bluuebunny/crossref_metadata_2025 huggingface dataset:
Glucocorticoids and steroid sparing medications monotherapies or in combination for IgG4-RD: a systematic review and network meta-analysis
Authors: Omar Dina , Chen Yu , Cong Ye , Dong Lingli
Published: August 2019

Objective

To assess the safety and efficacy of glucocorticoids (GCs), immunosuppressive agents (IM) and rituximab (RTX), alone or in combination, for the treatment of IgG4-RD.

Methods

Relevant articles published were searched in the databases with relevant key words. Network meta-analysis was conducted, with various outcomes including relapse rate, remission rate and adverse events. Data were calculated with odds ratio (ORs) and 95% CI. P-score was used to rank the treatments.

Results

A total of 15 studies involving 1169 patients were included. Network meta-analysis indicated that RTX maintenance therapy had the lowest relapse rate of all treatments (OR = 0.10, 95% CI [0.01, 1.63]), whereas GCs + IM was associated with a lower relapse rate compared with GCs alone (OR = 0.39, 95% CI [0.20, 0.80]). Further, patients treated with GCs + IM had a higher remission rate than those given GCs (OR= 3.36, 95% CI [1.44, 7.83]), IM (OR= 55.31, 95% CI [13.73, 222.73]) monotherapies or RTX induction therapy only (OR= 7.38, 95% CI [1.56, 34.94]). The rate of adverse events was comparable among the different treatment groups.

Conclusion

Treatment of IgG4-RD patients with GCs and IM was associated with higher remission rates and lower relapse rates, as well as comparable safety profiles compared with GC, IM and RTX induction therapy. RTX maintenance therapy had a larger reduction in the relapse rate compared with GC and IM. The current evidence should be carefully scrutinized as the included studies were observational in design. Larger randomized controlled trials are needed to confirm.
ESTIMATION OF Hp(3) TO THE EYE LENS OF INTERVENTIONAL RADIOLOGISTS—RELATION BETWEEN THE EYE LENS DOSE AND RADIOLOGIST’S HEIGHT
Authors: Tanaka Takuro , Matsubara Kosuke , Fukuda Atsushi , Kobayashi Satoshi
Published: July 2019

The aim of the study was to estimate occupational radiation dose to the eye lens of radiologists and the dose reduction ratio of lead glasses during interventional radiology. Three interventional radiologists monitored Hp(3) using small-type optically stimulated luminescence dosemeters attached to the left inside and outside of the lead glasses with 0.07-mmPb [Hp(3)eye]. Hp(10) and Hp(0.07) were monitored, respectively, by attaching the personal dosemeter to the lead neck collar above the lead apron. The median Hp(3)eye with lead glasses and the median dose reduction ratio of lead glasses for the three radiologists were 8.02 mSv/y and 57.7%, respectively. The median Hp(3)eye without lead glasses [Hp(3)eye-w/o] for the three radiologists was 18.6 mSv/y, but Hp(3)eye-w/o for one of the radiologists was 24.1 mSv/y. Monitoring occupational radiation dose to the eye lens is important because interventional radiologists are at risk of exceeding the new dose limit.
Important Bermuda trust decision concerning settlor’s wishes
Authors: Robinson Keith
Published: July 2019

The intersection between the court’s power to bless the decision of a trustee and the impact of a settlor’s wishes on trustee decision-making has recently been considered by the Supreme Court of Bermuda in the important decision of In the Matter of the R Trust. In blessing the decision of the trustee in this case, the court referred with approval of the dicta of the UK Supreme Court in Pitt v Holt that the settlor’s wishes are simply a “relevant consideration”.
Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic‐ and GPR109a‐mediated mechanisms
Authors: Felizardo Raphael J. F. , de Almeida Danilo C. , Pereira Rafael L. , Watanabe Ingrid K. M. , Doimo Nayara T. S. , Ribeiro Willian R. , Cenedeze Marcos A. , Hiyane Meire I. , Amano Mariane T. , Braga Tárcio T. , Ferreira Caroline M. , Parmigiani Raphael B. , Andrade‐Oliveira Vinicius , Volpini Rildo A. , Vinolo Marco Aurélio R. , Mariño Eliana , Robert Remy , Mackay Charles R. , Camara Niels O. S.
Published: August 2019

