Elevated HB-EGF expression in neural stem cells causes middle age obesity by suppressing Hypocretin/Orexin expression.

Obesity is common in the middle aged population and it increases the risks of diabetes, cardiovascular diseases, certain cancers, and dementia. Yet, its etiology remains incompletely understood. Here, we show that ectopic expression of HB-EGF, an important regulator of neurogenesis, in Nestin+ neuroepithelial progenitors with the Cre-LoxP system leads to development of spontaneous middle age obesity in male mice accompanied by hyperglycemia and insulin resistance. The Nestin-HB-EGF mice show decreases in food uptake, energy expenditure, and physical activity, suggesting that reduced energy expenditure underlies the pathogenesis of this obesity model. However, HB-EGF expression in appetite-controlling POMC or AgRP neurons or adipocytes fails to induce obesity. Mechanistically, HB-EGF suppresses expression of Hypocretin/Orexin, an orexigenic neuropeptide hormone, in the hypothalamus of middle aged Nestin-HB-EGF mice. Hypothalamus Orexin administration alleviates the obese and hyperglycemic phenotypes in Nestin-HB-EGF mice. This study uncovers an important role for HB-EGF in regulating Orexin expression and energy expenditure and establishes a midlife obesity model whose pathogenesis involves age-dependent changes in hypothalamus neurons.

The noncanonical BMP signaling pathway plays an important role in club cell regeneration.

The bronchiole is a major site for the development of several life-threatening disorders, including chronic obstructive pulmonary disease and lung adenocarcinomas. The bronchiolar epithelium is composed of club cells and ciliated epithelial cells, with club cells serving as progenitor cells. Presently, the identity of the cells involved in regeneration of bronchiolar epithelium and the underlying mechanisms remain incompletely understood. Here, we show that Prrx1, a homeobox transcription factor, can mark club cells in adult mice during homeostasis and regeneration. We further show that the noncanonical signaling pathway of BMPs, BMPR1A-Tak1-p38MAPK, plays a critical role in club cell regeneration. Ablation of Bmpr1a, Tak1, or Mapk14 (encoding p38α) in Prrx1+ club cells caused minimal effect on bronchiolar epithelium homeostasis, yet it resulted in severe defects in club cell regeneration and bronchiole repair in adult mice. We further show that this pathway supports proliferation and expansion of the regenerating club cells. Our findings thus identify a marker for club cells and reveal a critical role for the BMP noncanonical pathway in club cell regeneration.

Prevalence and Associated Factors of Antenatal Anxiety Symptoms in Bangladesh: A Repeated Measures Cluster Data Analysis.

BACKGROUND: Antenatal Anxiety affects the mothers and their child. Spontaneous abortion, preeclampsia, preterm birth, and low birth weight are the most common consequences. In Bangladesh, we have very limited understanding about the burden of antenatal anxiety and its associated factors. We conducted a prospective longitudinal study to estimate the prevalence of anxiety symptoms and identify associated factors in pregnant women. SUBJECTS AND METHODS: A total of 1360 pregnant women were enrolled from 14 antenatal care (ANC) hospitals during September 2015 to August 2017. All selected women were assessed longitudinally at first, second and third trimesters of pregnancy. The State Anxiety Inventory (STAI-S) scale was used to measure the antenatal anxiety symptom. Generalize estimating equations (GEE) and alternating logistic regression (ALR) model were used to measure the risk factors and repetitive anxiety symptom measurements, respectively. RESULTS: Over the study period, more than half (53.18%) of the women reported anxiety in at least one antenatal assessment. The prevalence of anxiety symptom in the first, second, and third trimesters was 29.5%, 23.5%, and 37.5%, respectively. Maternal anxiousness was significantly associated with the trimester, poor education, low blood hemoglobin, and low family income. CONCLUSION: Women were at high risk of getting anxious during first and third trimesters of pregnancy. Findings of the study can be useful in developing and designing intervention to reduce anxiety in women during pregnancy.

The effects of different intensities of exercise and active vitamin D on mouse bone mass and bone strength.

