bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome sequences of horticultural plants: past, present, and future
Authors: Chen Fei , Song Yunfeng , Li Xiaojiang , Chen Junhao , Mo Lan , Zhang Xingtan , Lin Zhenguo , Zhang Liangsheng
Published: October 2019

Horticultural plants play various and critical roles for humans by providing fruits, vegetables, materials for beverages, and herbal medicines and by acting as ornamentals. They have also shaped human art, culture, and environments and thereby have influenced the lifestyles of humans. With the advent of sequencing technologies, there has been a dramatic increase in the number of sequenced genomes of horticultural plant species in the past decade. The genomes of horticultural plants are highly diverse and complex, often with a high degree of heterozygosity and a high ploidy due to their long and complex history of evolution and domestication. Here we summarize the advances in the genome sequencing of horticultural plants, the reconstruction of pan-genomes, and the development of horticultural genome databases. We also discuss past, present, and future studies related to genome sequencing, data storage, data quality, data sharing, and data visualization to provide practical guidance for genomic studies of horticultural plants. Finally, we propose a horticultural plant genome project as well as the roadmap and technical details toward three goals of the project.
Melatonin enhances salt tolerance by promoting MYB108A-mediated ethylene biosynthesis in grapevines
Authors: Xu Lili , Xiang Guangqing , Sun Qinghua , Ni Yong , Jin Zhongxin , Gao Shiwei , Yao Yuxin
Published: October 2019

The signal molecules melatonin and ethylene play key roles in abiotic stress tolerance. The interplay between melatonin and ethylene in regulating salt tolerance and the underlying molecular mechanism of this interplay remain unclear. Here, we found that both melatonin and 1-aminocyclopropane-1-carboxylic acid (ACC, a precursor of ethylene) enhanced the tolerance of grapevine to NaCl; additionally, ethylene participated in melatonin-induced salt tolerance. Further experiments indicated that exogenous treatment and endogenous induction of melatonin increased the ACC content and ethylene production in grapevine and tobacco plants, respectively. The expression of MYB108A and ACS1, which function as a transcription factor and a key gene involved in ethylene production, respectively, was strongly induced by melatonin treatment. Additionally, MYB108A directly bound to the promoter of ACS1 and activated its transcription. MYB108A expression promoted ACC synthesis and ethylene production by activating ACS1 expression in response to melatonin treatment. The suppression of MYB108A expression partially limited the effect of melatonin on the induction of ethylene production and reduced melatonin-induced salt tolerance. Collectively, melatonin promotes ethylene biosynthesis and salt tolerance through the regulation of ACS1 by MYB108A.
Evolution and regulation of nitrogen flux through compartmentalized metabolic networks in a marine diatom
Authors: Smith Sarah R. , Dupont Chris L. , McCarthy James K. , Broddrick Jared T. , Oborník Miroslav , Horák Aleš , Füssy Zoltán , Cihlář Jaromír , Kleessen Sabrina , Zheng Hong , McCrow John P. , Hixson Kim K. , Araújo Wagner L. , Nunes-Nesi Adriano , Fernie Alisdair , Nikoloski Zoran , Palsson Bernhard O. , Allen Andrew E.
Published: October 2019

Diatoms outcompete other phytoplankton for nitrate, yet little is known about the mechanisms underpinning this ability. Genomes and genome-enabled studies have shown that diatoms possess unique features of nitrogen metabolism however, the implications for nutrient utilization and growth are poorly understood. Using a combination of transcriptomics, proteomics, metabolomics, fluxomics, and flux balance analysis to examine short-term shifts in nitrogen utilization in the model pennate diatom in Phaeodactylum tricornutum, we obtained a systems-level understanding of assimilation and intracellular distribution of nitrogen. Chloroplasts and mitochondria are energetically integrated at the critical intersection of carbon and nitrogen metabolism in diatoms. Pathways involved in this integration are organelle-localized GS-GOGAT cycles, aspartate and alanine systems for amino moiety exchange, and a split-organelle arginine biosynthesis pathway that clarifies the role of the diatom urea cycle. This unique configuration allows diatoms to efficiently adjust to changing nitrogen status, conferring an ecological advantage over other phytoplankton taxa.
Long-term memory is formed immediately without the need for protein synthesis-dependent consolidation in Drosophila
Authors: Zhao Bohan , Sun Jiameng , Zhang Xuchen , Mo Han , Niu Yijun , Li Qian , Wang Lianzhang , Zhong Yi
Published: October 2019

It is believed that long-term memory (LTM) cannot be formed immediately because it must go through a protein synthesis-dependent consolidation process. However, the current study uses Drosophila aversive olfactory conditioning to show that such processes are dispensable for context-dependent LTM (cLTM). Single-trial conditioning yields cLTM that is formed immediately in a protein-synthesis independent manner and is sustained over 14 days without decay. Unlike retrieval of traditional LTM, which requires only the conditioned odour and is mediated by mushroom-body neurons, cLTM recall requires both the conditioned odour and reinstatement of the training-environmental context. It is mediated through lateral-horn neurons that connect to multiple sensory brain regions. The cLTM cannot be retrieved if synaptic transmission from any one of these centres is blocked, with effects similar to those of altered encoding context during retrieval. The present study provides strong evidence that long-term memory can be formed easily without the need for consolidation.
Transient callosal projections of L4 neurons are eliminated for the acquisition of local connectivity
Authors: De León Reyes N. S. , Mederos S. , Varela I. , Weiss L. A. , Perea G. , Galazo M. J. , Nieto M.
Published: October 2019