Butyrate is a short‐chain fatty acid derived from the metabolism of indigestible carbohydrates by the gut microbiota. Butyrate contributes to gut homeostasis, but it may also control inflammatory responses and host physiology in other tissues. Butyrate inhibits histone deacetylases, thereby affecting gene transcription, and also signals through the metabolite‐sensing G protein receptor (GPR)109a. We produced an mAb to mouse GPR109a and found high expression on podocytes in the kidney. Wild‐type and Gpr109a–/– mice were induced to develop nephropathy by a single injection of Adriamycin and treated with sodium butyrate or high butyrate‐releasing high‐amylose maize starch diet. Butyrate improved proteinuria by preserving podocyte at glomerular basement membrane and attenuated glomerulosclerosis and tissue inflammation. This protective phenotype was associated with increased podocyte‐related proteins and a normalized pattern of acetylation and methylation at promoter sites of genes essential for podocyte function. We found that GPR109a is expressed by podocytes, and the use of Gpr109a–/– mice showed that the protective effects of butyrate depended on GPR109a expression. A prebiotic diet that releases high amounts of butyrate also proved highly effective for protection against kidney disease. Butyrate and GPR109a play a role in the pathogenesis of kidney disease and provide one of the important molecular connections between diet, the gut microbiota, and kidney disease.—Felizardo, R. J. F., de Almeida, D. C., Pereira, R. L., Watanabe, I. K. M., Doimo, N. T. S., Ribeiro, W. R., Cenedeze, M. A., Hiyane, M. I., Amano, M. T., Braga, T. T., Ferreira, C. M., Parmigiani, R. B., Andrade‐Oliveira, V., Volpini, R. A., Vinolo, M. A. R., Mariño, E., Robert, R., Mackay, C. R., Camara, N. O. S. Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic‐ and GPR109a‐mediated mechanisms. FASEB J. 33, 11894–11908 (2019). www.fasebj.org
Prevalence and Anatomical Distribution of Bone Stress Injuries in the Elite Para Athlete
Authors: Tenforde Adam S. , Brook Emily M. , Broad Elizabeth , Matzkin Elizabeth G. , Yang Heidi Y. , Collins Jamie E. , Braun Peter W. , Blauwet Cheri A.
Published: August 2019

Bone stress injury is a common overuse injury in athletes. Risk factors for bone stress injury in athletes include the female athlete triad (triad); this has not been evaluated in para athletes. The aim of this study was to identify risk factors, prevalence, and anatomical distribution of bone stress injury in para athletes. A cross-sectional online survey on health characteristics and previous fractures including bone stress injury was completed by para athletes training for the 2016 or 2018 Paralympic Games. Two hundred sixty para athletes completed the survey (659 invited, response rate = 40%). Half reported previous fracture, and bone stress injury was reported in 9.2% of all athletes. Twenty-four athletes (11 men and 13 women) sustained one or more bone stress injury, including 13 athletes with two bone stress injuries. No risk factors of the triad, disability type, or duration of disability were associated with bone stress injury. Injuries were most common in the metatarsals (n = 8) and hand/wrist (n = 7). In an elite para athlete population, locations for bone stress injury included both the upper and lower limbs. Clinically, para athletes presenting with pain localized to bone require further workup to evaluate for bone stress injury particularly for pain in both upper and lower limbs. Further research is required to identify risk factors for bone stress injury in para athletes.
Heritable temporal gene expression patterns correlate with metabolomic seed content in developing hexaploid oat seed
Authors: Hu Haixiao , Gutierrez-Gonzalez Juan J. , Liu Xinfang , Yeats Trevor H. , Garvin David F. , Hoekenga Owen A. , Sorrells Mark E. , Gore Michael A. , Jannink Jean-Luc
Published: July 2019

Oat ranks sixth in world cereal production and has a higher content of health-promoting compounds compared to other cereals. However, there is neither a robust oat reference genome nor transcriptome. Using deeply sequenced full-length mRNA libraries of oat cultivar Ogle-C, a de novo high-quality and comprehensive oat seed transcriptome was assembled. With this reference transcriptome and QuantSeq 3’ mRNA sequencing, gene expression was quantified during seed development from 22 diverse lines across six time points. Transcript expression showed higher correlations between adjacent time points. Based on differentially expressed genes, we identified 22 major temporal co-expression (TCoE) patterns of gene expression and revealed enriched gene ontology biological processes. Within each TCoE set, highly correlated transcripts, putatively commonly affected by genetic background, were clustered, and termed genetic co-expression (GCoE) sets. 17 of the 22 TCoE sets had GCoE sets with median heritabilities higher than 0.50, and these heritability estimates were much higher than that estimated from permutation analysis, with no divergence observed in cluster sizes between permutation and non-permutation analyses. Linear regression between 634 metabolites from mature seeds and the PC1 score of each of the GCoE sets showed significantly lower p-values than permutation analysis. Temporal expression patterns of oat avenanthramides and lipid biosynthetic genes were concordant with previous studies of avenanthramide biosynthetic enzyme activity and lipid accumulation. This study expands our understanding of physiological processes that occur during oat seed maturation and provides plant breeders the means to change oat seed composition through targeted manipulation of key pathways.
Non-nutritive sweetener consumption during pregnancy affects adiposity in mouse and human offspring
Authors: Azad Meghan B. , Archibald Alyssa , Tomczyk Mateusz M. , Head Alanna , Cheung Kyle G. , de Souza Russell J. , Becker Allan B. , Mandhane Piushkumar J. , Turvey Stuart E. , Moraes Theo J. , Sears Malcolm R. , Subbarao Padmaja , Dolinsky Vernon W.
Published: July 2019

Overweight and obesity affect over 20% of children worldwide. Emerging evidence shows that nonnutritive sweeteners (NNS) could adversely influence weight gain and metabolic health, particularly during critical periods of development. Thus, we aimed to investigate the impact of prenatal NNS exposure on postnatal growth and adiposity. Among 2298 families participating in the CHILD cohort study, children born to mothers who regularly consumed NNS during pregnancy had elevated body mass index and adiposity at 3 years of age. In a complementary study designed to eliminate confounding by human lifestyle factors and investigate causal mechanisms, we exposed pregnant mice and cultured adipocytes to NNS (aspartame or sucralose) at doses relevant to human consumption. In mice, maternal NNS exposure caused elevated body weight, adiposity and insulin resistance in offspring, especially in males. Further, in 3T3-L1 pre-adipocyte cells, sucralose exposure during early stages of differentiation caused increased lipid accumulation and expression of adipocyte differentiation genes (e.g. C/EBP-α, FABP4, FAS). The same genes were upregulated in the adipose tissue of male mouse offspring born to sucralose-fed dams. Together, these clinical and experimental findings provide evidence suggesting that maternal NNS consumption induces obesity risk in the offspring through effects on adiposity and adipocyte differentiation.