Physical exercise is beneficial to bone health. However, little is known how different intensities of exercise affect bone mass and strength. In the present study, we used young mice to study the effects of different intensities of exercise on bone mass and bone strength in comparison to pharmacological doses of active vitamin D (calcitriol). We found that only the medium level of exercise tested showed a positive effect on bone mineral density, trabecular bone volume, and bone strength, which are attributable to a decrease in bone resorption and an increase in bone formation, with the latter being accompanied by an increase in the number of osteogenic mesenchymal stem cells in the bone marrow. Calcitriol increases bone volume and bone strength, yet the combination of calcitriol and medium-intensity exercise did not further improve bone mass or strength. Moreover, calcitriol also showed some protective effect on the bone in mice with high levels of exercise. These results indicate that exercise at medium intensity increases bone mass and strength via affecting both bone formation and resorption and that its beneficial effects on bone mass cannot be further improved by calcitriol.

Endophytic bacteria Klebsiella spp. and Bacillus spp. from Alternanthera philoxeroides in Madiwala Lake exhibit additive plant growth-promoting and biocontrol activities.

BACKGROUND: The worldwide increase in human population and environmental damage has put immense pressure on the overall global crop production making it inadequate to feed the entire population. Therefore, the need for sustainable and environment-friendly practices to enhance agricultural productivity is a pressing priority. Endophytic bacteria with plant growth-promoting ability and biocontrol activity can strongly enhance plant growth under changing environmental biotic and abiotic conditions. Herein, we isolated halotolerant endophytic bacteria from an aquatic plant, Alternanthera philoxeroides, from the polluted waters of Madiwala Lake in Bangalore and studied their plant growth promotion (PGP) and biocontrol ability for use as bioinoculant. RESULTS: The isolated bacterial endophytes were screened for salt tolerance ranging from 5 to 15% NaCl concentration. Klebsiella pneumoniae showed halotolerant up to 10% NaCl and Bacillus amyloliquefaciens and Bacillus subtilis showed up to 15%. All three strains demonstrated good PGP abilities such as aminocyclopropane-1-carboxylic acid (ACC) deaminase activity, phosphate solubilization, ammonia production, and nitrogen fixation. In addition, K. pneumoniae also exhibited high indoleacetic acid (IAA) production (195.66 ± 2.51 µg/ml) and potassium solubilization (2.13 ± 0.07 ppm). B. amyloliquefaciens and B. subtilis showed good extracellular enzyme production against cellulase, lipase, protease, and amylase. Both the isolates showed a broad spectrum of antimicrobial activity against the tested organisms. The optimization of IAA production by K. pneumoniae was done by the response surface methodology (RSM) tool. Characterization of IAA produced by the isolate was done by gas chromatography-mass spectrometry (GCMS) analysis. The enhanced plant growth-promoting ability of K. pneumoniae was also demonstrated using various growth parameters in a pot trial experiment using the seeds of Vigna unguiculata. CONCLUSION: The isolated bacterial endophytes reported in this study can be utilized as PGP promotion and biocontrol agents in agricultural applications, to enhance crop yield under salinity stress. The isolate K. pneumoniae may be used as a biofertilizer in sustainable agriculture and more work can be done to optimize the best formulations for its application as a microbial inoculant for crops.

Understanding the Role of Antimicrobial Peptides in Neutrophil Extracellular Traps Promoting Autoimmune Disorders.

AMPs are small oligopeptides acting as integral elements of the innate immune system and are of tremendous potential in the medical field owing to their antimicrobial and immunomodulatory activities. They offer a multitude of immunomodulatory properties such as immune cell differentiation, inflammatory responses, cytokine production, and chemoattraction. Aberrancy in neutrophil or epithelial cell-producing AMPs leads to inflammation culminating in various autoimmune responses. In this review, we have tried to explore the role of prominent mammalian AMPs-defensins and cathelicidins, as immune regulators with special emphasis on their role in neutrophil extracellular traps which promotes autoimmune disorders. When complexed with self-DNA or self-RNA, AMPs act as autoantigens which activate plasmacytoid dendritic cells and myeloid dendritic cells leading to the production of interferons and cytokines. These trigger a series of self-directed inflammatory reactions, leading to the emergence of diverse autoimmune disorders. Since AMPs show both anti- and pro-inflammatory abilities in different ADs, there is a dire need for a complete understanding of their role before developing AMP-based therapy for autoimmune disorders.