Interhemispheric axons of the corpus callosum (CC) facilitate the higher order functions of the cerebral cortex. According to current views, callosal and non-callosal fates are determined early after a neuron’s birth, and certain populations, such as cortical layer (L) 4 excitatory neurons of the primary somatosensory (S1) barrel, project only ipsilaterally. Using a novel axonal-retrotracing strategy and GFP-targeted visualization of Rorb+ neurons, we instead demonstrate that L4 neurons develop transient interhemispheric axons. Locally restricted L4 connectivity emerges when exuberant contralateral axons are refined in an area- and layer-specific manner during postnatal development. Surgical and genetic interventions of sensory circuits demonstrate that refinement rates depend on distinct inputs from sensory-specific thalamic nuclei. Reductions in input-dependent refinement result in mature functional interhemispheric hyperconnectivity, demonstrating the plasticity and bona fide callosal potential of L4 neurons. Thus, L4 neurons discard alternative interhemispheric circuits as instructed by thalamic input. This may ensure optimal wiring.
Artificial intelligence reveals environmental constraints on colour diversity in insects
Authors: Wu Shipher , Chang Chun-Min , Mai Guan-Shuo , Rubenstein Dustin R. , Yang Chen-Ming , Huang Yu-Ting , Lin Hsu-Hong , Shih Li-Cheng , Chen Sheng-Wei , Shen Sheng-Feng
Published: October 2019

Explaining colour variation among animals at broad geographic scales remains challenging. Here we demonstrate how deep learning—a form of artificial intelligence—can reveal subtle but robust patterns of colour feature variation along an ecological gradient, as well as help identify the underlying mechanisms generating this biogeographic pattern. Using over 20,000 images with precise GPS locality information belonging to nearly 2,000 moth species from Taiwan, our deep learning model generates a 2048-dimension feature vector that accurately predicts each species’ mean elevation based on colour and shape features. Using this multidimensional feature vector, we find that within-assemblage image feature variation is smaller in high elevation assemblages. Structural equation modeling suggests that this reduced image feature diversity is likely the result of colder environments selecting for darker colouration, which limits the colour diversity of assemblages at high elevations. Ultimately, with the help of deep learning, we will be able to explore the endless forms of natural morphological variation at unpreceded depths.
Publisher Correction: Ca2+-regulated Ca2+ channels with an RCK gating ring control plant symbiotic associations
Authors: Kim Sunghoon , Zeng Weizhong , Bernard Shane , Liao Jun , Venkateshwaran Muthusubramanian , Ane Jean-Michel , Jiang Youxing
Published: October 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
A large data resource of genomic copy number variation across neurodevelopmental disorders
Authors: Zarrei Mehdi , Burton Christie L. , Engchuan Worrawat , Young Edwin J. , Higginbotham Edward J. , MacDonald Jeffrey R. , Trost Brett , Chan Ada J. S. , Walker Susan , Lamoureux Sylvia , Heung Tracy , Mojarad Bahareh A. , Kellam Barbara , Paton Tara , Faheem Muhammad , Miron Karin , Lu Chao , Wang Ting , Samler Kozue , Wang Xiaolin , Costain Gregory , Hoang Ny , Pellecchia Giovanna , Wei John , Patel Rohan V. , Thiruvahindrapuram Bhooma , Roifman Maian , Merico Daniele , Goodale Tara , Drmic Irene , Speevak Marsha , Howe Jennifer L. , Yuen Ryan K. C. , Buchanan Janet A. , Vorstman Jacob A. S. , Marshall Christian R. , Wintle Richard F. , Rosenberg David R. , Hanna Gregory L. , Woodbury-Smith Marc , Cytrynbaum Cheryl , Zwaigenbaum Lonnie , Elsabbagh Mayada , Flanagan Janine , Fernandez Bridget A. , Carter Melissa T. , Szatmari Peter , Roberts Wendy , Lerch Jason , Liu Xudong , Nicolson Rob , Georgiades Stelios , Weksberg Rosanna , Arnold Paul D. , Bassett Anne S. , Crosbie Jennifer , Schachar Russell , Stavropoulos Dimitri J. , Anagnostou Evdokia , Scherer Stephen W.
Published: October 2019

Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are NRXN1, SEH1L, LDLRAD4, GNAL, GNG13, MKRN1, DCTN2, KNDC1, PCMTD2, KIF5A, SYNM, and long non-coding RNAs: AK127244 and PTCHD1-AS. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.
Pyroglutamyl leucine, a peptide in fermented foods, attenuates dysbiosis by increasing host antimicrobial peptide
Authors: Shirako Saki , Kojima Yumi , Tomari Naohiro , Nakamura Yasushi , Matsumura Yasuki , Ikeda Kaori , Inagaki Nobuya , Sato Kenji
Published: October 2019

