bluuebunny/crossref_metadata_2025 huggingface dataset:
NEK7 interacts with NLRP3 to modulate the pyroptosis in inflammatory bowel disease via NF-κB signaling
Authors: Chen Xueliang , Liu Ganglei , Yuan Yuanyuan , Wu Guotao , Wang Shalong , Yuan Lianwen
Published: December 2019

Inflammatory bowel disease (IBD) is one of the most common diseases in the gastrointestinal tract related to aberrant inflammation. Pyroptosis, which is characterized by inflammasome formation, the activation of caspase-1, and the separation of the N- and C-terminals of GSDMD, might be related to IBD pathogenesis. NEK7 is an important component of the NLRP3 inflammasome in macrophages. We attempted to investigate the mechanism of NEK7 interacting with NLRP3 to modulate the pyroptosis in IBD. NEK7 mRNA and protein expression and pyroptosis-associated factors, including Caspase-1 (p45, p20), NLRP3, and GSDMD, were upregulated in IBD tissues. NEK7 knockdown abolish ATP + LPS-induced pyroptosis in vitro and improved DSS-induced chronic colitis in vivo. NEK7 interacted with NLRP3, as revealed by Co-IP and GST pull-down assays, to exert its effects. Moreover, short-term LPS treatment alone induced no significant changes in NEK7 protein level. TLR4/NF-κB signaling in MODE-K cells could be activated by LPS treatment. LPS-induced NEK7 upregulation could be significantly reversed by JSH-23, an inhibitor of p65. Furthermore, LUC and ChIP assays revealed that RELA might activate the transcription of NEK7 via targeting its promoter region. LPS-induced TLR4/NF-κB activation causes an increase in NEK7 expression by RELA binding NEK7 promoter region. In conclusion, NEK7 interacts with NLRP3 to modulate NLRP3 inflammasome activation, therefore modulating the pyroptosis in MODE-K cells and DSS-induced chronic colitis in mice. We provide a novel mechanism of NEK7-NLRP3 interaction affecting IBD via pyroptosis.
Genome-wide transcriptome analysis reveals molecular pathways involved in leafy head formation of Chinese cabbage (Brassica rapa)
Authors: Sun XiaoXue , Basnet Ram Kumar , Yan Zhichun , Bucher Johan , Cai Chengcheng , Zhao Jianjun , Bonnema Guusje
Published: December 2019

Chinese cabbage plants go through seedling and rosette stages before forming their leafy head. Chinese cabbage plants resemble pak-choi plants at their seedling stage, but in their rosette stage the leaves of Chinese cabbage differentiate, as they increase in size with shorter petioles. In order to understand the molecular pathways that play a role in leafy head formation, transcript abundance of young emerging leaves was profiled during development of two Chinese cabbage genotypes and a single pak-choi genotype. The two Chinese cabbages differed in many aspects, among others earliness, leaf size and shape, leaf numbers, and leafy head shape. Genome-wide transcriptome analysis clearly separated the seedling stages of all three genotypes together with the later stages from pak-choi, from the later developmental stages of both Chinese cabbages (rosette, folding, and heading). Weighted correlation network analysis and hierarchical clustering using Euclidean distances resulted in gene clusters with transcript abundance patterns distinguishing the two Chinese cabbages from pak-choi. Three clusters included genes with transcript abundance affected by both genotype and developmental stage, whereas two clusters showed only genotype effects. This included a genotype by developmental stage cluster highly enriched with the MapMan category photosynthesis, with high expression during rosette and folding in Chinese cabbages and low expression in the heading inner leaves that are not exposed to light. The other clusters contained many genes in the MapMan categories Cell, showing again differences between pak-choi and both Chinese cabbages. We discuss how this relates to the differences in leaf blade growth between Chinese cabbage and pak-choi, especially at the rosette stage. Overall, comparison of the transcriptome between leaves of two very different Chinese cabbages with pak-choi during plant development allowed the identification of specific gene categories associated with leafy head formation.
Minor alleles are associated with white rust (Albugo occidentalis) susceptibility in spinach (Spinacia oleracea)
Authors: Awika Henry O. , Marconi Thiago G. , Bedre Renesh , Mandadi Kranthi K. , Avila Carlos A.
Published: December 2019

Minor alleles (MA) have been associated with disease incidence in human studies, enabling the identification of diagnostic risk factors for various diseases. However, allelic mapping has rarely been performed in plant systems. The goal of this study was to determine whether a difference in MA prevalence is a strong enough risk factor to indicate a likely significant difference in disease resistance against white rust (WR;Albugo occidentalis) in spinach (Spinacia oleracea). We used WR disease severity ratings (WR-DSRs) in a diversity panel of 267 spinach accessions to define resistant- and susceptibility-associated groups within the distribution scores and then tested the single-nucleotide polymorphism (SNP) variants to interrogate the MA prevalence in the most susceptible (MS) vs. most resistant (MR) individuals using permutation-based allelic association tests. A total of 448 minor alleles associated with WR severity were identified in the comparison between the 25% MS and the 25% MR accessions, while the MA were generally similar between the two halves of the interquartile range. The minor alleles in the MS group were distributed across all six chromosomes and made up ~71% of the markers that were also strongly associated with WR in parallel performed genome-wide association study. These results indicate that susceptibility may be highly determined by the disproportionate overrepresentation of minor alleles, which could be used to select for resistant plants. Furthermore, by focusing on the distribution tails, allelic mapping could be used to identify plant markers associated with quantitative traits on the most informative segments of the phenotypic distribution.
Global analysis of lysine succinylation in patchouli plant leaves
Authors: Wang Xiaobing , Chen Xiuzhen , Li Junren , Zhou Xuanxuan , Liu Yanting , Zhong Liting , Tang Yun , Zheng Hai , Liu Jiyun , Zhan Ruoting , Chen Likai
Published: December 2019