Formulation of Water Sustainability Index for India as a performance gauge for realizing the United Nations Sustainable Development Goal 6.

Anthropogenic activities targeting economic progress have triggered changes in the Earth system processes causing depletion of resources and degradation of ecosystems. Water is a critical natural resource which has been severely impacted through groundwater depletion, surface water contamination and ocean acidification resulting in repercussions on human health and biodiversity losses. Likewise, India, a mega biodiversity nation has been critically affected by degradation and drawdown of water resources with far-reaching consequences on environmental vitality and socio-economic development. In order to prevent extreme water scarcity in the near future, the country needs to promote sustainable utilisation of water resources by adhering to the targets of Goal 6 of the United Nations Sustainable Development Goals (UN-SDGs). The present work, therefore, has focussed on the development of a Water Sustainability Index (WSI) for India that would help attaining the targets of SDG 6. A total of 12 indicators categorized under biophysical and social development dimensions and synonymous with the targets of SDG 6 have been used for the formulation of WSI and thereby understanding how much water resources are used annually in a sustainable manner. The study also highlights the interrelationship between the diverse social development and health indicators (SDG 3) of Indian community. The research has the potential to provide guidance for efficient use of water resources in India. Acting as a yardstick and guiding star, the sustainability metric will help the nation to monitor whether it is on the right track and navigate its journey towards achieving water sustainability. It also calls for cautious course correction and restructuring of current Indian policy and operational instruments for effective green governance and sustainable water management.

Notch1 signaling in keratocytes maintains corneal transparency by suppressing VEGF expression.

The cornea fends off chemicals, dirt, and infectious particles and provides most of the eye's focusing power. Corneal transparency is of paramount importance to normal vision, yet how it is established and maintained remains unclear. Here, we ablated Notch1 in keratocytes using Twist2-Cre mice and found that Twist2-Cre; Notch1f/f mice developed stroma expansion and neovascularization, followed by hyperproliferation and metaplasia of corneal epithelial progenitor cells and plaque formation at central cornea, leading to loss of transparency. Development of these phenotypes does not involve bacteria-caused inflammation; instead, Notch1 deletion upregulates Vegfa and Vegfc via Hif1α in keratocytes. Vascular endothelial growth factor (VEGF) receptor inhibitor axitinib prevented development of these anomalies in Twist2-Cre; Notch1f/f mice, suggesting that VEGFs secreted by keratocytes promote not only neovascularization but also proliferation and metaplasia of epithelial progenitor cells at central cornea. This study uncovers a Notch1-Hif1α-VEGF pathway in keratocytes that maintains corneal transparency and represents a potential target for treatment of related corneal disorders.

Prrx1 marks stem cells for bone, white adipose tissue and dermis in adult mice.

Specialized connective tissues, including bone and adipose tissues, control various physiological activities, including mineral and energy homeostasis. However, the identity of stem cells maintaining these tissues throughout adulthood remains elusive. By conducting genetic lineage tracing and cell depletion experiments in newly generated knock-in Cre/CreERT2 lines, we show here that rare Prrx1-expressing cells act as stem cells for bone, white adipose tissue and dermis in adult mice, which are indispensable for the homeostasis and repair of these tissues. Single-cell profiling reveals the cycling and multipotent nature of Prrx1-expressing cells and the stemness of these cells is further validated by transplantation assays. Moreover, we identify the cell surface markers for Prrx1-expressing stem cells and show that the activities of these stem cells are regulated by Wnt signaling. These findings expand our knowledge of connective tissue homeostasis/regeneration and may help improve stem-cell-based therapies.

Measurement of mass transfer during dip-pen nanolithography with phospholipids.

Dip-pen nanolithography (DPN) has been extensively used before for patterning surfaces; however a complete understanding of the ink transport mechanisms is still lacking. Moreover, quality control of the fabricated structures is a bottleneck in DPN fabrication, and one aspect of this is the quantification of the ink mass transfer to the substrate during the lithographic process. There is a demand for measuring the exact amount of molecules deposited on a surface by lithographic methods, especially for biological applications. This article demonstrates a quantitative method for measuring the amount of ink transferred onto the substrate in DPN with phospholipids by dynamic force spectroscopy. To achieve this, the harmonic oscillation of a microcantilever in an atomic force microscope is used, obtaining picogram mass sensitivity in the determination of mass deposition.

