Efficient approximations for stationary single-channel calcium nanodomains

Mathematical and computational modeling plays an important role in the study of local Ca2+ signals underlying many fundamental physiological processes such as synaptic neurotransmitter release and myocyte contraction. Closed-form approximations describing steady-state distribution of Ca2+ in the vicinity of an open Ca2+ channel have proved particularly useful for the qualitative modeling of local Ca2+ signals. This dissertation presents several simple and efficient approximants for the equilibrium Ca2+ concentration near a point source in the presence of a mobile Ca2+ buffer, which achieve great accuracy over a wide range of model parameters. Such approximations provide an efficient method for estimating Ca2+ and buffer concentrations without resorting to numerical simulations and allow to study the qualitative dependence of nanodomain Ca2+ distribution on the buffer’s Ca2+ binding properties and its diffusivity. The new approximants presented here for the case of a simple, one-to-one Ca2+ buffer have a functional form that combines rational and exponential functions, which is similar to that of the well-known Excess Buffer Approximation and the linear approximation, but with parameters estimated using two novel methods. One of the methods involves interpolation between the short-range Taylor series of the buffer concentration and its long-range asymptotic series in inverse powers of distance from the channel. A second method is based on the variational approach and involves a global minimization of an appropriate functional with respect to parameters of the chosen approximations. Extensive parameter sensitivity analysis is presented, comparing approximants found using these two methods with the previously developed approximants. Apart from increased accuracy, the strength of the new approximants is that they can be extended to more realistic buffers with multiple Ca2+ binding sites, such as calmodulin and calretinin. In the second part of the dissertation, the series interpolation method is extended to buffers with two Ca2+ binding sites, yielding closed-form interpolants combining exponential and rational functions that achieve reasonable accuracy even in the case of buffers characterized by significant Ca2+ binding cooperativity. Finally, open challenges and potential future extensions of this work are discussed in detail

Improved cellulolytic efficacy in Penicilium decumbens via heterologous expression of Hypocrea jecorina endoglucanase II

Hypocrea jecorina endoglucanase II (Hjegl2) was heterologously expressed in Penicillium decumbens (yielding strain Pd::Hjegl2). After induction in cellulose containing media, strain Pd::Hjeg2 displayed increased carboxymethylcellulase activity (CMCase, 5.77 IU/ml, representing a 21% increase) and cellulose degradation determined with a filter paper assay (FPA, 0.40 IU/ml, 67% increase), as compared to the parent strain. In media supplemented with glucose (2%), Pd::Hjegl2, displayed 51.2-fold and 3-fold higher CMCase and FPA activities, respectively, as compared to the parent strain. No changes in the expression levels of the four main native cellulase genes of P. decumbens (Pdegl1, Pdegl2, Pdcbh1, and Pdcbh2) were noted between the transformant and wild-type strains. These data support the idea that Hjegl2 cleaves both internal and terminal glycosidic residues, in a relatively random and processive manner. In situ polyacrylamide gelactivity staining of extracts derived from wild-type and Pd::Hjegl2 revealed two additional active fractions in the latter strain; one with a molecular mass ~50-65 KDa and another ~80-116 kDa

Rethinking Knowledge Graph Propagation for Zero-Shot Learning

Graph convolutional neural networks have recently shown great potential for the task of zero-shot learning. These models are highly sample efficient as related concepts in the graph structure share statistical strength allowing generalization to new classes when faced with a lack of data. However, multi-layer architectures, which are required to propagate knowledge to distant nodes in the graph, dilute the knowledge by performing extensive Laplacian smoothing at each layer and thereby consequently decrease performance. In order to still enjoy the benefit brought by the graph structure while preventing dilution of knowledge from distant nodes, we propose a Dense Graph Propagation (DGP) module with carefully designed direct links among distant nodes. DGP allows us to exploit the hierarchical graph structure of the knowledge graph through additional connections. These connections are added based on a node's relationship to its ancestors and descendants. A weighting scheme is further used to weigh their contribution depending on the distance to the node to improve information propagation in the graph. Combined with finetuning of the representations in a two-stage training approach our method outperforms state-of-the-art zero-shot learning approaches.Comment: The first two authors contributed equally. Code at https://github.com/cyvius96/adgpm. To appear in CVPR 201

The burden of skin and subcutaneous diseases: findings from the global burden of disease study 2019

BackgroundThe small number of existing integrative studies on the global distribution and burden of all types of skin and subcutaneous diseases hinders relevant comparisons.ObjectiveThis study aimed to determine the latest distribution, epidemiological differences, and factors potentially influencing each skin and subcutaneous disease and the policy implications.MethodsData on the skin and subcutaneous diseases were obtained from the Global Burden of Disease Study 2019. The incidence, disability-adjusted life years (DALYs), and deaths due to skin and subcutaneous diseases in 204 countries and regions from 1990 to 2019 were analyzed and stratified by sex, age, geographical location, and sociodemographic index (SDI). The annual age-standardized rate of change in the incidence was obtained to evaluate temporal trends.ResultsOf 4,859,267,654 (95% uncertainty interval [UI], 4,680,693,440–5,060,498,767) new skin and subcutaneous disease cases that were identified, most were fungal (34.0%) and bacterial (23.0%) skin diseases, which accounted for 98,522 (95% UI 75,116–123,949) deaths. The burden of skin and subcutaneous diseases measured in DALYs was 42,883,695.48 (95%UI, 28,626,691.71-63,438,210.22) in 2019, 5.26% of which were years of life lost, and 94.74% of which were years lived with disability. The highest number of new cases and deaths from skin and subcutaneous diseases was in South Asia. Globally, most new cases were in the 0–4-year age group, with skin and subcutaneous disease incidence slightly higher in men than in women.ConclusionFungal infections are major contributors to skin and subcutaneous diseases worldwide. Low–middle SDI states had the highest burden of skin and subcutaneous diseases, and this burden has increased globally. Targeted and effective management strategies based on the distribution characteristics of each country are, thus, required to reduce the burden of skin and subcutaneous diseases