PyroGlu-Leu is present in certain food protein hydrolysates and traditional Japanese fermented foods. Our previous study demonstrated that the oral administration of pyroGlu-Leu (0.1 mg/kg body weight) attenuates dysbiosis in mice with experimental colitis. The objective of this study was to elucidate why such a low dose of pyroGlu-Leu attenuates dysbiosis in different animal models. High fat diet extensively increased the ratio of Firmicutes/Bacteroidetes in feces of rats compared to control diet. Oral administration of pyroGlu-Leu (1 mg/kg body weight) significantly attenuated high fat diet-induced dysbiosis. By focusing on the production of intestinal antimicrobial peptides, we found that pyroGlu-Leu significantly increased the level of 4962 Da peptides, which identified as the propeptide of rattusin or defensin alpha 9, in ileum. We also observed increased tryptic fragment peptides from rattusin in the lumen. Here, we report that orally administered pyroGlu-Leu attenuates dysbiosis by increasing in the host antimicrobial peptide, rattusin.
Author Correction: Characterization of Retinal Ganglion Cell and Optic Nerve Phenotypes Caused by Sustained Intracranial Pressure Elevation in Mice
Authors: Shen Guofu , Link Schuyler , Kumar Sandeep , Nusbaum Derek M. , Tse Dennis Y. , Fu Yingbin , Wu Samuel M. , Frankfort Benjamin J.
Published: October 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Complete chloroplast genome sequence and phylogenetic analysis of wasabi (Eutrema japonicum) and its relatives
Authors: Haga Natsuko , Kobayashi Masaaki , Michiki Nana , Takano Tomoyuki , Baba Fujio , Kobayashi Keiko , Ohyanagi Hajime , Ohgane Jun , Yano Kentaro , Yamane Kyoko
Published: October 2019

In Japan, two Eutrema species, wasabi (Eutrema japonicum, the important traditional Japanese condiment) and yuriwasabi (E. tenue), have been recognized as endemic species. We sequenced complete chloroplast (cp) genomes of seven wasabi and yuriwasabi accessions from Japan to study their phylogeny and evolution, using molecular dating of species divergence. Phylogenetic analyses of the complete cp DNA of these two Japanese species and five other Eurasian Eutrema species revealed that wasabi and yuriwasabi did not form a monophyletic group. One yuriwasabi accession (Gifu) formed a clade with E. yunnanense from China, indicating that this accession should be considered as a different species from the other yuriwasabi accessions. We reveal that Japanese Eutrema species diverged from the ‘E. yunnanense–yuriwasabi (Gifu)’ clade approximately 1.3 million years ago (Mya), suggesting that the connection between Japan and the Eurasian continent has existed more recently than the Quaternary period. The abundance of cp sequence data in this study also allowed the detection of genetic differentiation among wasabi cultivars. The two polymorphic sites detected between ‘Fujidaruma’ and ‘Shimane No.3’ were used to develop genotyping markers. The cp genome information provided here will thus inform the evolutionary histories of Japanese Eutrema species and help in genotyping wasabi cultivars.
CD138 plasma cells may predict brain metastasis recurrence following resection and stereotactic radiosurgery
Authors: Soike Michael H. , Logue Jennifer , Qasem Shadi , Hughes Ryan T. , McTyre Emory , Su Jing , Triozzi Pierre , Bendandi Maurizio , Lo Hui-Wen , Ahmed Tamjeed , O’Neill Stacey S. , Debinski Waldemar , Pasche Boris , Watabe Kounosuke , Miller Lance D. , Chan Michael D. , Ruiz Jimmy
Published: October 2019

We sought to identify candidate biomarkers for early brain metastasis (BM) recurrence in patients who underwent craniotomy followed by adjuvant stereotactic radiosurgery. RNA sequencing was performed on eight resected brain metastasis tissue samples and revealed B-cell related genes to be highly expressed in patients who did not experience a distant brain failure and had prolonged overall survival. To translate the findings from RNA sequencing data, we performed immunohistochemistry to stain for B and T cell markers from formalin-fixed parffin-embedded tissue blocks on 13 patients. CD138 expressing plasma cells were identified and quantitatively assessed for each tumor sample. Patients’ tumor tissues that expressed high levels of CD138 plasma cells (N = 4) had a statistically significant improvement in OS compared to low levels of CD138 (N = 9) (p = 0.01). Although these findings are preliminary, the significance of CD138 expressing plasma cells within BM specimens should be investigated in a larger cohort. Immunologic markers based on resection cavity analysis could be predictive for determining patient outcomes following cavity-directed SRS.
A novel high-throughput molecular counting method with single base-pair resolution enables accurate single-gene NIPT
Authors: Tsao David S. , Silas Sukrit , Landry Brian P. , Itzep Nelda P. , Nguyen Amy B. , Greenberg Samuel , Kanne Celeste K. , Sheehan Vivien A. , Sharma Rani , Shukla Rahul , Arora Prem N. , Atay Oguzhan
Published: October 2019

Next-generation DNA sequencing is currently limited by an inability to accurately count the number of input DNA molecules. Molecular counting is particularly needed when accurate quantification is required for diagnostic purposes, such as in single gene non-invasive prenatal testing (sgNIPT) and liquid biopsy. We developed Quantitative Counting Template (QCT) molecular counting to reconstruct the number of input DNA molecules using sequencing data. We then used QCT molecular counting to develop sgNIPTs of sickle cell disease, cystic fibrosis, spinal muscular atrophy, alpha-thalassemia, and beta-thalassemia. The analytical sensitivity and specificity of sgNIPT was >98% and >99%, respectively. Validation of sgNIPTs was further performed with maternal blood samples collected during pregnancy, and sgNIPTs were 100% concordant with newborn follow-up.
Long-term Prognostic Value of Estimated Plasma Volume in Heart Failure with Preserved Ejection Fraction
Authors: Huang Chen-Yu , Lin Ting-Tse , Wu Yi-Fan , Chiang Fu-Tien , Wu Cho-Kai
Published: October 2019