Canonical NF-κB signaling maintains corneal epithelial integrity and prevents corneal aging via retinoic acid.

Disorders of the transparent cornea affect millions of people worldwide. However, how to maintain and/or regenerate this organ remains unclear. Here, we show that Rela (encoding a canonical NF-κB subunit) ablation in K14+ corneal epithelial stem cells not only disrupts corneal regeneration but also results in age-dependent epithelial deterioration, which triggers aberrant wound-healing processes including stromal remodeling, neovascularization, epithelial metaplasia, and plaque formation at the central cornea. These anomalies are largely recapitulated in normal mice that age naturally. Mechanistically, Rela deletion suppresses expression of Aldh1a1, an enzyme required for retinoic acid synthesis from vitamin A. Retinoic acid administration blocks development of ocular anomalies in Krt14-Cre; Relaf/f mice and naturally aged mice. Moreover, epithelial metaplasia and plaque formation are preventable by inhibition of angiogenesis. This study thus uncovers the major mechanisms governing corneal maintenance, regeneration, and aging and identifies the NF-κB-retinoic acid pathway as a therapeutic target for corneal disorders.

mTOR Activation Initiates Renal Cell Carcinoma Development by Coordinating ERK and p38MAPK.

Renal cell carcinoma (RCC) mainly originates from renal proximal tubules. Intriguingly, disruption of genes frequently mutated in human RCC samples thus far has only generated RCC originated from other renal tubule parts in mouse models. This hampers our understanding of the pathogenesis of RCC. Here we show that mTOR signaling, often activated in RCC samples, initiates RCC development from renal proximal tubules. Ablation of Tsc1, encoding an mTOR suppressor, in proximal tubule cells led to multiple precancerous renal cysts. mTOR activation increased MEK1 expression and ERK activation, and Mek1 ablation or inhibition diminished cyst formation in Tsc1-deficient mice. mTOR activation also increased MKK6 expression and p38MAPK activation, and ablation of the p38α-encoding gene further enhanced cyst formation and led to RCC with clear cell RCC features. Mechanistically, Tsc1 deletion induced p53 and p16 expression in a p38MAPK-dependent manner, and deleting Tsc1 and Trp53 or Cdkn2a (encoding p16) enhanced renal cell carcinogenesis. Thus, mTOR activation in combination with inactivation of the p38MAPK-p53/p16 pathway drives RCC development from renal proximal tubules. Moreover, this study uncovers previously unidentified mechanisms by which mTOR controls cell proliferation and suggests the MEK-ERK axis to be a potential target for treatment of RCC. SIGNIFICANCE: Mouse modeling studies show that mTOR activation in combination with inactivation of the p38MAPK-p53/p16 axis initiates renal cell carcinoma that mimics human disease, identifying potential therapeutic targets for RCC treatment.

Changes in Depressive Symptoms During the Antenatal Period: A Cohort Study from Bangladesh.

BACKGROUND: Antenatal depressive symptoms adversely affect the health and well-being of women, babies, and their families. This study aimed to explore the prevalence and probable associated factors of depressivse symptoms. METHODS: A prospective cohort approach was adopted, and 435 pregnant women were assessed longitudinally at an antenatal clinic in the first, second, and third trimesters. Edinburgh Postnatal Depression Scale (EPDS) was used to measure self-reported depressive symptoms. The multivariate approach of the general linear model was used to evaluate the mean differences of depression scores among the trimesters. To investigate the associated factors of depressive symptoms, generalized estimating equation (GEE) was used to take into account the clustering effect. RESULTS: More than half (58.13%) of the pregnant women had antenatal depressive symptoms in at least one trimester. Depressive symptoms decreased throughout the pregnancy; they were higher in the first trimester and declined toward the third trimester. Significant mean differences were found in depression scores among the three trimesters. GEE showed that trimester, education, family income, and body mass index (BMI) are significantly associated with antenatal depressive symptoms. CONCLUSIONS: First trimester is the most critical period for identification of depressive symptoms. At-risk women need to be treated. Proper education achievement, economic solvency, and adequate nutrition could reduce the depressive symptoms.