Lysine succinylation is a novel, naturally occurring posttranslational modification (PTM) in living organisms. Global lysine succinylation identification has been performed at the proteomic level in various species; however, the study of lysine succinylation in plant species is relatively limited. Patchouli plant (P. cablin (Blanco) Benth., Lamiaceae) is a globally important industrial plant and medicinal herb. In the present study, lysine succinylome analysis was carried out in patchouli plants to determine the potential regulatory role of lysine succinylation in patchouli growth, development, and physiology. The global succinylation sites and proteins in patchouli plants were screened with an immunoprecipitation affinity enrichment technique and advanced mass spectrometry-based proteomics. Several bioinformatic analyses, such as function classification and enrichment, subcellular location predication, metabolic pathway enrichment and protein−protein interaction networking, were conducted to characterize the functions of the identified sites and proteins. In total, 1097 succinylation sites in 493 proteins were detected in patchouli plants, among which 466 succinylation sites in 241 proteins were repeatedly identified within three independent experiments. The functional characterization of these proteins indicated that the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, photosynthesis processes, and amino acid biosynthesis may be regulated by lysine succinylation. In addition, these succinylated proteins showed a wide subcellular location distribution, although the chloroplast and cytoplasm were the top two preferred cellular components. Our study suggested the important role of lysine succinylation in patchouli plant physiology and biology and could serve as a useful reference for succinylation studies in other medicinal plants.
A detached petal disc assay and virus-induced gene silencing facilitate the study of Botrytis cinerea resistance in rose flowers
Authors: Cao Xiaoqian , Yan Huijun , Liu Xintong , Li Dandan , Sui Mengjie , Wu Jie , Yu Hongqiang , Zhang Zhao
Published: December 2019

Fresh-cut roses (Rosa hybrida) are one of the most important ornamental crops worldwide, with annual trade in the billions of dollars. Gray mold disease caused by the pathogen Botrytis cinerea is the most serious fungal threat to cut roses, causing extensive postharvest losses. In this study, we optimized a detached petal disc assay (DPDA) for artificial B. cinerea inoculation and quantification of disease symptoms in rose petals. Furthermore, as the identification of rose genes involved in B. cinerea resistance could provide useful genetic and genomic resources, we devised a virus-induced gene silencing (VIGS) procedure for the functional analysis of B. cinerea resistance genes in rose petals. We used RhPR10.1 as a reporter of silencing efficiency and found that the rose cultivar ‘Samantha’ showed the greatest decrease in RhPR10.1 expression among the cultivars tested. To determine whether jasmonic acid and ethylene are required for B. cinerea resistance in rose petals, we used VIGS to silence the expression of RhLOX5 and RhEIN3 (encoding a jasmonic acid biosynthesis pathway protein and an ethylene regulatory protein, respectively) and found that petal susceptibility to B. cinerea was affected. Finally, a VIGS screen of B. cinerea-induced rose transcription factors demonstrated the potential benefits of this method for the high-throughput identification of gene function in B. cinerea resistance. Collectively, our data show that the combination of the DPDA and VIGS is a reliable and high-throughput method for studying B. cinerea resistance in rose.
PbGA2ox8 induces vascular-related anthocyanin accumulation and contributes to red stripe formation on pear fruit
Authors: Zhai Rui , Wang Zhigang , Yang Chengquan , Lin-Wang Kui , Espley Richard , Liu Jianlong , Li Xieyu , Wu Zhongying , Li Pengmin , Guan Qingmei , Ma Fengwang , Xu Lingfei
Published: December 2019

Fruit with stripes, which are generally longitudinal, can occur naturally, but the bioprocesses underlying this phenomenon are unclear. Previously, we observed an atypical anthocyanin distribution that caused red-striped fruit on the spontaneous pear bud sport “Red Zaosu” (Pyrus bretschneideri Rehd.). In this study, comparative transcriptome analysis of the sport and wild-type “Zaosu” revealed that this atypical anthocyanin accumulation was tightly correlated with abnormal overexpression of the gene-encoding gibberellin (GA) 2-beta-dioxygenase 8, PbGA2ox8. Consistently, decreased methylation was also observed in the promoter region of PbGA2ox8 from “Red Zaosu” compared with “Zaosu”. Moreover, the GA levels in “Red Zaosu” seedlings were lower than those in “Zaosu” seedlings, and the application of exogenous GA4 reduced abnormal anthocyanin accumulation in “Red Zaosu”. Transient overexpression of PbGA2ox8 reduced the GA4 level and caused anthocyanin accumulation in pear fruit skin. Moreover, the presence of red stripes indicated anthocyanin accumulation in the hypanthial epidermal layer near vascular branches (VBs) in “Red Zaosu”. Transient overexpression of PbGA2ox8 resulting from vacuum infiltration induced anthocyanin accumulation preferentially in calcium-enriched areas near the vascular bundles in pear leaves. We propose a fruit-striping mechanism, in which the abnormal overexpression of PbGA2ox8 in “Red Zaosu” induces the formation of a longitudinal array of anthocyanin stripes near vascular bundles in fruit.
Photoresponsive spiro-polymers generated in situ by C–H-activated polyspiroannulation
Authors: Han Ting , Yao Zhanshi , Qiu Zijie , Zhao Zheng , Wu Kaiyi , Wang Jianguo , Poon Andrew W. , Lam Jacky W. Y. , Tang Ben Zhong
Published: December 2019