One Sentence Summary

Maternal consumption of non-nutritive sweeteners during pregnancy stimulates adipocyte differentiation, insulin resistance, weight gain, and adiposity in mouse and human offspring.
Is shed hair the most effective non-invasive resource for estimating wild pedigrees?
Authors: Khan Anubhab , Patel Kaushal , Bhattacharjee Subhadeep , Sharma Sudarshan , Chugani Anup N , Sivaraman Karthikeyan , Hosawad Vinayak , Sahu Yogesh Kumar , Reddy Goddilla V , Ramakrishnan Uma
Published: July 2019

Wild pedigrees are critical for better understanding mating systems and inbreeding scenarios to inform conservation strategies for endangered species. To delineate pedigrees in wild populations, many identified individuals will have to be genotyped at thousands of loci, mostly from non-invasive samples. This requires us to quantify (a) the most common non-invasive sample available from identified individuals (b) the ability to acquire genome-wide data from such samples, and (c) the quality of such genome-wide data, and its ability to reconstruct relationships between animals within a population. We followed identified individuals from a wild endangered tiger population, and found that shed hair samples were most common compared to fecal samples, carcasses and opportunistic invasive samples. DNA extraction, library preparation and whole genome sequencing resulted in between 126,129 and 512,689 SNPs from across the genome for four such samples. Exploratory population genetic analyses revealed that these data were free of holistic biases, and could recover expected population structure and relatedness. Mitochondrial genomes recovered matrilineages as suggested by long-term monitoring data. Even with these few samples, we were able to uncover the matrilineage for an individual with unknown ancestry. In summary, we demonstrated that non-invasive shed hair samples yielded adequate quality/quantity DNA AND in conjunction with sensitive library preparation methods, provided reliable data from hundreds of thousands of SNPs across the genome. This makes shed hair are an effective resource for studying individual-based genetics of elusive endangered species.
Four chemoreceptors govern bidirectional pH taxis inBacillus subtilis
Authors: Tohidifar Payman , Plutz Matthew J. , Ordal George W. , Rao Christopher V.
Published: July 2019

We investigated pH taxis inBacillus subtilis. This bacterium was found to perform bidirectional taxis in response to external pH gradients, enabling it to preferentially migrate to neutral environments. We next investigated the chemoreceptors involved in sensing pH gradients. We found that four chemoreceptors are involved in sensing pH: McpA and TlpA for sensing acidic environments and McpB and TlpB for alkaline ones. In addition, TlpA was found to also weakly sense alkaline environments. By analyzing chimeras between McpA and TlpB, the principal acid and base-sensing chemoreceptors, we identified four critical amino-acid residues – Thr199, Gln200, His273, and Glu274on McpA and Lys199, Glu200, Gln273, and Asp274on TlpB – involved in sensing pH. Swapping these four residues between McpA and TlpB converted the former into a base receptor and the latter into an acid receptor. Based on the results, we propose that disruption of hydrogen bonding between the adjacent residues upon pH changes induces signaling. Collectively, our results further our understanding of chemotaxis inB. subtilisand provide a new model for pH sensing in bacteria.

IMPORTANCE

Many bacteria can sense the pH in their environment and then use this information to direct their movement towards more favorable locations. In this study, we investigated the pH sensing mechanism inBacillus subtilis. This bacterium preferentially migrates to neutral environments. It employs four chemoreceptors to sense pH. Two are involved in sensing acidic environments and two are involved in sensing alkaline ones. To identify the mechanism for pH sensing, we constructed receptor chimeras of acid and base sensing chemoreceptors. By analyzing the response of these chimeric receptors, we were able to identify four critical amino-acid residues involved in pH sensing and propose a model for the pH sensing mechanism inB. subtilis.
Canine distemper in Nepal’s Annapurna Conservation Area - The implications of dog husbandry and human behaviour for wildlife disease
Authors: Ng Debby , Carver Scott , Gotame Mukhiya , Karmasharya Dibesh , Karmacharya Dikpal , Pradhan Saman Man , Rana Ajay N. , Johnson Christopher N.
Published: July 2019