Plasma volume, estimated by several indirect methods, has been viewed as a biological surrogate for intravascular fluid status. The clinical implication of estimated plasma volume status (ePVS) for long term outcomes in heart failure with preserved ejection fraction (HFpEF) remains unclear. We investigate the prognostic value of ePVS calculated by Strauss formula and its association with cardiovascular events and mortality in a prospective HFpEF cohort. There were 449 individuals met the inclusion criteria of our cohort. Estimated plasma volume variation (ΔePVS) and its instantaneous derivatives were calculated by the Strauss formula. Our study endpoints were events of heart failure hospitalization and mortality. Kaplan–Meier estimates and Cox regression analysis were applied to determine the power of ΔePVS and baseline ePVS in predicting long term cardiovascular outcomes. Both baseline ePVS and ΔePVS were independent predictors of heart failure hospitalization and mortality. Kaplan-Meier estimates of these outcomes stratified by optimal cut-off value showed that HFpEF individuals with higher baseline ePVS and ΔePVS were associated with elevated risk of composite endpoint of heart failure hospitalization and mortality. This study demonstrated the prognostic value of a novel biological surrogate, instantaneous derivatives ePVS, in predicting long term cardiovascular outcomes in HFpEF population. Monitoring instantaneous plasma volume may assist in identifying patients at high risk for future cardiovascular events. Further prospective studies validating the role of ePVS in predicting long-term prognosis in patients with HFpEF are warranted.
Finding Hadamard Matrices by a Quantum Annealing Machine
Authors: Suksmono Andriyan Bayu , Minato Yuichiro
Published: October 2019

Finding a Hadamard matrix (H-matrix) among the set of all binary matrices of corresponding order is a hard problem, which potentially can be solved by quantum computing. We propose a method to formulate the Hamiltonian of finding H-matrix problem and address its implementation limitation on existing quantum annealing machine (QAM) that allows up to quadratic terms, whereas the problem naturally introduces higher order ones. For an M-order H-matrix, such a limitation increases the number of variables from M2 to (M3 + M2 − M)/2, which makes the formulation of the Hamiltonian too exhaustive to do by hand. We use symbolic computing techniques to manage this problem. Three related cases are discussed: (1) finding N < M orthogonal binary vectors, (2) finding M-orthogonal binary vectors, which is equivalent to finding a H-matrix, and (3) finding N-deleted vectors of an M-order H-matrix. Solutions of the problems by a 2-body simulated annealing software and by an actual quantum annealing hardware are also discussed.
On Information Extraction and Decoding Mechanisms Improved by Noisy Amplification in Signaling Pathways
Authors: Vazquez-Jimenez Aaron , Rodriguez-Gonzalez Jesus
Published: October 2019

The cells need to process information about extracellular stimuli. They encode, transmit and decode the information to elicit an appropriate response. Studies aimed at understanding how such information is decoded in the signaling pathways to generate a specific cellular response have become essential. Eukaryotic cells decode information through two different mechanisms: the feed-forward loop and the promoter affinity. Here, we investigate how these two mechanisms improve information transmission. A detailed comparison is made between the stochastic model of the MAPK/ERK pathway and a stochastic minimal decoding model. The maximal amount of transmittable information was computed. The results suggest that the decoding mechanism of the MAPK/ERK pathway improve the channel capacity because it behaves as a noisy amplifier. We show a positive dependence between the noisy amplification and the amount of information extracted. Additionally, we show that the extrinsic noise can be tuned to improve information transmission. This investigation has revealed that the feed-forward loop and the promoter affinity motifs extract information thanks to processes of amplification and noise addition. Moreover, the channel capacity is enhanced when both decoding mechanisms are coupled. Altogether, these findings suggest novel characteristics in how decoding mechanisms improve information transmission.
A microcosm approach highlights the response of soil mineral weathering bacterial communities to an increase of K and Mg availability
Authors: Nicolitch O. , Feucherolles M. , Churin J.-L. , Fauchery L. , Turpault M.-P. , Uroz S.
Published: October 2019

The access and recycling of the base cations are essential processes for the long-lasting functioning of forest ecosystems. While the role of soil bacterial communities has been demonstrated in mineral weathering and tree nutrition, our understanding of the link between the availability of base cations and the functioning of these communities remains limited. To fill this gap, we developed a microcosm approach to investigate how an increase in key base cations (potassium or magnesium) impacted the taxonomic and functional structures of the bacterial communities. During a 2-month period after fertilization with available potassium or magnesium, soil properties, global functions (metabolic potentials and respiration) as well as mineral weathering bioassays and 16S rRNA amplicon pyrosequencing were monitored. Our analyses showed no or small variations in the taxonomic structure, total densities and global functions between the treatments. In contrast, a decrease in the frequency and effectiveness of mineral weathering bacteria was observed in the fertilized treatments. Notably, quantitative PCR targeting specific genera known for their mineral weathering ability (i.e., Burkholderia and Collimonas) confirmed this decrease. These new results suggest that K and Mg cation availability drives the distribution of the mineral weathering bacterial communities in forest soil.
Enhanced flow-motion complexity of skin microvascular perfusion in Sherpas and lowlanders during ascent to high altitude
Authors: Carey Deborah , Thanaj Marjola , Davies Thomas , Gilbert-Kawai Edward , Mitchell Kay , Levett Denny Z. H. , Mythen Michael G. , Martin Daniel S. , Grocott Michael P. , Chipperfield Andrew J. , Clough Geraldine F.
Published: October 2019