The development of facile and efficient polymerizations toward functional polymers with unique structures and attractive properties is of great academic and industrial significance. Here we develop a straightforward C–H-activated polyspiroannulation route to in situ generate photoresponsive spiro-polymers with complex structures. The palladium(II)-catalyzed stepwise polyspiroannulations of free naphthols and internal diynes proceed efficiently in dimethylsulfoxide at 120 °C without the constraint of apparent stoichiometric balance in monomers. A series of functional polymers with multisubstituted spiro-segments and absolute molecular weights of up to 39,000 are produced in high yields (up to 99%). The obtained spiro-polymers can be readily fabricated into different well-resolved fluorescent photopatterns with both turn-off and turn-on modes based on their photoinduced fluorescence change. Taking advantage of their photoresponsive refractive index, we successfully apply the polymer thin films in integrated silicon photonics techniques and achieve the permanent modification of resonance wavelengths of microring resonators by UV irradiation.
Genome-wide CRISPR screen identifies ELP5 as a determinant of gemcitabine sensitivity in gallbladder cancer
Authors: Xu Sunwang , Zhan Ming , Jiang Cen , He Min , Yang Linhua , Shen Hui , Huang Shuai , Huang Xince , Lin Ruirong , Shi Yongheng , Liu Qiang , Chen Wei , Mohan Man , Wang Jian
Published: December 2019

Gemcitabine is the first-line treatment for locally advanced and metastatic gallbladder cancer (GBC), but poor gemcitabine response is universal. Here, we utilize a genome-wide CRISPR screen to identify that loss of ELP5 reduces the gemcitabine-induced apoptosis in GBC cells in a P53-dependent manner through the Elongator complex and other uridine 34 (U34) tRNA-modifying enzymes. Mechanistically, loss of ELP5 impairs the integrity and stability of the Elongator complex to abrogate wobble U34 tRNA modification, and directly impedes the wobble U34 modification-dependent translation of hnRNPQ mRNA, a validated P53 internal ribosomal entry site (IRES) trans-acting factor. Downregulated hnRNPQ is unable to drive P53 IRES-dependent translation, but rescuing a U34 modification-independent hnRNPQ mutant could restore P53 translation and gemcitabine sensitivity in ELP5-depleted GBC cells. GBC patients with lower ELP5, hnRNPQ, or P53 expression have poor survival outcomes after gemcitabine chemotherapy. These results indicate that the Elongator/hnRNPQ/P53 axis controls gemcitabine sensitivity in GBC cells.
Magnetic field-tuned Fermi liquid in a Kondo insulator
Authors: Kushwaha Satya K. , Chan Mun K. , Park Joonbum , Thomas S. M. , Bauer Eric D. , Thompson J. D. , Ronning F. , Rosa Priscila F. S. , Harrison Neil
Published: December 2019

Kondo insulators are expected to transform into metals under a sufficiently strong magnetic field. The closure of the insulating gap stems from the coupling of a magnetic field to the electron spin, yet the required strength of the magnetic field–typically of order 100 T–means that very little is known about this insulator-metal transition. Here we show that Ce$${}_{3}$$

3

Bi$${}_{4}$$

4

Pd$${}_{3}$$

3

, owing to its fortuitously small gap, provides an ideal Kondo insulator for this investigation. A metallic Fermi liquid state is established above a critical magnetic field of only $${B}_{{\rm{c}}}\approx$$

B

c

≈
11 T. A peak in the strength of electronic correlations near $${B}_{{\rm{c}}}$$

B

c

, which is evident in transport and susceptibility measurements, suggests that Ce$${}_{3}$$

3

Bi$${}_{4}$$

4

Pd$${}_{3}$$

3

may exhibit quantum criticality analogous to that reported in Kondo insulators under pressure. Metamagnetism and the breakdown of the Kondo coupling are also discussed.
Phylogenomics of 10,575 genomes reveals evolutionary proximity between domains Bacteria and Archaea
Authors: Zhu Qiyun , Mai Uyen , Pfeiffer Wayne , Janssen Stefan , Asnicar Francesco , Sanders Jon G. , Belda-Ferre Pedro , Al-Ghalith Gabriel A. , Kopylova Evguenia , McDonald Daniel , Kosciolek Tomasz , Yin John B. , Huang Shi , Salam Nimaichand , Jiao Jian-Yu , Wu Zijun , Xu Zhenjiang Z. , Cantrell Kalen , Yang Yimeng , Sayyari Erfan , Rabiee Maryam , Morton James T. , Podell Sheila , Knights Dan , Li Wen-Jun , Huttenhower Curtis , Segata Nicola , Smarr Larry , Mirarab Siavash , Knight Rob
Published: December 2019