Dogs are often commensal with human settlements. In areas where settlements are adjacent to wildlife habitat, the management of dogs can affect risk of spillover of disease to wildlife. We assess dog husbandry practices, and measure the prevalence of Canine Distemper Virus (CDV) in dogs, in 10 villages in Nepal’s Annapurna Conservation Area (ACA), an important region for Himalayan wildlife. A high proportion (58%) of owned dogs were allowed by their owners to roam freely, and many village dogs originated from urban areas outside the region. CDV antibodies, indicating past exposure, were detected in 70% of dogs, and 13% were positive for P-gene, suggesting current circulation of CDV. This is the first detection of canine distemper virus in a National Park in Nepal Himalaya. Dogs were generally in good condition, and none exhibited clinical signs of CDV infection, which suggests that infections were asymptomatic. CDV exposure varied with village location and age of dogs, but this variation was minor, consistent with high rates of movement of dogs across the region maintaining high seroprevalence. Residents reported the occurrence of several species of wild carnivores in or close to villages. These results suggest a high potential for transmission of CDV from village dogs to wild carnivores in ACA. We suggest that control of dog immigration, along with vaccination and neutering of dogs could mitigate the risk of CDV spillover into wild carnivore populations.
Photoswitchable microtubule inhibitors enabling robust, GFP-orthogonal optical control over the tubulin cytoskeleton
Authors: Gao Li , Kraus Yvonne , Wranik Maximilian , Weinert Tobias , Pritzl Stefanie D. , Meiring Joyce , Bingham Rebekkah , Olieric Natacha , Akhmanova Anna , Lohmüller Theobald , Steinmetz Michel O. , Thorn-Seshold Oliver
Published: July 2019

Here we present GFP-orthogonal optically controlled reagents for reliable and repetitive in cellulo modulation of microtubule dynamics and its dependent processes. Optically controlled reagents (“photopharmaceuticals”) have developed into powerful tools for high-spatiotemporal-precision control of endogenous biology, with numerous applications in neuroscience, embryology, and cytoskeleton research. However, the restricted chemical domain of photopharmaceutical scaffolds has constrained their properties and range of applications. Styrylbenzothiazoles are an as-yet unexplored scaffold for photopharmaceuticals, which we now rationally design to feature potent photocontrol, switching microtubule cytoskeleton function off and on according to illumination conditions. We show more broadly that this scaffold is exceptionally chemically and biochemically robust as well as substituent-tolerant, and offers particular advantages for intracellular biology through a range of desirable photopharmaceutical and drug-like properties not accessible to the current classes of photoswitches. We expect that these reagents will find powerful applications enabling robust, high precision, optically controlled cell biological experimentation in cytoskeleton research and beyond.
On Some Problems of Estimating Fundamental Niche from Physiological Data
Authors: Jesús Salvador Gutiérrez-Ruelas , Jiménez Laura , Quiroz-Reyes Ana Patricia , Sotelo-Pedroza Sabrina Cherizar , Jorge Soberon
Published: July 2019

Hutchinson proposed the idea of the fundamental niche, determined by physiological properties of a species, more than 50 years ago. The idea remains both central to ecological thinking and largely unexplored experimentally. In this note, we describe some problems of using physiological experiments databases to estimate fundamental niches, show some solutions, and the apply our solution to testing the prediction that fundamental niches contain realized niches, for some species of marine fishes and terrestrial beetles. Our results were concordant with Hutchinson’s predictions.
Functional significance and therapeutic potential of miR-15a mimic in pancreatic ductal adenocarcinoma
Authors: Guo Shixiang , Fesler Andrew , Huang Wenjie , Wang Yunchao , Yang Jiali , Wang Xianxing , Zheng Yao , Hwang Ga-Ram , Wang Huaizhi , Ju Jingfang
Published: July 2019

Treatment of pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge. There is an urgent need to develop novel strategies to enhance survival and improve patient prognosis. microRNAs (miRNAs) play critical roles as oncogenes or tumor suppressors in the regulation of cancer development and progression. In this study, we demonstrate that low expression of miR-15a is associated with poor prognosis of PDAC patients. miR-15a expression is reduced in PDAC while closely related miR-16 expression remains relatively unchanged. miR-15a suppresses several important targets such as Wee1, Chk1, Yap-1, and BMI-1 causing cell cycle arrest and inhibiting cell proliferation. Ectopic expression of miR-15a sensitizes PDAC cells to gemcitabine reducing the IC50over 6.5-fold. To investigate the therapeutic potential of miR-15a, we used a modified miR-15a (5-FU-miR-15a) with uracil (U) residues in the guide strand replaced with 5-fluorouracil (5-FU). We demonstrated enhanced inhibition of PDAC cell proliferation by 5-FU-miR-15a compared to native miR-15a.In vivowe showed the therapeutic power of 5-FU-miR-15a alone or in combination with gemcitabine with near complete elimination of PDAC lung metastatic tumor growth. These results support the future development of 5-FU-miR-15a as a novel therapeutic agent as well as a prognostic biomarker in the clinical management of PDAC.
A Clinical Phenotyping Algorithm to Identify Cases of Chronic Obstructive Pulmonary Disease in Electronic Health Records
Authors: Martucci Victoria L. , Liu Nancy , Kerchberger V. Eric , Osterman Travis J. , Torstenson Eric , Richmond Bradley , Aldrich Melinda C.
Published: July 2019

Rationale

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality in the United States. Electronic health records provide large-scale healthcare data for clinical research, but have been underutilized in COPD research due to challenges identifying these individuals, especially in the absence of pulmonary function testing data.

Objectives

To develop an algorithm to electronically phenotype individuals with COPD at a large tertiary care center.

Methods

We identified individuals over 45 years of age at last clinic visit within Vanderbilt University Medical Center electronic health records. We tested phenotyping algorithms using combinations of both structured and unstructured text and examined the clinical characteristics of the resulting case sets.