An increased and more effective microvascular perfusion is postulated to play a key role in the physiological adaptation of Sherpa highlanders to the hypobaric hypoxia encountered at high altitude. To investigate this, we used Lempel-Ziv complexity (LZC) analysis to explore the spatiotemporal dynamics of the variability of the skin microvascular blood flux (BF) signals measured at the forearm and finger, in 32 lowlanders (LL) and 46 Sherpa highlanders (SH) during the Xtreme Everest 2 expedition. Measurements were made at baseline (BL) (LL: London 35 m; SH: Kathmandu 1300 m) and at Everest base camp (LL and SH: EBC 5,300 m). We found that BF signal content increased with ascent to EBC in both SH and LL. At both altitudes, LZC of the BF signals was significantly higher in SH, and was related to local slow-wave flow-motion activity over multiple spatial and temporal scales. In SH, BF LZC was also positively associated with LZC of the simultaneously measured tissue oxygenation signals. These data provide robust mechanistic information of microvascular network functionality and flexibility during hypoxic exposure on ascent to high altitude. They demonstrate the importance of a sustained heterogeneity of network perfusion, associated with local vaso-control mechanisms, to effective tissue oxygenation during hypobaric hypoxia.
Contribution of SLC22A12 on hypouricemia and its clinical significance for screening purposes
Authors: Cha Do Hyeon , Gee Heon Yung , Cachau Raul , Choi Jong Mun , Park Daeui , Jee Sun Ha , Ryu Seungho , Kim Kyeong Kyu , Won Hong-Hee , Limou Sophie , Myung Woojae , Winkler Cheryl A. , Cho Sung Kweon
Published: October 2019

Differentiating between inherited renal hypouricemia and transient hypouricemic status is challenging. Here, we aimed to describe the genetic background of hypouricemia patients using whole-exome sequencing (WES) and assess the feasibility for genetic diagnosis using two founder variants in primary screening. We selected all cases (N = 31) with extreme hypouricemia (<1.3 mg/dl) from a Korean urban cohort of 179,381 subjects without underlying conditions. WES and corresponding downstream analyses were performed for the discovery of rare causal variants for hypouricemia. Two known recessive variants within SLC22A12 (p.Trp258*, pArg90His) were identified in 24 out of 31 subjects (77.4%). In an independent cohort, we identified 50 individuals with hypouricemia and genotyped the p.Trp258* and p.Arg90His variants; 47 of the 50 (94%) hypouricemia cases were explained by only two mutations. Four novel coding variants in SLC22A12, p.Asn136Lys, p.Thr225Lys, p.Arg284Gln, and p.Glu429Lys, were additionally identified. In silico studies predict these as pathogenic variants. This is the first study to show the value of genetic diagnostic screening for hypouricemia in the clinical setting. Screening of just two ethnic-specific variants (p.Trp258* and p.Arg90His) identified 87.7% (71/81) of Korean patients with monogenic hypouricemia. Early genetic identification of constitutive hypouricemia may prevent acute kidney injury by avoidance of dehydration and excessive exercise.
Identification of somatic alterations in lipoma using whole exome sequencing
Authors: Kanojia Deepika , Dakle Pushkar , Mayakonda Anand , Parameswaran Rajeev , Puhaindran Mark E. , Min Victor Lee Kwan , Madan Vikas , Koeffler Phillip
Published: October 2019

Lipomas are benign fatty tumors with a high prevalence rate, mostly found in adults but have a good prognosis. Until now, reason for lipoma occurrence not been identified. We performed whole exome sequencing to define the mutational spectrum in ten lipoma patients along with their matching control samples. We presented genomic insight into the development of lipomas, the most common benign tumor of soft tissue. Our analysis identified 412 somatic variants including missense mutations, splice site variants, frameshift indels, and stop gain/lost. Copy number variation analysis highlighted minor aberrations in patients. Kinase genes and transcriptions factors were among the validated mutated genes critical for cell proliferation and survival. Pathway analysis revealed enrichment of calcium, Wnt and phospholipase D signaling in patients. In conclusion, whole exome sequencing in lipomas identified mutations in genes with a possible role in development and progression of lipomas.
Memory influences haptic perception of softness
Authors: Metzger Anna , Drewing Knut
Published: October 2019

The memory of an object’s property (e.g. its typical colour) can affect its visual perception. We investigated whether memory of the softness of every-day objects influences their haptic perception. We produced bipartite silicone rubber stimuli: one half of the stimuli was covered with a layer of an object (sponge, wood, tennis ball, foam ball); the other half was uncovered silicone. Participants were not aware of the partition. They first used their bare finger to stroke laterally over the covering layer to recognize the well-known object and then indented the other half of the stimulus with a probe to compare its softness to that of an uncovered silicone stimulus. Across four experiments with different methods we showed that silicon stimuli covered with a layer of rather hard objects (tennis ball and wood) were perceived harder than the same silicon stimuli when being covered with a layer of rather soft objects (sponge and foam ball), indicating that haptic perception of softness is affected by memory.
Functional redundancy of HSPA1, HSPA2 and other HSPA proteins in non-small cell lung carcinoma (NSCLC); an implication for NSCLC treatment
Authors: Sojka Damian Robert , Gogler-Pigłowska Agnieszka , Vydra Natalia , Cortez Alexander Jorge , Filipczak Piotr Teodor , Krawczyk Zdzisław , Scieglinska Dorota
Published: October 2019