Rapid growth of genome data provides opportunities for updating microbial evolutionary relationships, but this is challenged by the discordant evolution of individual genes. Here we build a reference phylogeny of 10,575 evenly-sampled bacterial and archaeal genomes, based on a comprehensive set of 381 markers, using multiple strategies. Our trees indicate remarkably closer evolutionary proximity between Archaea and Bacteria than previous estimates that were limited to fewer “core” genes, such as the ribosomal proteins. The robustness of the results was tested with respect to several variables, including taxon and site sampling, amino acid substitution heterogeneity and saturation, non-vertical evolution, and the impact of exclusion of candidate phyla radiation (CPR) taxa. Our results provide an updated view of domain-level relationships.
Sustainable polycarbonate adhesives for dry and aqueous conditions with thermoresponsive properties
Authors: Beharaj Anjeza , McCaslin Ethan Z. , Blessing William A. , Grinstaff Mark W.
Published: December 2019

Pressure sensitive adhesives are ubiquitous in commodity products such as tapes, bandages, labels, packaging, and insulation. With single use plastics comprising almost half of yearly plastic production, it is essential that the design, synthesis, and decomposition products of future materials, including polymer adhesives, are within the context of a healthy ecosystem along with comparable or superior performance to conventional materials. Here we show a series of sustainable polymeric adhesives, with an eco-design, that perform in both dry and wet environments. The terpolymerization of propylene oxide, glycidyl butyrate, and CO2, catalyzed by a cobalt salen complex bearing a quaternary ammonium salt, yields the poly(propylene-co-glycidyl butyrate carbonate)s (PPGBC)s. This polymeric adhesive system, composed of environmentally benign building blocks, implements carbon dioxide sequestration techniques, poses minimal environmental hazards, exhibits varied peel strengths from scotch tape to hot-melt wood-glue, and adheres to metal, glass, wood, and Teflon® surfaces.
Weyl-like points from band inversions of spin-polarised surface states in NbGeSb
Authors: Marković I. , Hooley C. A. , Clark O. J. , Mazzola F. , Watson M. D. , Riley J. M. , Volckaert K. , Underwood K. , Dyer M. S. , Murgatroyd P. A. E. , Murphy K. J. , Fèvre P. Le , Bertran F. , Fujii J. , Vobornik I. , Wu S. , Okuda T. , Alaria J. , King P. D. C.
Published: December 2019

Band inversions are key to stabilising a variety of novel electronic states in solids, from topological surface states to the formation of symmetry-protected three-dimensional Dirac and Weyl points and nodal-line semimetals. Here, we create a band inversion not of bulk states, but rather between manifolds of surface states. We realise this by aliovalent substitution of Nb for Zr and Sb for S in the ZrSiS family of nonsymmorphic semimetals. Using angle-resolved photoemission and density-functional theory, we show how two pairs of surface states, known from ZrSiS, are driven to intersect each other near the Fermi level in NbGeSb, and to develop pronounced spin splittings. We demonstrate how mirror symmetry leads to protected crossing points in the resulting spin-orbital entangled surface band structure, thereby stabilising surface state analogues of three-dimensional Weyl points. More generally, our observations suggest new opportunities for engineering topologically and symmetry-protected states via band inversions of surface states.
Seawater softening of suture zones inhibits fracture propagation in Antarctic ice shelves
Authors: Kulessa Bernd , Booth Adam D. , O’Leary Martin , McGrath Daniel , King Edward C. , Luckman Adrian J. , Holland Paul R. , Jansen Daniela , Bevan Suzanne L. , Thompson Sarah S. , Hubbard Bryn
Published: December 2019

Suture zones are abundant on Antarctic ice shelves and widely observed to impede fracture propagation, greatly enhancing ice-shelf stability. Using seismic and radar observations on the Larsen C Ice Shelf of the Antarctic Peninsula, we confirm that such zones are highly heterogeneous, consisting of multiple meteoric and marine ice bodies of diverse provenance fused together. Here we demonstrate that fracture detainment is predominantly controlled by enhanced seawater content in suture zones, rather than by enhanced temperature as previously thought. We show that interstitial seawater can reduce fracture-driving stress by orders of magnitude, promoting both viscous relaxation and the development of micro cracks, the incidence of which scales inversely with stress intensity. We show how simple analysis of viscous buckles in ice-penetrating radar data can quantify the seawater content of suture zones and their modification of the ice-shelf’s stress regime. By limiting fracture, enhancing stability and restraining continental ice discharge into the ocean, suture zones act as vital regulators of Antarctic mass balance.
Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A
Authors: Steward Charles A. , Roovers Jolien , Suner Marie-Marthe , Gonzalez Jose M. , Uszczynska-Ratajczak Barbara , Pervouchine Dmitri , Fitzgerald Stephen , Viola Margarida , Stamberger Hannah , Hamdan Fadi F. , Ceulemans Berten , Leroy Patricia , Nava Caroline , Lepine Anne , Tapanari Electra , Keiller Don , Abbs Stephen , Sanchis-Juan Alba , Grozeva Detelina , Rogers Anthony S. , Diekhans Mark , Guigó Roderic , Petryszak Robert , Minassian Berge A. , Cavalleri Gianpiero , Vitsios Dimitrios , Petrovski Slavé , Harrow Jennifer , Flicek Paul , Lucy Raymond F. , Lench Nicholas J. , Jonghe Peter De , Mudge Jonathan M. , Weckhuysen Sarah , Sisodiya Sanjay M. , Frankish Adam
Published: December 2019