Measurement and Main Results

A simple algorithm consisting of 3 International Classification of Disease codes for COPD achieved a sensitivity of 97.6%, a specificity of 76.0%, a positive predictive value of 57.1%, and a negative predictive value of 99.0%. A more complex algorithm consisting of both billing codes and a mention of oxygen on the problem list that achieved a positive predictive value of 86.5%. However, the association of known risk factors with chronic obstructive pulmonary disease was consistent in both algorithm sets, suggesting a simple code-only algorithm may suffice for many research applications.

Conclusions

Simple code-only phenotyping algorithms for chronic obstructive pulmonary disease can identify case populations with epidemiologic and genetic profiles consistent with published literature. Implementation of this phenotyping algorithm will expand opportunities for clinical research and pragmatic trials for COPD.
Rapid degradation ofC. elegansproteins at single-cell resolution with a synthetic auxin
Authors: Martinez Michael A. Q. , Kinney Brian A. , Medwig-Kinney Taylor N. , Ashley Guinevere , Ragle James M. , Johnson Londen , Aguilera Joseph , Hammell Christopher M. , Ward Jordan D. , Matus David Q.
Published: July 2019

As developmental biologists in the age of genome editing, we now have access to an ever-increasing array of tools to manipulate endogenous gene expression. The auxin-inducible degradation system, allows for spatial and temporal control of protein degradation, functioning through the activity of a hormone-inducibleArabidopsisF-box protein, transport inhibitor response 1 (TIR1). In the presence of auxin, TIR1 serves as a substrate recognition component of the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF), ubiquitinating auxin-inducible degron (AID)-tagged proteins for proteasomal degradation. Here, we optimize theCaenorhabditis elegansAID method, utilizing 1-naphthaleneacetic acid (NAA), an indole-free synthetic analog of the natural auxin indole-3-acetic acid (IAA). We take advantage of the photostability of NAA to demonstrate via quantitative high-resolution microscopy that rapid degradation of target proteins can be detected in single cells within 30 minutes of exposure. Additionally, we show that NAA works robustly in both standard growth media and physiological buffer. We also demonstrate that K-NAA, the water-soluble, potassium salt of NAA, can be combined with microfluidics for targeted protein degradation inC. eleganslarvae. We provide insight into how the AID system functions inC. elegansby determining that TIR1 interacts withC. elegansSKR-1/2, CUL-1, and RBX-1 to degrade target proteins. Finally, we present highly penetrant defects from NAA-mediated degradation of the Ftz-F1 nuclear hormone receptor, NHR-25, duringC. elegansuterine-vulval development. Together, this work provides a conceptual improvement to the AID system for dissecting gene function at the single-cell level duringC. elegansdevelopment.
High resolution structure of a partially folded insulin aggregation intermediate
Authors: Ratha Bhisma N , Kar Rajiv K , Brender Jeffrey R , Sahoo Bankanidhi , Kalita Sujan , Bhunia Anirban
Published: July 2019

Insulin has long served as a model for protein aggregation, both because of the importance of aggregation in insulin manufacture and because the structural biology of insulin has been extensively characterized. Despite intensive study, details about the initial triggers for aggregation have remained elusive at the molecular level. We show here that at acidic pH, the aggregation of insulin is likely initiated by a partially folded monomeric intermediate whose concentration is controlled by an off-pathway micellar species. High resolution structures of the partially folded intermediate show that it is coarsely similar to the initial monomeric structure but differs in subtle details – the A chain helices on the receptor interface are more disordered and the B chain helix moves away from C-terminal A chain helix. The result of these movements is the creation of a hydrophobic cavity in the center of the protein that may serve as nucleation site for oligomer formation. Knowledge of this transition may aid in the engineering of insulin variants that retain the favorable pharamacokinetic properties of monomeric insulin but are more resistant to aggregation.
Adding Extra Knowledge in Scalable Learning of Sparse Differential Gaussian Graphical Models
Authors: Sekhon Arshdeep , Wang Beilun , Qi Yanjun
Published: July 2019

We focus on integrating different types of extra knowledge (other than the observed samples) for estimating the sparse structure change between two p-dimensional Gaussian Graphical Models (i.e. differential GGMs). Previous differential GGM estimators either fail to include additional knowledge or cannot scale up to a high-dimensional (large p) situation. This paper proposes a novel method KDiffNet that incorporates Additional Knowledge in identifying Differential Networks via an Elementary Estimator. We design a novel hybrid norm as a superposition of two structured norms guided by the extra edge information and the additional node group knowledge. KDiffNet is solved through a fast parallel proximal algorithm, enabling it to work in large-scale settings. KDiffNet can incorporate various combinations of existing knowledge without re-designing the optimization. Through rigorous statistical analysis we show that, while considering more evidence, KDiffNet achieves the same convergence rate as the state-of-the-art. Empirically on multiple synthetic datasets and one real-world fMRI brain data, KDiffNet significantly outperforms the cutting edge baselines with regard to the prediction performance, while achieving the same level of time cost or less.
AnIn silicoAlgorithm for Identifying Amino Acids that Stabilize Oligomeric Membrane-Toxin Pores through Electrostatic Interactions
Authors: Desikan Rajat , Maiti Prabal K. , Ayappa K. Ganapathy
Published: July 2019

