocampus versus the motor cortex. In terms of duration, NREM state is the most heterogeneous in the hippocampus, whereas the REM state is the most heterogeneous in the motor cortex. Whereas the hippocampal NREM duration was increased due to the prolongation of NREM episodes, the hippocampal REM duration decreased due to the decreased number of REM episodes. The heterogeneity of sleep in the motor cortex and hippocampus in control rats was particularly expressed through the inverse alteration of sigma amplitude during NREM sleep and beta/gamma amplitudes during REM sleep in the hippocampus, along with the delta, sigma, beta and gamma amplitudes only during non-simultaneous NREM/REM sleep in the hippocampus. We demonstrated the brain structure-related and NREM/REM state-related heterogeneity of the motor cortical and hippocampal local sleep in control rats. The distinctly altered local NREM/REM states, alongside their episode dynamics and electroencephalographic (EEG) microstructures, suggest the importance of both the local neuronal network substrate and the NREM/REM neurochemical substrate in the control mechanisms of sleep.

Biomagnetic Priming-Possible Strategy to Revitalize Old Mustard Seeds.

Different priming methods were developed to improve seed germination and the early growth of seedlings. This study aimed to examine the combined effect of bacterial inoculation and static magnetic field on white mustard (Sinapis alba L.) germination. A plant growth-promoting bacterial strain Bacillus amyloliquefaciens D5 ARV was used for biopriming. The static magnetic field of 90 mT was applied for 5 and 15 min. Analyses of abscisic acid, chlorophyll, anthocyanins, flavonoids content, nitrogen balance index, and bacterial indole-3-acetic acid were used to explain observed effects. Bacterial inoculation improved seed germination, whereas exposure to 90 mT for 15 min suppressed germination. Such an unfavorable effect was neutralized when the treatment with the static magnetic field was combined with bacterial inoculation. The highest germination percentage was a result of synergistic action of B. amyloliquefaciens D5 ARV and 15 min long exposure to 90 mT, which induced an increase of 53.20% in the number of germinated seeds. The static magnetic field induced the increase of bacterial indole-3-acetic acid production threefold times. Biomagnetic priming caused a metabolic shift from primary to secondary metabolism in the white mustard seedlings. An adequate combination of biological priming and static magnetic field treatment can be successfully used in old seed revitalization and germination improvements. © 2021 Bioelectromagnetics Society.

Radon-222: environmental behavior and impact to (human and non-human) biota.

As an inert radioactive gas, 222Rn could be easily transported to the atmosphere via emanation, migration, or exhalation. Research measurements pointed out that 222Rn activity concentration changes during the winter and summer months, as well as during wet and dry season periods. Changes in radon concentration can affect the atmospheric electric field. At the boundary layer near the ground, short-lived daughters of 222Rn can be used as natural tracers in the atmosphere. In this work, factors controlling 222Rn pathways in the environment and its levels in soil gas and outdoor air are summarized. 222Rn has a short half-life of 3.82 days, but the dose rate due to radon and its radioactive progeny could be significant to the living beings. Epidemiological studies on humans pointed out that up to 14% of lung cancers are induced by exposure to low and moderate concentrations of radon. Animals that breed in ground holes have been exposed to the higher doses due to radiation present in soil air. During the years, different dose-effect models are developed for risk assessment on human and non-human biota. In this work are reviewed research results of 222Rn exposure of human and non-human biota.

Hippocampal and Reticulo-Thalamic Parvalbumin Interneurons and Synaptic Re-Organization during Sleep Disorders in the Rat Models of Parkinson's Disease Neuropathology.

We investigated the alterations of hippocampal and reticulo-thalamic (RT) GABAergic parvalbumin (PV) interneurons and their synaptic re-organizations underlying the prodromal local sleep disorders in the distinct rat models of Parkinson's disease (PD). We demonstrated for the first time that REM sleep is a predisposing state for the high-voltage sleep spindles (HVS) induction in all experimental models of PD, particularly during hippocampal REM sleep in the hemiparkinsonian models. There were the opposite underlying alterations of the hippocampal and RT GABAergic PV+ interneurons along with the distinct MAP2 and PSD-95 expressions. Whereas the PD cholinopathy enhanced the number of PV+ interneurons and suppressed the MAP2/PSD-95 expression, the hemiparkinsonism with PD cholinopathy reduced the number of PV+ interneurons and enhanced the MAP2/PSD-95 expression in the hippocampus. Whereas the PD cholinopathy did not alter PV+ interneurons but partially enhanced MAP2 and suppressed PSD-95 expression remotely in the RT, the hemiparkinsonism with PD cholinopathy reduced the PV+ interneurons, enhanced MAP2, and did not change PSD-95 expression remotely in the RT. Our study demonstrates for the first time an important regulatory role of the hippocampal and RT GABAergic PV+ interneurons and the synaptic protein dynamic alterations in the distinct rat models of PD neuropathology.