The developmental and epileptic encephalopathies (DEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60–65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for a lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 putative transcript models. Our annotations increase the transcriptional ‘footprint’ of these genes by over 674 kb. Using SCN1A as a case study, due to its close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome or a similar phenotype with a panel of exon sequences representing eight established genes and identified two de novo SCN1A variants that now - through improved gene annotation - are ascribed to residing among our exons. These two (from 122 screened people, 1.6%) molecular diagnoses carry significant clinical implications. Furthermore, we identified a previously classified SCN1A intronic Dravet syndrome-associated variant that now lies within a deeply conserved exon. Our findings illustrate the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders.
Pembrolizumab microgravity crystallization experimentation
Authors: Reichert Paul , Prosise Winifred , Fischmann Thierry O. , Scapin Giovanna , Narasimhan Chakravarthy , Spinale April , Polniak Ray , Yang Xiaoyu , Walsh Erika , Patel Daya , Benjamin Wendy , Welch Johnathan , Simmons Denarra , Strickland Corey
Published: December 2019

Crystallization processes have been widely used in the pharmaceutical industry for the manufacture, storage, and delivery of small-molecule and small protein therapeutics. However, the identification of crystallization processes for biologics, particularly monoclonal antibodies, has been prohibitive due to the size and the flexibility of their overall structure. There remains a challenge and an opportunity to utilize the benefits of crystallization of biologics. The research laboratories of Merck Sharp & Dome Corp. (MSD) in collaboration with the International Space Station (ISS) National Laboratory performed crystallization experiments with pembrolizumab (Keytruda®) on the SpaceX-Commercial Resupply Services-10 mission to the ISS. By leveraging microgravity effects such as reduced sedimentation and minimal convection currents, conditions producing crystalline suspensions of homogeneous monomodal particle size distribution (39 μm) in high yield were identified. In contrast, the control ground experiments produced crystalline suspensions with a heterogeneous bimodal distribution of 13 and 102 μm particles. In addition, the flight crystalline suspensions were less viscous and sedimented more uniformly than the comparable ground-based crystalline suspensions. These results have been applied to the production of crystalline suspensions on earth, using rotational mixers to reduce sedimentation and temperature gradients to induce and control crystallization. Using these techniques, we have been able to produce uniform crystalline suspensions (1–5 μm) with acceptable viscosity (<12 cP), rheological, and syringeability properties suitable for the preparation of an injectable formulation. The results of these studies may help widen the drug delivery options to improve the safety, adherence, and quality of life for patients and caregivers.
Mesenchymal stem cell perspective: cell biology to clinical progress
Authors: Pittenger Mark F. , Discher Dennis E. , Péault Bruno M. , Phinney Donald G. , Hare Joshua M. , Caplan Arnold I.
Published: December 2019

The terms MSC and MSCs have become the preferred acronym to describe a cell and a cell population of multipotential stem/progenitor cells commonly referred to as mesenchymal stem cells, multipotential stromal cells, mesenchymal stromal cells, and mesenchymal progenitor cells. The MSCs can differentiate to important lineages under defined conditions in vitro and in limited situations after implantation in vivo. MSCs were isolated and described about 30 years ago and now there are over 55,000 publications on MSCs readily available. Here, we have focused on human MSCs whenever possible. The MSCs have broad anti-inflammatory and immune-modulatory properties. At present, these provide the greatest focus of human MSCs in clinical testing; however, the properties of cultured MSCs in vitro suggest they can have broader applications. The medical utility of MSCs continues to be investigated in over 950 clinical trials. There has been much progress in understanding MSCs over the years, and there is a strong foundation for future scientific research and clinical applications, but also some important questions remain to be answered. Developing further methods to understand and unlock MSC potential through intracellular and intercellular signaling, biomedical engineering, delivery methods and patient selection should all provide substantial advancements in the coming years and greater clinical opportunities. The expansive and growing field of MSC research is teaching us basic human cell biology as well as how to use this type of cell for cellular therapy in a variety of clinical settings, and while much promise is evident, careful new work is still needed.
Altered levels of dopamine transporter in the frontal pole and dorsal striatum in schizophrenia
Authors: Sekiguchi Hirotaka , Pavey Geoff , Dean Brian
Published: December 2019

The dopamine hypothesis proposes that there is a hypodopaminergic state in the prefrontal cortex and a hyperdopaminergic state in the striatum of patients with schizophrenia. Evidence suggests the hyperdopaminergic state in the striatum is due to synaptic dopamine elevation, particularly in the dorsal striatum. However, the molecular mechanisms causing disrupted dopaminergic function in schizophrenia remains unclear. We postulated that the dopamine transporter (DAT), which regulates intra-synaptic dopamine concentrations by transporting dopamine from the synaptic cleft into the pre-synaptic neuron, could be involved in dopaminergic dysfunction in schizophrenia. Therefore, we measured levels of DAT in the cortex and striatum from patients with schizophrenia and controls using postmortem human brain tissue. Levels of desmethylimipramine-insensitive mazindol-sensitive [3H]mazindol binding to DAT were measured using in situ radioligand binding and autoradiography in gray matter from Brodmann’s area (BA) 10, BA 17, the dorsal striatum, and nucleus accumbens from 15 patients with schizophrenia and 15 controls. Levels of desmethylimipramine-insensitive mazindol-sensitive [3H]mazindol binding were significantly higher in BA 10 from patients with schizophrenia (p = 0.004) and significantly lower in the dorsal striatum (dorsal putamen p = 0.005; dorsal caudate p = 0.007) from those with the disorder. There were no differences in levels of desmethylimipramine-insensitive [3H]mazindol binding in BA 17 or nucleus accumbens. These data raise the possibility that high levels of DAT in BA 10 could be contributing to lower synaptic cortical dopamine, whereas lower levels of DAT could be contributing to a hyperdopaminergic state in the dorsal striatum.
A low-carbohydrate ketogenic diet induces the expression of very-low-density lipoprotein receptor in liver and affects its associated metabolic abnormalities
Authors: Okuda Tetsuya
Published: December 2019