Pore forming toxins (PFTs) are a class of proteins which have specifically evolved to form unregulated pores in target plasma membranes, and represent the single largest class of bacterial virulence factors. With increasingly prevalent antibiotic-resistant bacterial strains, next generation therapies are being developed to target bacterial PFTs rather than the pathogens themselves. However, structure-based design of inhibitors that could block pore formation are hampered by a paucity of structural information about pore intermediates. On similar lines, observations of the inter-subunit interfaces in fully-formed pore complexes to identify druggable residues, whose interactions could potentially be blocked to hamper pore formation or destabilize pore assemblies, are often limited because of the presence of a large number of protein-protein interaction sites across pore inter-subunit interfaces. Narrowing down the list of plausible target residues requires a quantitative assessment of their contributions towards pore stability, which cannot be gleaned from a single, static, crystal or cryo-EM pore structure. We overcome this limitation by developing anin silicoscreening algorithm that employs fully atomistic molecular dynamics simulations coupled with knowledge-based screening to identify residues engaged in persistent and stabilizing electrostatic interactions across inter-subunit interfaces in membrane-inserted PFT pores. Application of this algorithm to prototypicalα-PFT (cytolysin A) andβ-PFT (α-hemolysin) pores yielded a small predicted subset of highly interacting residues, blocking of which could destabilize pore complexes as shown in previous mutagenesis experiments for some of these predicted residues. The algorithm also yielded a novel set of residues in both cytolysin A andα-hemolysin pores for which no mutagenesis and stability data exists to the best of our knowledge, and therefore could serve as hitherto un-recognised potential targets for PFT inhibitors. The algorithm worked equally well for bothαandβ-PFT pores, and could thus be potentially applicable to all pores with known structures to generate a database of pore-destabilizing mutations, which could then serve as a starting point for experimental validation and structure-based PFT-inhibitor design.
The Aging Microenvironment Shapes Alveolar Macrophage Identity in Aging
Authors: McQuattie-Pimentel Alexandra C. , Ren Ziyou , Joshi Nikita , Watanabe Satoshi , Stoeger Thomas , Chi Monica , Lu Ziyan , Sichizya Lango , Piseaux Raul , Chen Ching-I , Soberanes Saul , Reyfman Paul A. , Walter James M. , Anekalla Kishore R. , Davis Jennifer M. , Helmin Kathryn A. , Runyan Constance E. , Abdala-Valencia Hiam , Nam Kiwon , Meliton Angelo Y. , Winter Deborah R. , Morimoto Richard I. , Mutlu Gökhan M. , Bharat Ankit , Perlman Harris , Gottardi Cara J. , Ridge Karen M. , Chandel Navdeep S. , Sznajder Jacob I. , Balch William E. , Singer Benjamin D. , Misharin Alexander V. , Budinger GR Scott
Published: July 2019

A dysfunctional response to inhaled pathogens and toxins drives a substantial portion of the susceptibility to acute and chronic lung disease in the elderly. We used transcriptomic profiling combined with genetic lineage tracing, heterochronic adoptive transfer, parabiosis and treatment with metformin to show that the lung microenvironment defines the phenotype of long-lived alveolar macrophages during aging. While tissue-resident alveolar macrophages persist in the lung without input from monocytes over the lifespan, severe lung injury results in their replacement with monocyte-derived alveolar macrophages. These monocyte-derived alveolar macrophages are also shaped by the microenvironment both during aging and in response to a subsequent environmental challenge to become transcriptionally and functionally similar to tissue-resident alveolar macrophages. These findings show that changes in alveolar macrophage phenotypes during injury and aging are not cell autonomous but instead are shaped by changes in the aging lung microenvironment.
Tyrosine-based Signals Regulate the assembly of Daple•PARD3 Complex at Cell-cell Junctions during Polarized Planar Cell Migration
Authors: Ear Jason , Saklecha Anokhi , Rajapakse Navin , Choi Julie , Ghassemian Majid , Kufareva Irina , Ghosh Pradipta
Published: July 2019

Polarized distribution of organelles and molecules inside a cell is vital for a range of cellular processes and its loss is frequently encountered in disease. Polarization during planar cell migration is a special condition in which cellular orientation is triggered by cell-cell contact. Here, we demonstrate that the multi-modular signaling scaffold Daple (CCDC88C) is a component of cell junctions in epithelial cells which serves like a cellular ‘compass’ for establishing and maintaining contact-triggered planar polarityviaits interaction with the polarity regulator PARD3, which has been implicated in both apical-basal and planar polarity. This interaction, mediated by Daple’s PDZ-binding motif (PBM) and the third PDZ domain of PARD3, is fine-tuned by two tyrosine phosphoevents on Daple’s PBM that are known to be triggered by a multitude of receptor and non-receptor tyrosine kinases, such as Src. Hypophosphorylation strengthens the interaction, whereas hyperphosphorylation disrupts it. These findings reveal an unexpected role of Daple within the planar cell polarity pathway as a platform for signal integration and gradient sensing for tyrosine-based signals.
Transcriptome analysis of apple leaves infected by the rust fungus Gymnosporangium yamadae at two sporulation stages (spermogonia and aecia) reveals specific host responses, rust pathogenesis-related genes and a shift in the phyllosphere fungal community composition
Authors: Tao Si-Qi , Auer Lucas , Morin Emmanuelle , Liang Ying-Mei , Duplessis Sébastien
Published: July 2019