Robust estimation of albedo for illumination-invariant matching and shape recovery.

We present a nonstationary stochastic filtering framework for the task of albedo estimation from a single image. There are several approaches in the literature for albedo estimation, but few include the errors in estimates of surface normals and light source direction to improve the albedo estimate. The proposed approach effectively utilizes the error statistics of surface normals and illumination direction for robust estimation of albedo, for images illuminated by single and multiple light sources. The albedo estimate obtained is subsequently used to generate albedo-free normalized images for recovering the shape of an object. Traditional Shape-from-Shading (SFS) approaches often assume constant/piecewise constant albedo and known light source direction to recover the underlying shape. Using the estimated albedo, the general problem of estimating the shape of an object with varying albedo map and unknown illumination source is reduced to one that can be handled by traditional SFS approaches. Experimental results are provided to show the effectiveness of the approach and its application to illumination-invariant matching and shape recovery. The estimated albedo maps are compared with the ground truth. The maps are used as illumination-invariant signatures for the task of face recognition across illumination variations. The recognition results obtained compare well with the current state-of-the-art approaches. Impressive shape recovery results are obtained using images downloaded from the Web with little control over imaging conditions. The recovered shapes are also used to synthesize novel views under novel illumination conditions.

Generalized Zero-Shot Cross-Modal Retrieval.

Cross-modal retrieval is an important research area due to its wide range of applications, and several algorithms have been proposed to address this task. We feel that it is the right time to take a step back and analyze the current status of research in this area. As new object classes are continuously being discovered over time, it is necessary to design algorithms that can generalize to data from previously unseen classes. Towards that goal, our first contribution is to establish protocols for generalized zero-shot cross-modal retrieval and analyze the generalization ability of the standard cross-modal algorithms. Second, we propose a semantic-aware ranking algorithm that can be used as an add-on to any existing cross-modal approach to improve its performance on both seen and unseen classes. Finally, we propose a modification of the standard evaluation metric (MAP for single-label data and NDCG for multi-label data), which we feel is a more intuitive measure of the cross-modal retrieval performance. Extensive experiments on two single-label and three multi-label cross-modal datasets show the effectiveness of the proposed approach.

Generalized Semantic Preserving Hashing for Cross-Modal Retrieval.

Cross-modal retrieval is gaining importance due to the availability of large amounts of multimedia data. Hashing-based techniques provide an attractive solution to this problem when the data size is large. For cross-modal retrieval, data from the two modalities may be associated with a single label or multiple labels, and in addition, may or may not have a one-to-one correspondence. This work proposes a simple hashing framework which has the capability to work with different scenarios while effectively capturing the semantic relationship between the data items. The work proceeds in two stages in which the first stage learns the optimum hash codes by factorizing an affinity matrix, constructed using the label information. In the second stage, ridge regression and kernel logistic regression is used to learn the hash functions for mapping the input data to the bit domain. We also propose a novel iterative solution for cases where the training data is very large, or when the whole training data is not available at once. Extensive experiments on single label data set like Wiki and multi-label datasets like MirFlickr, NUS-WIDE, Pascal, and LabelMe, and comparisons with the state-of-the-art, shows the usefulness of the proposed approach.

Activation of hedgehog signaling in mesenchymal stem cells induces cartilage and bone tumor formation via Wnt/ß-Catenin.

Indian Hedgehog (IHH) signaling, a key regulator of skeletal development, is highly activated in cartilage and bone tumors. Yet deletion of Ptch1, encoding an inhibitor of IHH receptor Smoothened (SMO), in chondrocyte or osteoblasts does not cause tumorigenesis. Here, we show that Ptch1 deletion in mice Prrx1+mesenchymal stem/stromal cells (MSCs) promotes MSC proliferation and osteogenic and chondrogenic differentiation but inhibits adipogenic differentiation. Moreover, Ptch1 deletion led to development of osteoarthritis-like phenotypes, exostoses, enchondroma, and osteosarcoma in Smo-Gli1/2-dependent manners. The cartilage and bone tumors are originated from Prrx1+ lineage cells and express low levels of osteoblast and chondrocyte markers, respectively. Mechanistically, Ptch1 deletion increases the expression of Wnt5a/6 and leads to enhanced ß-Catenin activation. Inhibiting Wnt/ß-Catenin pathway suppresses development of skeletal anomalies including enchondroma and osteosarcoma. These findings suggest that cartilage/bone tumors arise from their early progenitor cells and identify the Wnt/ß-Catenin pathway as a pharmacological target for cartilage/bone neoplasms.