A low-carbohydrate ketogenic diet (LCKD) promotes the progression of hepatic steatosis in C57BL/6 wild-type mice, but improves the condition in leptin-deficient obese (ob/ob) mice. Here, we show a novel effect of LCKD associated with the conflicting effects on these mice. Gene expression microarray analyses showed that expression of the Vldlr gene, which encodes the very-low-density lipoprotein receptor (VLDLR), was induced in LCKD-fed ob/ob mice. Although the VLDLR is not normally expressed in the liver, the LCKD led to VLDLR expression in both ob/ob and wild-type mice. To clarify this effect on VLDL dynamics, we analyzed the lipid content of serum lipoproteins and found a marked decrease in VLDL-triglycerides only in LCKD-fed wild-type mice. Further analyses suggested that transport of triglycerides via VLDL from the liver to extrahepatic tissues was inhibited by LCKD-induced hepatic VLDLR expression, but rescued under conditions of leptin deficiency.
Brain activity links performance in science reasoning with conceptual approach
Authors: Bartley Jessica E. , Riedel Michael C. , Salo Taylor , Boeving Emily R. , Bottenhorn Katherine L. , Bravo Elsa I. , Odean Rosalie , Nazareth Alina , Laird Robert W. , Sutherland Matthew T. , Pruden Shannon M. , Brewe Eric , Laird Angela R.
Published: December 2019

Understanding how students learn is crucial for helping them succeed. We examined brain function in 107 undergraduate students during a task known to be challenging for many students—physics problem solving—to characterize the underlying neural mechanisms and determine how these support comprehension and proficiency. Further, we applied module analysis to response distributions, defining groups of students who answered by using similar physics conceptions, and probed for brain differences linked with different conceptual approaches. We found that integrated executive, attentional, visual motion, and default mode brain systems cooperate to achieve sequential and sustained physics-related cognition. While accuracy alone did not predict brain function, dissociable brain patterns were observed when students solved problems by using different physics conceptions, and increased success was linked to conceptual coherence. Our analyses demonstrate that episodic associations and control processes operate in tandem to support physics reasoning, offering potential insight to support student learning.
Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma
Authors: Liu David , Schilling Bastian , Liu Derek , Sucker Antje , Livingstone Elisabeth , Jerby-Arnon Livnat , Zimmer Lisa , Gutzmer Ralf , Satzger Imke , Loquai Carmen , Grabbe Stephan , Vokes Natalie , Margolis Claire A. , Conway Jake , He Meng Xiao , Elmarakeby Haitham , Dietlein Felix , Miao Diana , Tracy Adam , Gogas Helen , Goldinger Simone M. , Utikal Jochen , Blank Christian U. , Rauschenberg Ricarda , von Bubnoff Dagmar , Krackhardt Angela , Weide Benjamin , Haferkamp Sebastian , Kiecker Felix , Izar Ben , Garraway Levi , Regev Aviv , Flaherty Keith , Paschen Annette , Van Allen Eliezer M. , Schadendorf Dirk
Published: December 2019

Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.
Author Correction: Ground reference data for sugarcane biomass estimation in São Paulo state, Brazil
Authors: Molijn Ramses A. , Iannini Lorenzo , Rocha Jansle Vieira , Hanssen Ramon F.
Published: December 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Structural genomics applied to the rust fungus Melampsora larici-populina reveals two candidate effector proteins adopting cystine knot and NTF2-like protein folds
Authors: de Guillen Karine , Lorrain Cécile , Tsan Pascale , Barthe Philippe , Petre Benjamin , Saveleva Natalya , Rouhier Nicolas , Duplessis Sébastien , Padilla André , Hecker Arnaud
Published: December 2019

Rust fungi are plant pathogens that secrete an arsenal of effector proteins interfering with plant functions and promoting parasitic infection. Effectors are often species-specific, evolve rapidly, and display low sequence similarities with known proteins. How rust fungal effectors function in host cells remains elusive, and biochemical and structural approaches have been scarcely used to tackle this question. In this study, we produced recombinant proteins of eleven candidate effectors of the leaf rust fungus Melampsora larici-populina in Escherichia coli. We successfully purified and solved the three-dimensional structure of two proteins, MLP124266 and MLP124017, using NMR spectroscopy. Although both MLP124266 and MLP124017 show no sequence similarity with known proteins, they exhibit structural similarities to knottins, which are disulfide-rich small proteins characterized by intricate disulfide bridges, and to nuclear transport factor 2-like proteins, which are molecular containers involved in a wide range of functions, respectively. Interestingly, such structural folds have not been reported so far in pathogen effectors, indicating that MLP124266 and MLP124017 may bear novel functions related to pathogenicity. Our findings show that sequence-unrelated effectors can adopt folds similar to known proteins, and encourage the use of biochemical and structural approaches to functionally characterize effector candidates.
A Computational Method to Quantify the Effects of Slipped Strand Mispairing on Bacterial Tetranucleotide Repeats
Authors: Harhay Gregory P. , Harhay Dayna M. , Bono James L. , Capik Sarah F. , DeDonder Keith D. , Apley Michael D. , Lubbers Brian V. , White Bradley J. , Larson Robert L. , Smith Timothy P. L.
Published: December 2019