Apple rust disease caused by Gymnosporangium yamadae is one of the major threats to apple orchards. In this study, dual RNA-seq analysis was conducted to simultaneously monitor gene expression profiles of G. yamadae and infected apple leaves during the formation of rust spermogonia and aecia. The molecular mechanisms underlying this compatible interaction at 10 and 30 days post inoculation (dpi) indicate a significant reaction from the host plant and comprise detoxication pathways at the earliest stage and the induction of secondary metabolism related pathways at 30dpi. Such host reactions have been previously reported in other rust pathosystems and may represent a general reaction to rust infection. G. yamadae transcript profiling indicates a conserved genetic program in spermogonia and aecia that is shared with other rust fungi, whereas secretome prediction reveals the presence of specific secreted candidate effector proteins expressed during apple infection. Unexpectedly, the survey of fungal unigenes in the transcriptome assemblies of inoculated and mock-inoculated apple leaves reveals that G. yamadae infection modifies the fungal community composition in the apple phyllosphere at 30 dpi. Collectively, our results provide novel insights into the compatible apple-apple rust interaction and advance the knowledge of this heteroecious demicyclic rust fungus.
High Resolution Imaging Mass Spectrometry of Bacterial Microcolonies at Ecological Scales
Authors: de Cassia Pessotti Rita , Hansen Bridget L. , Zacharia Vineetha M. , Polyakov Daniel , Traxler Matthew F.
Published: July 2019

Microbes interact with the world around them at the chemical level. However, directly examining the chemical exchange between microbes, and microbes and their environment, at ecological scales,i.e.the scale of a single bacterial cell or small groups of cells, remains a key challenge. Here we address this obstacle by presenting a methodology that enablesMatrix-assistedlaserdesorption/ionization (MALDI)imagingmassspectrometry (IMS) of bacterial microcolonies. By combining optimized sample preparation with sub-atmospheric pressure MALDI, we demonstrate that chemical output from groups of as few as ~50 cells can be visualized with MALDI-IMS. Application of this methodology toBacillus subtilisandStreptomyces coelicolorrevealed heterogeneity in chemical output across microcolonies, and asymmetrical metabolite production when cells grew within physiological gradients produced byMedicago sativaroots. Taken together, these results indicate that MALDI-IMS can readily visualize metabolites made by very small assemblages of bacterial cells, and that even these small groups of cells can differentially produce metabolites in response to local chemical gradients.
Response to CAR T cell therapy can be explained by ecological cell dynamics and stochastic extinction events
Authors: Kimmel Gregory J. , Locke Frederick L. , Altrock Philipp M.
Published: July 2019

Chimeric antigen receptor (CAR) T cell therapy is a remarkably effective immunotherapy that relies on in vivo expansion of engineered CAR T cells, after lymphodepletion by chemotherapy. The laws underlying this expansion and subsequent tumor eradication remain unknown. Still, about 60% of CAR T-treated patients are likely to progress; their tumors are not eradicated. Here we seek to understand and disentangle the multiple processes that contribute to CAR expansion and tumor eradication. We developed a mathematical model of T cell-tumor cell interactions, and demonstrate that CAR T cell expansion is shaped by immune reconstitution dynamics after lymphodepletion and predator prey-like dynamics. Our cell population model was parameterized using patient population-level data over time and recapitulates progression free survival. As an intrinsic property, we find that tumor eradication is a stochastic event. Our cell population-based approach renders CAR T cell therapy as an ecological dynamic process that drives tumors toward an extinction vortex. Even if a clinical event, such as progression, is likely, its timing can be highly variable. We predict how clinical interventions that increase CAR T memory populations could improve the likelihood of tumor eradication and improve progression free survival. Our model can be leveraged to propose new CAR composition and dosing strategies, assess the need for multiple doses, and identify patient populations most likely to benefit from CAR T with or without additional interventions.
Uncover the Mechanism of Nucleotide Import by HIV-1 Capsid
Authors: Song Guang
Published: July 2019

In this work, we carry out a series of Brownian diffusion simulations to elucidate the nucleotide importing process through the hexamer pores of HIV-1 capsid. Our simulations reveal the mechanism by which deoxynucleoside triphosphates (dNTPs) diffuse through the arginine ring, the role of electrostatic potential within the pore in the importing process, and surprisingly, how IP6s and ATPs, though competing with dNTPs for binding at the arginine ring, end up accelerating the nucleotide import rate by thousands of folds so that it is sufficiently high to fuel the encapsidated DNA synthesis.

IMPORTANCE

Efficient nucleotide import is critical to fuel the reverse DNA synthesis that takes place within the capsid. However, the mechanism by which capsid imports the nucleotides is presently unclear. The current study through Brownian simulations shed insights into the process. A clear understanding of the mechanism of nucleotide import can be informative in developing drugs that target the process.
Ionpair-π interactions favor cell penetration of arginine/tryptophan-rich cell-penetrating peptides
Authors: Walrant Astrid , Bauzá Antonio , Girardet Claudia , Alves Isabel D. , Lecomte Sophie , Illien Françoise , Cardon Sébastien , Chaianantakul Natpasit , Pallerla Manjula , Burlina Fabienne , Frontera Antonio , Sagan Sandrine
Published: July 2019