Development of an incoherent broad-band cavity-enhanced aerosol extinction spectrometer and its application to measurement of aerosol optical hygroscopicity

We report on the development of a blue light-emitting-diode-based incoherent broad-band cavity-enhanced absorption spectroscopy (IBBCEAS) instrument for the measurement of the aerosol extinction coefficient at \u1d706=461  nm. With an effective absorption path length of 2.8 km, an optimum detection limit of 0.05  Mm−1 (5×10−10  cm−1) was achieved with an averaging time of 84 s. The baseline drift of the developed spectrometer was about ±0.3  Mm−1 over 2.5 h (1\u1d70e standard deviation). The performance of the system was evaluated with laboratory-generated monodispersed polystyrene latex (PSL) spheres. The retrieved complex refractive index of PSL agreed well with previously reported values. The relative humidity (RH) dependence of the aerosol extinction coefficient was measured using IBBCEAS. The measured extinction enhancement factor values for 200 nm dry ammonium sulphate particles at different RH were in good agreement with the modeled values. Field performance of the aerosol extinction spectrometer was demonstrated at the Hefei Radiation Observatory site

Gastrodin Rescues Autistic-Like Phenotypes in Valproic Acid-Induced Animal Model

Autism spectrum disorder (ASD) is an immensely challenging developmental disorder characterized by impaired social interaction, restricted/repetitive behavior, and anxiety. GABAergic dysfunction has been postulated to underlie these autistic symptoms. Gastrodin is widely used clinically in the treatment of neurological disorders and showed to modulate GABAergic signaling in the animal brain. The present study aimed to determine whether treatment with gastrodin can rescue valproic acid (VPA) induced autistic-like phenotypes, and to determine its possible mechanism of action. Our results showed that administration of gastrodin effectively alleviated the autistic-associated behavioral abnormalities as reflected by an increase in social interaction and decrement in repetitive/stereotyped behavior and anxiety in mice as compared to those in untreated animals. Remarkably, the amelioration in autistic-like phenotypes was accompanied by the restoration of inhibitory synaptic transmission, α5 GABAA receptor, and type 1 GABA transporter (GAT1) expression in the basolateral amygdala (BLA) of VPA-treated mice. These findings indicate that gastrodin may alleviate the autistic symptoms caused by VPA through regulating GABAergic synaptic transmission, suggesting that gastrodin may be a potential therapeutic target in autism

A Homeodomain-Containing Transcriptional Factor PoHtf1 Regulated the Development and Cellulase Expression in Penicillium oxalicum

Homeodomain-containing transcription factors (Htfs) play important roles in animals, fungi, and plants during some developmental processes. Here, a homeodomain-containing transcription factor PoHtf1 was functionally characterized in the cellulase-producing fungi Penicillium oxalicum 114-2. PoHtf1 was shown to participate in colony growth and conidiation through regulating the expression of its downstream transcription factor BrlA, the key regulator of conidiation in P. oxalicum 114-2. Additionally, PoHtf1 inhibited the expression of the major cellulase genes by coordinated regulation of cellulolytic regulators CreA, AmyR, ClrB, and XlnR. Furthermore, transcriptome analysis showed that PoHtf1 participated in the secondary metabolism including the pathway synthesizing conidial yellow pigment. These data show that PoHtf1 mediates the complex transcriptional-regulatory network cascade between developmental processes and cellulolytic gene expression in P. oxalicum 114-2. Our results should assist the development of strategies for the metabolic engineering of mutants for applications in the enzymatic hydrolysis for biochemical production

Linkage Mapping of Stem Saccharification Digestibility in Rice

Rice is the staple food of almost half of the world population, and in excess 90% of it is grown and consumed in Asia, but the disposal of rice straw poses a problem for farmers, who often burn it in the fields, causing health and environmental problems. However, with increased focus on the development of sustainable biofuel production, rice straw has been recognized as a potential feedstock for non-food derived biofuel production. Currently, the commercial realization of rice as a biofuel feedstock is constrained by the high cost of industrial saccharification processes needed to release sugar for fermentation. This study is focused on the alteration of lignin content, and cell wall chemotypes and structures, and their effects on the saccharification potential of rice lignocellulosic biomass. A recombinant inbred lines (RILs) population derived from a cross between the lowland rice variety IR1552 and the upland rice variety Azucena with 271 molecular markers for quantitative trait SNP (QTS) analyses was used. After association analysis of 271 markers for saccharification potential, 1 locus and 4 pairs of epistatic loci were found to contribute to the enzymatic digestibility phenotype, and an inverse relationship between reducing sugar and lignin content in these recombinant inbred lines was identified. As a result of QTS analyses, several cell-wall associated candidate genes are proposed that may be useful for marker-assisted breeding and may aid breeders to produce potential high saccharification rice varieties