The virulence and pathogenicity of bacterial pathogens are related to their adaptability to changing environments. One process enabling adaptation is based on minor changes in genome sequence, as small as a few base pairs, within segments of genome called simple sequence repeats (SSRs) that consist of multiple copies of a short sequence (from one to several nucleotides), repeated in series. SSRs are found in eukaryotes as well as prokaryotes, and length variation in them occurs at frequencies up to a million-fold higher than bacterial point mutations through the process of slipped strand mispairing (SSM) by DNA polymerase during replication. The characterization of SSR length by standard sequencing methods is complicated by the appearance of length variation introduced during the sequencing process that obscures the lower abundance repeat number variants in a population. Here we report a computational approach to correct for sequencing process-induced artifacts, validated for tetranucleotide repeats by use of synthetic constructs of fixed, known length. We apply this method to a laboratory culture of Histophilus somni, prepared from a single colony, and demonstrate that the culture consists of populations of distinct sequence phase and length variants at individual tetranucleotide SSR loci.
Identification of the amino acid residue responsible for the myricetin sensitivity of human proton-coupled folate transporter
Authors: Yamashiro Takahiro , Yasujima Tomoya , Ohta Kinya , Inoue Katsuhisa , Yuasa Hiroaki
Published: December 2019

Human proton-coupled folate transporter (hPCFT/SLC46A1) has recently been found to be inhibited by myricetin by a sustained mechanism, raising a concern that the inhibition might lead to malabsorption of folates in the intestine, where hPCFT works for their epithelial uptake. However, rat PCFT (rPCFT) has more recently been found not to be inhibited by myricetin. Prompted by this finding, we attempted to determine the amino acid residue involved in that by analyses comparing between hPCFT and rPCFT. In the initial analysis, chimeric constructs prepared from hPCFT and rPCFT were examined for myricetin sensitivity to determine the hPCFT segment involved in the sensitivity. Focusing on the thereby determined segment from 83rd to 186th amino acid residue, hPCFT mutants having a designated amino acid residue replaced with its counterpart in rPCFT were prepared for the subsequent analysis. Among them, only G158N-substituted hPCFT was found to be transformed to be insensitive to myricetin and, accordingly, oppositely N158G-substituted rPCFT was transformed to be sensitive to myricetin. These results indicate the critical role of Gly158 in the myricetin sensitivity of hPCFT. This finding would help advance the elucidation of the mechanism of the myricetin-induced inhibition of hPCFT and manage the potential risk arising from that.
Hemocyte-hemocyte adhesion by granulocytes is associated with cellular immunity in the cricket, Gryllus bimaculatus
Authors: Cho Youngwoo , Cho Saeyoull
Published: December 2019

In this study, more than 1,000 cricket (Gryllus bimaculatus) hemocytes were classified based on their size and morphology. These hemocytes were classified into six types: granulocytes, plasmatocytes, prohemocytes, spherulocytes, coagulocytes, and oenocytoids. Hemocyte cultures was observed in real time to determine which hemocytes were associated with cellular immune responses against potential pathogens. Granulocytes were identified as the professional immune cell that mediates nodulation, encapsulation, and phagocytosis of pathogens. Granulocytes have been shown to actively produce various sticky nets (amoeba-like hairs and extracellular traps) from their plasma membranes that they use to gather other hemocytes and to implement cellular immune responses. The activation of lysosomes in granulocytes started at 4 h, peaked at 12 h, and returned to baseline by 24 h post-infection. At 48 h post-infection, cells could be found within the cytoplasm of granulocytes and reactivated lysosomes surrounding these cells were visible. This result seems to reflect a phenomenon in which necrotic granulocytes are removed by other healthy granulocytes. This unique mechanism of cellular immunity is therefore a way to efficiently and effectively remove pathogens and simultaneously maintain healthy hemocytes.
TSLRF: Two-Stage Algorithm Based on Least Angle Regression and Random Forest in genome-wide association studies
Authors: Sun Jiali , Wu Qingtai , Shen Dafeng , Wen Yangjun , Liu Fengrong , Gao Yu , Ding Jie , Zhang Jin
Published: December 2019

One of the most important tasks in genome-wide association analysis (GWAS) is the detection of single-nucleotide polymorphisms (SNPs) which are related to target traits. With the development of sequencing technology, traditional statistical methods are difficult to analyze the corresponding high-dimensional massive data or SNPs. Recently, machine learning methods have become more popular in high-dimensional genetic data analysis for their fast computation speed. However, most of machine learning methods have several drawbacks, such as poor generalization ability, over-fitting, unsatisfactory classification and low detection accuracy. This study proposed a two-stage algorithm based on least angle regression and random forest (TSLRF), which firstly considered the control of population structure and polygenic effects, then selected the SNPs that were potentially related to target traits by using least angle regression (LARS), furtherly analyzed this variable subset using random forest (RF) to detect quantitative trait nucleotides (QTNs) associated with target traits. The new method has more powerful detection in simulation experiments and real data analyses. The results of simulation experiments showed that, compared with the existing approaches, the new method effectively improved the detection ability of QTNs and model fitting degree, and required less calculation time. In addition, the new method significantly distinguished QTNs and other SNPs. Subsequently, the new method was applied to analyze five flowering-related traits in Arabidopsis. The results showed that, the distinction between QTNs and unrelated SNPs was more significant than the other methods. The new method detected 60 genes confirmed to be related to the target trait, which was significantly higher than the other methods, and simultaneously detected multiple gene clusters associated with the target trait.
Sustainable synthesis of graphene-based adsorbent using date syrup
Authors: Khan Shaihroz , Achazhiyath Edathil Anjali , Banat Fawzi
Published: December 2019