Heat shock proteins (HSPs) are a large group of chaperones considered critical for maintaining cellular proteostasis. Their aberrant expression in tumors can modulate the course of processes defined as hallmarks of cancer. Previously, we showed that both stress-inducible HSPA1 and testis-enriched HSPA2, highly homologous members of the HSPA (HSP70) family, are often overexpressed in non-small cell lung carcinoma (NSCLC). HSPA1 is among the best characterized cancer-related chaperones, while the significance of HSPA2 for cancer remains poorly understood. Previously we found that in primary NSCLC, HSPA1 was associated with good prognosis while HSPA2 correlated with bad prognosis, suggesting possible different roles of these proteins in cancer. Therefore, in this work we investigated the impact of HSPA1 and HSPA2 on NSCLC cell phenotype. We found that neither paralog-selective nor simultaneous knockdown of HSPA1 and HSPA2 gene expression reduced growth and chemoresistance of NSCLC cells. Only blocking of HSPA proteins using pan-HSPA inhibitors, VER-155008 or JG-98, exerted potent anticancer effect on NSCLC cells, albeit the final outcome was cell type-dependent. Pan-HSPA inhibition sensitized NSCLC cells to bortezomib, but not to platinum derivates. Our result suggests the inhibitors of proteasome and HSPAs seem an effective drug combination for pre-clinical development in highly aggressive NSCLC.
Tuberculosis Infection in Chinese Patients with Giant Cell Arteritis
Authors: Zhang Yun , Wang Dongmei , Yin Yue , Wang Yu , Fan Hongwei , Zhang Wen , Zeng Xuejun
Published: October 2019

Giant cell arteritis (GCA) is a medium- and large-vessel vasculitis with an onset age after 50 years. Takayasu arteritis (TA), which is also a large-vessel vasculitis with an onset age earlier than 40 years, was suggested to be associated with tuberculosis (TB). However, the association between GCA and TB was rarely reported. This study was to retrospectively analyze clinical data of GCA patients at Peking Union Medical College Hospital and elucidate the association between GCA and TB. Ninety-one patients diagnosed with GCA were included in the study. A total of 20 patients (22.0%) had a history of active tuberculosis and received anti-tuberculosis therapy. On comparing the clinical features of patients with GCA and concomitant TB and those without TB, obvious weight loss (P = 0.011), lower percentage of dyslipidemia (P = 0.042), higher percentage of anti-phospholipid antibodies (P = 0.010), and lower white blood cells (P = 0.006) were noted in the TB group. In conclusion, this study demonstrated the percentage of TB history in patients with GCA was higher than that in the Chinese general population. Clinicians should recognize the possibility of comorbid TB in patients with obvious weight loss and relatively lower white blood cell count.
Patterns of distribution, population genetics and ecological requirements of field-occurring resistant and susceptible Pseudosuccinea columella snails to Fasciola hepatica in Cuba
Authors: Alba Annia , Vázquez Antonio A. , Sánchez Jorge , Lounnas Manon , Pointier Jean-Pierre , Hurtrez-Boussès Sylvie , Gourbal Benjamin
Published: October 2019

Pseudosuccinea columella snails transmit the trematode Fasciola hepatica, but in Cuba, six naturally occurring populations successfully resist parasite infection. Here, we present an updated distribution of P. columella in Cuba; 68 positive sites with the earliest records more abundant in west-central Cuba and with east-central populations generally corresponding to the newest samples. No records were found farther east. The IPA site reported 10.5% prevalence of F. hepatica-infected snails. Population genetics, studied through microsatellites, showed low allelic and multilocus genotypic richness (MLGT), mainly in susceptible populations, strong deviations from panmixia and high self-fertilization rates. Susceptible individuals were grouped in one major cluster containing the majority of MLGT, and two independent clusters grouped the MLGT of resistant individuals from western and central populations, respectively. From these, we propose that several introductions of P. columella occurred in Cuba, primarily in the west, with the early arrivals deriving on the resistant populations. A more recent introduction of susceptible P. columella carrying MLGT T and Y may have occurred, where the latter spread quickly through the island and possibly increase the risk of parasite transmission in Cuba since all snails naturally infected with F. hepatica were carriers of the MLGT Y. Interestingly, even though resistant populations are highly diverse and are likely the oldest within Cuba, they are only found in six localities characterized by soft (total hardness, TH = 6.3 ± 1.03°d) and slightly acidic (pH = 6.2 ± 0.12) waters with low richness in snail species (3.2 ± 1.02). This tendency was also observed in a two-year follow-up ecological study that was conducted on a farm where both phenotypes occurred in sympatry; colonization events by resistant over susceptible snails coincided with a reduction in the pH and TH of the water. A comparison of life traits in susceptible and resistant isolates reared at two different pH/TH conditions (5.9/4°d or 7.8/14°d) showed that low pH/TH negatively affects P. columella, irrespective of the phenotype. However, evidence of higher tolerance (higher survival, life expectancy, egg viability) to such conditions was observed in resistant isolates. Finally, we speculate that the limited distribution of resistant populations might be related to a better exploitation of sites that are less suitable to snails (thus, with lower competition), rather than to a differential ecological restriction to specific environmental conditions from susceptible P. columella.
Expression of PD-1/PD-L1 in primary breast tumours and metastatic axillary lymph nodes and its correlation with clinicopathological parameters
Authors: Yuan Chenxi , Liu Zhaoyun , Yu Qian , Wang Xinzhao , Bian Mengxue , Yu Zhiyong , Yu Jinming
Published: October 2019