Reducing uncertainties in energy dissipation measurements in atomic force spectroscopy of molecular networks and cell-adhesion studies.

Atomic force microscope (AFM) based single molecule force spectroscopy (SMFS) is a valuable tool in biophysics to investigate the ligand-receptor interactions, cell adhesion and cell mechanics. However, the force spectroscopy data analysis needs to be done carefully to extract the required quantitative parameters correctly. Especially the large number of molecules, commonly involved in complex networks formation; leads to very complicated force spectroscopy curves. One therefore, generally characterizes the total dissipated energy over a whole pulling cycle, as it is difficult to decompose the complex force curves into individual single molecule events. However, calculating the energy dissipation directly from the transformed force spectroscopy curves can lead to a significant over-estimation of the dissipated energy during a pulling experiment. The over-estimation of dissipated energy arises from the finite stiffness of the cantilever used for AFM based SMFS. Although this error can be significant, it is generally not compensated for. This can lead to significant misinterpretation of the energy dissipation (up to the order of 30%). In this paper, we show how in complex SMFS the excess dissipated energy caused by the stiffness of the cantilever can be identified and corrected using a high throughput algorithm. This algorithm is then applied to experimental results from molecular networks and cell-adhesion measurements to quantify the improvement in the estimation of the total energy dissipation.

BMPRIA is required for osteogenic differentiation and RANKL expression in adult bone marrow mesenchymal stromal cells.

Bone morphogenetic proteins (BMPs) activate the canonical Smad1/5/8 and non-canonical Tak1-MAPK pathways via BMP receptors I and II to regulate skeletal development and bone remodeling. Specific ablation of Bmpr1a in immature osteoblasts, osteoblasts, or osteocytes results in an increase in cancellous bone mass, yet opposite results have been reported regarding the underlying mechanisms. Moreover, the role for BMPRIA-mediated signaling in bone marrow mesenchymal stromal cells (BM-MSCs) has not been explored. Here, we specifically ablated Bmpr1a in BM-MSCs in adult mice to study the function of BMPR1A in bone remodeling and found that the mutant mice showed an increase in cancellous and cortical bone mass, which was accompanied by a decrease in bone formation rate and a greater decrease in bone resorption. Decreased bone formation was associated with a defect in BM-MSC osteogenic differentiation whereas decreased bone resorption was associated with a decrease in RANKL production and osteoclastogenesis. However, ablation of Tak1, a critical non-canonical signaling molecule downstream of BMP receptors, in BM-MSCs at adult stage did not affect bone remodeling. These results suggest that BMP signaling through BMPRIA controls BM-MSC osteogenic differentiation/bone formation and RANKL expression/osteoclastogenesis in adult mice independent of Tak1 signaling.

Bayesian Modeling of Temporal Coherence in Videos for Entity Discovery and Summarization.

A video is understood by users in terms of entities present in it. Entity Discovery is the task of building appearance model for each entity (e.g., a person), and finding all its occurrences in the video. We represent a video as a sequence of tracklets, each spanning 10-20 frames, and associated with one entity. We pose Entity Discovery as tracklet clustering, and approach it by leveraging Temporal Coherence (TC): the property that temporally neighboring tracklets are likely to be associated with the same entity. Our major contributions are the first Bayesian nonparametric models for TC at tracklet-level. We extend Chinese Restaurant Process (CRP) to TC-CRP, and further to Temporally Coherent Chinese Restaurant Franchise (TC-CRF) to jointly model entities and temporal segments using mixture components and sparse distributions. For discovering persons in TV serial videos without meta-data like scripts, these methods show considerable improvement over state-of-the-art approaches to tracklet clustering in terms of clustering accuracy, cluster purity and entity coverage. The proposed methods can perform online tracklet clustering on streaming videos unlike existing approaches, and can automatically reject false tracklets. Finally we discuss entity-driven video summarization- where temporal segments of the video are selected based on the discovered entities, to create a semantically meaningful summary.