Here we demonstrate, a facile in-situ strategy for the synthesis of environmentally benign and scalable graphene sand hybrid using date syrup as a sustainable carbon source through pyrolysis at 750 °C. Raman and SEM images revealed that the as-prepared date syrup-based graphene sand hybrid (D-GSH) had imperfections with macroporous 2-D graphene sheet-like structures stacked on the inorganic sand support. The applicability of the D-GSH for decontaminating the water from cationic (Methyl Violet, MV) and anionic (Congo Red, CR) dye and heavy metals (Pb2+ and Cd2+) was tested. Batch experiments demonstrated that D-GSH showcased exceptional capability for both dye and heavy metals removal with fast adsorption following pseudo-second-order kinetics. The adsorption capacities for MV, Pb2+, and Cd2+ were respectively 2564, 781 and 793 mg/g at 25 °C, the highest capacity graphene-based adsorbent reported in the literature to date. In addition, D-GSH also exhibited high adsorption capacity for anionic dye, CR (333 mg g−1) and good recyclability (3 cycles) for all the contaminants. The thermodynamic studies further confirmed that the adsorption of all contaminants was thermodynamically feasible, spontaneous and endothermic with ∆H° of 48.38, 89.10, 16.89 and 14.73 kJ/mol for MV, CR, Pb2+ and Cd2+, respectively. Thus, utilization of a simple one-step strategy to produce graphenic sand hybrid using date syrup helped in developing a cost-effective and environmentally friendly dye and heavy metal scavenger that can be used as a one-step solution for water decontamination.
Estimating Rates of Progression and Predicting Future Visual Fields in Glaucoma Using a Deep Variational Autoencoder
Authors: Berchuck Samuel I. , Mukherjee Sayan , Medeiros Felipe A.
Published: December 2019

In this manuscript we develop a deep learning algorithm to improve estimation of rates of progression and prediction of future patterns of visual field loss in glaucoma. A generalized variational auto-encoder (VAE) was trained to learn a low-dimensional representation of standard automated perimetry (SAP) visual fields using 29,161 fields from 3,832 patients. The VAE was trained on a 90% sample of the data, with randomization at the patient level. Using the remaining 10%, rates of progression and predictions were generated, with comparisons to SAP mean deviation (MD) rates and point-wise (PW) regression predictions, respectively. The longitudinal rate of change through the VAE latent space (e.g., with eight dimensions) detected a significantly higher proportion of progression than MD at two (25% vs. 9%) and four (35% vs 15%) years from baseline. Early on, VAE improved prediction over PW, with significantly smaller mean absolute error in predicting the 4th, 6thand 8thvisits from the first three (e.g., visit eight: VAE8: 5.14 dB vs. PW: 8.07 dB; P < 0.001). A deep VAE can be used for assessing both rates and trajectories of progression in glaucoma, with the additional benefit of being a generative technique capable of predicting future patterns of visual field damage.
Dynamical Mechanism of Polarons and Bipolarons in Poly(p-Phenylene Vinylene)
Authors: Paula Fábio Luís de Oliveira , Castro Leonardo Luiz e , Junior Luiz Antonio Ribeiro , Júnior Rafael Timóteo de Sousa , Silva Geraldo Magela e , Neto Pedro Henrique de Oliveira
Published: December 2019

Studies on Poly(p-Phenylene Vinylene) (PPV) and derivatives have experienced enormous growth since they were successfully used to fabricate the first efficient prototypes of Polymer Light-Emitting Diodes in the 90s. Despite this rapid progress, understanding the relationship between charge transport and the morphology in these materials remains a challenge. Here, we shed light on the understanding of the transport mechanism of polarons and bipolarons in PPVs by developing a two-dimensional tight-binding approach that includes lattice relaxation effects. Remarkably, the results show that the PPV lattice loses the energy related to its conjugation during time by transferring this amount of energy to electrons. Such a process for energy transfer permits the quasiparticles to overcome the potential barrier imposed by the local lattice deformations, that are formed in the presence of an additional charge and, consequently, their electric field assisted transport takes place. Within the framework of this transport mechanism, a better insight into the origin of the carrier mobility in PPV and derivatives can be achieved and would be a useful guide for improving their chemical structures and morphologies.
De novodesign of thioredoxin reductase-targeted heterometallic titanocene–gold compounds of chlorambucil for mechanistic insights into renal cancer
Authors: Tabrizi Leila , Olasunkanmi Lukman O. , Fadare Olatomide A.
Published: December 2019

A chlorambucil-alkynyl mononuclear gold(i) complex and heteronuclear titanocene–gold(i) complex were studied for mechanism of action in renal cancer by experimental and computational methods.