The aim of this study was to compare the expression of PD-1/PD-L1 in primary breast tumours to that in metastatic axillary lymph nodes and to determine the correlation between the PD-1/PD-L1 status and clinicopathologic characteristics. In total, 47 paired breast tumour and metastatic axillary lymph node samples were collected in this study. Immunohistochemical technology was used to determine the positivity or negativity of PD-1/PD-L1. Other patient information was retrieved from medical records. Significant differences in PD-L1 expression were observed between primary breast tumours and paired axillary lymph nodes. We also observed that the presence of PD-1/PD-L1 positivity in metastatic lymph nodes was significantly associated with poor prognostic features, such as a high Ki-67 index (p = 0.048), a high TNM stage (p = 0.012), a large number of metastatic lymph nodes (p = 0.002), and a high histology grade (p = 0.029). Since heterogeneity exists, it is necessary to determine the PD-L1 status in both the primary tumour and metastatic lymph nodes.
Plant apomixis is rare in Himalayan high-alpine flora
Authors: Brožová Viktorie , Koutecký Petr , Doležal Jiří
Published: October 2019

Gametophytic apomixis is a way of asexual plant reproduction by seeds. It should be advantageous under stressful high altitude or latitude environment where short growing seasons, low temperatures, low pollinator activity or unstable weather may hamper sexual reproduction. However, this hypothesis remains largely untested. Here, we assess the reproductive mode in 257 species belonging to 45 families from the world’s broadest alpine belt (2800–6150 m) in NW Himalayas using flow cytometric seed screen. We found only 12 apomictic species, including several members of Poaceae (Festuca, Poa and Stipa), Rosaceae (Potentilla) and Ranunculaceae (Halerpestes, Ranunculus), which are families typical for high apomict frequency. However, several apomictic species were newly discovered, including the first known apomictic species from the family Biebersteiniaceae (Biebersteinia odora), and first apomicts from the genera Stipa (Stipa splendens) and Halerpestes (Halerpestes lancifolia). Apomicts showed no preference for higher elevations, even in these extreme Himalayan alpine habitats. Additional trait-based analyses revealed that apomicts differed from sexuals in comprising more rhizomatous graminoids and forbs, higher soil moisture demands, sharing the syndrome of dominant species with broad geographical and elevation ranges typical for the late-successional habitats. Apomicts differ from non-apomicts in greater ability of clonal propagation and preference for wetter, more productive habitats.
Enhanced endothelial motility and multicellular sprouting is mediated by the scaffold protein TKS4
Authors: Mehes Elod , Barath Monika , Gulyas Marton , Bugyik Edina , Geiszt Miklos , Szoor Arpad , Lanyi Arpad , Czirok Andras
Published: October 2019

Endothelial cell motility has fundamental role in vasculogenesis and angiogenesis during developmental or pathological processes. Tks4 is a scaffold protein known to organize the cytoskeleton of lamellipodia and podosomes, and thus modulating cell motility and invasion. In particular, Tks4 is required for the localization and activity of membrane type 1-matrix metalloproteinase, a key factor for extracellular matrix (ECM) cleavage during cell migration. While its role in transformed cells is well established, little is known about the function of Tks4 under physiological conditions. In this study we examined the impact of Tks4 gene silencing on the functional activity of primary human umbilical vein endothelial cells (HUVEC) and used time-lapse videomicrosopy and quantitative image analysis to characterize cell motility phenotypes in culture. We demonstrate that the absence of Tks4 in endothelial cells leads to impaired ECM cleavage and decreased motility within a 3-dimensional ECM environment. Furthermore, absence of Tks4 also decreases the ability of HUVEC cells to form multicellular sprouts, a key requirement for angiogenesis. To establish the involvement of Tks4 in vascular development in vivo, we show that loss of Tks4 leads sparser vasculature in the fetal chorion in the Tks4-deficient ‘nee’ mouse strain.
An anthropomorphic phantom representing a prematurely born neonate for digital x-ray imaging using 3D printing: Proof of concept and comparison of image quality from different systems
Authors: Irnstorfer Nikolaus , Unger Ewald , Hojreh Azadeh , Homolka Peter
Published: October 2019

An anthropomorphic phantom for image optimization in neonatal radiography was developed, and its usability in optimizing image acquisition and processing demonstrated. The phantom was designed to mimic a patient image of a prematurely born neonate. A clinical x-ray (neonate <1 kg) taken with an effective dose of 11 µSv on a needle-crystal storage phosphor system was retrospectively selected from anonymized images as an appropriate template representing a standard case in neonatology imaging. The low dose level used in clinical imaging results in high image noise content. Therefore, the image had to be processed using structure preserving noise reduction. Pixel values were related to printing material thickness to result in a similar attenuation pattern as the original patient including support mattress. A 3D model generating a similar x-ray attenuation pattern on an image detector as a patient was derived accounting for beam hardening and perspective, and printed using different printing technologies. Best printing quality was achieved using a laser stereolithography printer. Phantom images from different digital radiography systems used in neonatal imaging were compared. Effects of technology, image processing, and radiation dose on diagnostic image quality can be assessed for otherwise identical anthropomorphic neonatal images not possible with patient images, facilitating optimization and standardization of imaging parameters and image appearance.
Reduced Myelin Signal in Normal-appearing White Matter in Neuromyelitis Optica Measured by 7T Magnetic Resonance Imaging
Authors: Chou I-Jun , Tanasescu Radu , Mougin Olivier E. , Gowland Penny A. , Tench Christopher R. , Whitehouse William P. , Gran Bruno , Nikfekr Esmaeil , Sharrack Basil , Mazibrada Gordon , Constantinescu Cris S.
Published: October 2019