Cell-penetrating peptides (CPPs) internalization can occur both by endocytosis and direct translocation through the cell membrane. These different entry routes suggest that molecular partners at the plasma membrane, phospholipids or glycosaminoglycans (GAGs), bind CPPs with different affinity or selectivity. The analysis of sequence-dependent interactions of CPPs with lipids and GAGs should lead to a better understanding of the molecular mechanisms underlying their internalization. CPPs are short sequences generally containing a high number of basic arginines and lysines and sometimes aromatic residues, in particular tryptophans. Tryptophans are crucial residues in membrane-active peptides, because they are important for membrane interaction. Membrane-active peptides often present facial amphiphilicity, which also promote the interaction with lipid bilayers. To study the role of Trp and facial amphiphilicity in cell interaction and penetration of CPPs, a nonapeptide series containing only Arg, Trp or D-Trp residues at different positions was designed. Our quantitative study indicates that to maintain/increase the uptake efficiency, Arg can be advantageously replaced by Trp in the nonapeptides. The presence of Trp in oligoarginines increases the uptake in cells expressing GAGs at their surface, when it only compensates for the loss of Arg and maintains similar peptide uptake in GAG-deficient cells. In addition, we show that facial amphiphilicity is not required for efficient uptake of these nonapeptides. Thermodynamic analyses point towards a key role of Trp that highly contributes to the binding enthalpy of complexes formation. Density functional theory (DFT) analysis highlights that salt bridge-π interactions play a crucial role for the GAG-dependent entry mechanisms.
Detecting changes in the Caenorhabditis elegans intestinal environment using an engineered bacterial biosensor
Authors: Rutter Jack W. , Ozdemir Tanel , Quintaneiro Leonor M. , Thomas Geraint , Cabreiro Filipe , Barnes Chris P.
Published: July 2019

Caenorhabditis elegans has become a key model organism within biology. In particular, the transparent gut, rapid growing time and ability to create a defined gut microbiota make it an ideal candidate organism for understanding and engineering the host microbiota. Here we present the development of an experimental model which can be used to characterise whole-cell bacterial biosensors in vivo. A dual-plasmid sensor system responding to isopropyl β-D-1-thiogalactopyranoside was developed and fully characterised in vitro. Subsequently, we show the sensor was capable of detecting and reporting on changes in the intestinal environment of C. elegans after introducing exogenous inducer into the environment. The protocols presented here may be used for aiding the rational design of engineered bacterial circuits, primarily for diagnostic applications. In addition, the model system may serve to reduce the use of current animal models and aid in the exploration of complex questions within general nematode and host-microbe biology.
Multiple probabilistic models extract features from protein sequence data and resolve functional diversity of very different protein families
Authors: Vicedomini R. , Bouly J.P. , Laine E. , Falciatore A. , Carbone A.
Published: July 2019

Sequence functional classification has become a critical bottleneck in understanding the myriad of protein sequences that accumulate in our databases. The great diversity of homologous sequences hides, in many cases, a variety of functional activities that cannot be anticipated. Their identification appears critical for a fundamental understanding of living organisms and for biotechnological applications.

ProfileView is a sequence-based computational method, designed to functionally classify sets of homologous sequences. It relies on two main ideas: the use of multiple probabilistic models whose construction explores evolutionary information in available databases, and a new definition of a representation space where to look at sequences from the point of view of probabilistic models combined together. ProfileView classifies families of proteins for which functions should be discovered or characterised within known groups.

We validate ProfileView on seven classes of widespread proteins, involved in the interaction with nucleic acids, amino acids and small molecules, and in a large variety of functions and enzymatic reactions. ProfileView agrees with the large set of functional data collected for these proteins from the literature regarding the organisation into functional subgroups and residues that characterize the functions. Furthermore, ProfileView resolves undefined functional classifications and extracts the molecular determinants underlying protein functional diversity, showing its potential to select sequences towards accurate experimental design and discovery of new biological functions.

ProfileView proves to outperform three functional classification approaches, CUPP, PANTHER, and a recently developed neural network approach based on Restricted Boltzmann Machines. It overcomes time complexity limitations of the latter.
GARDEN-NET and ChAseR: a suite of tools for the analysis of chromatin networks
Authors: Madrid-Mencía Miguel , Raineri Emanuele , Pancaldi Vera
Published: July 2019

We introduce an R package and a web-based visualization tool for the representation, analysis and integration of epigenomic data in the context of 3D chromatin interaction networks. GARDEN-NET allows for the projection of user-submitted genomic features on pre-loaded chromatin interaction networks exploiting the functionalities of the ChAseR package to explore the features in combination with chromatin network topology. We demonstrate the approach on epigenomic and chromatin structure datasets in haematopoietic cells.
Influence of human population density on spatial distribution patterns of environmental suitability for triatomine vectors of Chagas disease
Authors: Eduardo Anderson A. , Santos Lucas A. B. O. , Rebouças Mônica C. , Martinez Pablo A.
Published: July 2019

Previous work on Chagas Disease disease at large spatial scales has not explored how interaction with humans can affect projections for geographical distribution of environmental suitability of vector species. Here, we compare niche-based species distribution models with climatic variables as predictors (SDMclim) and with climatic variables + human population density (SDMHuman). Our results show that accounting for human population density helps refine the models to finer geographical scales. Also, different spatial patterns of accumulated environmental suitability were obtained by SDMclim and SDMHuman. Moreover, projections were more accurate for SDMHuman than for SDMclim. Our results show that considering human populations in SDMs for epidemiologically relevant triatomiane species can improve our understanding of macroecology and biogeography of environmental suitability for vectors of Chagas disease.