Impact of hydrochar and biochar amendments on sorption and biodegradation of organophosphorus pesticides during transport through Danube alluvial sediment.

This work investigates the transport behaviour of selected organophosphorus pesticides, OPPs (chlorpyrifos, CP; chlorpyrifos-methyl, CPM; chlorfenvinphos, CF) through Danube alluvial sediment in the presence of hydrochars and biochars. The investigated hydrochar, obtained at three different temperatures (180 °C, 200 °Cand 220 °C), originated from sugar beet shreds (SBS) and Miscanthus×giganteus (MIS). Results are described by conventional advective-dispersive equation (ADE). Retardation coefficients (Rd) for all OPPs were in the range 6.2-16. Biodegradation was 4.15 and 1.80 for CPM and CP, respectively, while for CF biodegradation did not occur. The addition of carbon rich materials increases retardation of all OPPs in the range from 4 to 18 times depending on the material. Column experiment results indicated that biodegradation of OPPs occurred (up to λ = 13). In order to confirm that biodegradation occurred in the column experiments, we isolated OPPs degrading microorganisms for the first time from the alluvial sediment. A strain capable of degrading CP and CPM was isolated and identified as Bacillus megaterium BD5 based on biochemical properties, MALDI TOF and 16S rRNA analysis (99.54% identity). The results demonstrate that hydrochars, biochars and isolated degrading bacteria may be effective agents for reducing the mobility of or removing OPPs in contaminated soils or sediments.

Reciprocal Negative Regulation Between Lmx1a and Lmo4 Is Required for Inner Ear Formation.

LIM-domain containing transcription factors (LIM-TFs) are conserved factors important for embryogenesis. The specificity of these factors in transcriptional regulation is conferred by the complexes that they form with other proteins such as LIM-domain-binding (Ldb) proteins and LIM-domain only (LMO) proteins. Unlike LIM-TFs, these proteins do not bind DNA directly. LMO proteins are negative regulators of LIM-TFs and function by competing with LIM-TFs for binding to Ldb's. Although the LIM-TF Lmx1a is expressed in the developing mouse hindbrain, which provides many of the extrinsic signals for inner ear formation, conditional knock-out embryos of both sexes show that the inner ear source of Lmx1a is the major contributor of ear patterning. In addition, we have found that the reciprocal interaction between Lmx1a and Lmo4 (a LMO protein within the inner ear) mediates the formation of both vestibular and auditory structures. Lmo4 negatively regulates Lmx1a to form the three sensory cristae, the anterior semicircular canal, and the shape of the utricle in the vestibule. Furthermore, this negative regulation blocks ectopic sensory formation in the cochlea. In contrast, Lmx1a negatively regulates Lmo4 in mediating epithelial resorption of the canal pouch, which gives rise to the anterior and posterior semicircular canals. We also found that Lmx1a is independently required for the formation of the endolymphatic duct and hair cells in the basal cochlear region.SIGNIFICANCE STATEMENT The mammalian inner ear is a structurally complex organ responsible for detecting sound and maintaining balance. Failure to form the intricate 3D structure of this organ properly during development most likely will result in sensory deficits on some level. Here, we provide genetic evidence that a transcription factor, Lmx1a, interacts with its negative regulator, Lmo4, to pattern various vestibular and auditory components of the mammalian inner ear. Identifying these key molecules that mediate formation of this important sensory organ will be helpful for designing strategies and therapeutics to alleviate hearing loss and balance disorders.

Performance of aquatic weed - Waste Myriophyllum spicatum immobilized in alginate beads for the removal of Pb(II).

A new biosorbent - alginate encapsulated with Myriophyllum spicatum - MsA was investigated for lead ions removal. This biosorbent was characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), zeta potential, X ray Diffraction (XRD) and size distribution analysis. FT-IR analysis demonstrated that the lead ions sequestration mechanism included ion exchange and lead complexation with the carboxyl, carbonyl and hydroxyl groups in MsA. In order to better understand the mechanisms of the binding of Pb(II) on immobilized M. spicatum beads, 3 reaction and one diffusion based kinetic models were applied on kinetic data removal lead ions on three materials: M. spicatum, Ca-alginate and MsA. Myriophyllum spicatum encapsulated with alginate - MsA have higher adsorption capacity than M. spicatum. Among examined six isotherms Redlich-Peterson and the Langmuir isotherm model exhibited the best fit to the experimental data, with capacities ranging from 230 to 268.7 mg/g. Among the various tested desorption agents, nitric acid has proven to be the best. The obtained results suggest that the immobilized M. spicatum biosorbent holds great potential for lead wastewater treatment applications.