Whether the integrity of normal-appearing white matter (NAWM) is preserved in neuromyelitis optica spectrum disorders (NMOSD) is open to debate. To examine whether the tissue integrity of NAWM in NMOSD is compromised compared to that in healthy controls and patients with multiple sclerosis (MS), we prospectively enrolled 14 patients with NMOSD, 12 patients with MS, and 10 controls for clinical functional assessments and quantitative imaging, including T1 relaxation time (T1) and magnetization transfer ratio (MTR) at 7 Tesla. Cognitive performance on the Paced Auditory Serial Addition Test with a 3-second interstimulus interval (PASAT-3) was significantly lower in the NMOSD compared to the MS group (mean number of correct answers, 34.1 vs. 47.6; p = 0.006), but there were no differences in disease duration or disability. Histograms of T1 and MTR maps of NAWM demonstrated a decreased peak height in patients with NMOSD compared to the healthy controls, but not compared to patients with MS. Using 7T quantitative magnetic resonance imaging (MRI), this study showed that the NAWM in patients with NMOSD is abnormal, with reduced myelin signal; this was not previously observed using MRI at a lower field strength.
Nuclear shape, protrusive behaviour and in vivo retention of human bone marrow mesenchymal stromal cells is controlled by Lamin-A/C expression
Authors: Dorland Yvonne L. , Cornelissen Anne S. , Kuijk Carlijn , Tol Simon , Hoogenboezem Mark , van Buul Jaap D. , Nolte Martijn A. , Voermans Carlijn , Huveneers Stephan
Published: October 2019

Culture expanded mesenchymal stromal cells (MSCs) are being extensively studied for therapeutic applications, including treatment of graft-versus-host disease, osteogenesis imperfecta and for enhancing engraftment of hematopoietic stem cells after transplantation. Thus far, clinical trials have shown that the therapeutic efficiency of MSCs is variable, which may in part be due to inefficient cell migration. Here we demonstrate that human MSCs display remarkable low migratory behaviour compared to other mesodermal-derived primary human cell types. We reveal that specifically in MSCs the nucleus is irregularly shaped and nuclear lamina are prone to wrinkling. In addition, we show that expression of Lamin A/C is relatively high in MSCs. We further demonstrate that in vitro MSC migration through confined pores is limited by their nuclei, a property that might correlate to the therapeutic inefficiency of administered MSC in vivo. Silencing expression of Lamin A/C in MSCs improves nuclear envelope morphology, promotes the protrusive activity of MSCs through confined pores and enhances their retention in the lung after intravenous administration in vivo. Our findings suggest that the intrinsic nuclear lamina properties of MSCs underlie their limited capacity to migrate, and that strategies that target the nuclear lamina might alter MSC-based cellular therapies.
Corticostriatal stimulation compensates for medial frontal inactivation during interval timing
Authors: Emmons Eric B. , Kennedy Morgan , Kim Youngcho , Narayanan Nandakumar S.
Published: October 2019

Prefrontal dysfunction is a common feature of brain diseases such as schizophrenia and contributes to deficits in executive functions, including working memory, attention, flexibility, inhibitory control, and timing of behaviors. Currently, few interventions improve prefrontal function. Here, we tested whether stimulating the axons of prefrontal neurons in the striatum could compensate for deficits in temporal processing related to prefrontal dysfunction. We used an interval-timing task that requires working memory for temporal rules and attention to the passage of time. Our previous work showed that inactivation of the medial frontal cortex (MFC) impairs interval timing and attenuates ramping activity, a key form of temporal processing in the dorsomedial striatum (DMS). We found that 20-Hz optogenetic stimulation of MFC axon terminals increased curvature of time-response histograms and improved interval-timing behavior. Furthermore, optogenetic stimulation of terminals modulated time-related ramping of medium spiny neurons in the striatum. These data suggest that corticostriatal stimulation can compensate for deficits caused by MFC inactivation and they imply that frontostriatal projections are sufficient for controlling responses in time.
Development of Thermally Conductive Polyurethane Composite by Low Filler Loading of Spherical BN/PMMA Composite Powder
Authors: Su Kai-Han , Su Cherng-Yuh , Cho Cheng-Ta , Lin Chung-Hsuan , Jhou Guan-Fu , Chang Chung-Chieh
Published: October 2019

The issue of electronic heat dissipation has received much attention in recent times and has become one of the key factors in electronic components such as circuit boards. Therefore, designing of materials with good thermal conductivity is vital. In this work, a thermally conductive SBP/PU composite was prepared wherein the spherical h-BN@PMMA (SBP) composite powders were dispersed in the polyurethane (PU) matrix. The thermal conductivity of SBP was found to be significantly higher than that of the pure h-BN/PU composite at the same h-BN filler loading. The SBP/PU composite can reach a high thermal conductivity of 7.3 Wm−1 K−1 which is twice as high as that of pure h-BN/PU composite without surface treatment in the same condition. This enhancement in the property can be attributed to the uniform dispersion of SBP in the PU polymer matrix that leads to a three-dimensional continuous heat conduction thereby improving the heat diffusion of the entire composite. Hence, we provide a valuable method for preparing a 3-dimensional heat flow path in polyurethane composite, leading to a high thermal conductivity with a small amount of filler.