bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and Functional Modulation of Regulatory T Cells by Transcription Factors and Epigenetics
Authors: Ito Minako , Iizuka-Koga Mana , Ando Makoto , Yoshimura Akihiko
Published: September 2018

Regulatory T cells (Tregs) are essential for the maintenance of immune homeostasis. Studies of Treg are not only necessary for understanding the mechanism of immune homeostasis but also extremely useful for the development of treatments of various immune diseases. Forkhead box P3 (Foxp3) was identified as the master gene responsible for the immune-suppressing activity of Tregs. The promoter region and several intronic enhancers, designated conserved noncoding sequence (CNS) 0, 1, 2, and 3, at the Foxp3 gene locus have important roles in Foxp3 expression and Treg development. We demonstrated that transcription factors Nr4a and Smad2/3 are required for development of thymic Tregs and induced Tregs, respectively. In addition to transcription factors, Treg-specific DNA demethylation has been shown to be important for Treg stability. In particular, DNA demethylation of CNS2 was implicated in Treg stability, and members of the ten-eleven translocation family of demethylation factors were recently demonstrated to have important roles in 5′-C-phosphate-G-3′ demethylation at CNS2. This article summarizes recent findings regarding the roles of transcription factors and epigenetic modifications in the differentiation, maintenance, and function of Tregs. This review will facilitate clinical application of Tregs to diseases in the field of ophthalmology, including uveitis and age-related macular degeneration.
The Evolving Story of Pterygium
Authors: Young Alvin L. , Cao Di , Chu Wai Kit , Ng Tsz Kin , Yip Yolanda W.Y. , Jhanji Vishal , Pang Chi Pui
Published: September 2018

Pterygium is a fibrovascular subepithelial growth of degenerative tissue over the limbus. It is a common condition worldwide that is especially prevalent in tropical countries within the “pterygium belt.” Its exact etiology remains to be elucidated; however, it is strongly associated with exposure to ultraviolet light. The high expression levels of tumor protein p53 (TP53) observed in laboratory studies of pterygium seem to contradict the fast-growing nature of its clinical behavior, and TP53 mutations have been suggested. We demonstrated that mouse double minute 2 (MDM2), a TP53-binding protein, contributes to the inhibition of TP53 activity in human pterygium. Thus, disruption of the MDM2-TP53 interaction should attenuate human pterygium cell growth. For primary pterygium, treatment is relatively straightforward and involves surgical excision. To minimize the risk of recurrence, many adjunctive therapies are adopted, including antimetabolites, such as mitomycin C and 5-fluorouracil, amniotic membrane, different variations on conjunctival and/or limbal conjunctival grafts, and other medications such as anti-vascular endothelial growth factor. In the future, MDM2 antagonists may help further lower the recurrence rates after the treatment of pterygium.
Post-Laser In Situ Keratomileusis Epithelial Ingrowth: Treatment, Recurrence, and Long-Term Results
Authors: Yesilirmak Nilufer , Chhadva Priyanka , Cabot Florence , Galor Anat , Yoo Sonia H.
Published: September 2018

Purpose:

To study outcomes after surgical removal of epithelial ingrowth (EI) in post-laser in situ keratomileusis patients, specifically comparing visual results and recurrence rates between 2 different EI management techniques.

Methods:

In this retrospective chart review of 67 eyes of 54 patients who underwent surgical treatment for EI after laser in situ keratomileusis between July 1999 and July 2014 at the Bascom Palmer Eye Institute, Miami, FL, surgical techniques, recurrence rates, visual acuity (VA), and refractive error were assessed.

Results:

Of the 67 eyes, 56 eyes (83.6%) had flap lift + scraping alone, and 11 eyes (16.4%) had flap lift + scraping + suturing. After mean follow-up of 2.5 years, 11 of 56 eyes (19.6%) treated with flap lift + scraping alone had EI recurrence, whereas no eyes treated with flap lift + scraping + suturing had EI recurrence. VA results and refractive errors were better in eyes treated with lift + scraping alone compared with lift + scraping + suturing at 1 month. In the 67 eyes with 1-year follow-up, VA and refractive errors improved from preoperative values and were comparable between groups.

Conclusions:

Scraping alone provides significantly better initial visual outcomes but higher EI recurrence rates compared with scrape–suturing. Long-term visual outcomes are comparable between 2 techniques.
Necrosis of the Glabella After Injection With Hyaluronic Acid Into the Forehead
Authors: Han Jingjian , He Yanzi , Liu Kuikui , Yang Qinghua
Published: September 2018

Skin necrosis is a rare but severe potential complication after injection of hyaluronic acid (HA). Based on the understanding of the causes and mechanisms of this complication, many precautions have been proposed. Still, this adverse reaction happened from time to time. Here, the authors present a patient with glabellar skin necrosis following an injection into the forehead using HA filler. Although not uncommon, this patient might suggest an alternative cause or mechanism of tissue necrosis following HA injection besides intravascular injection or extravascular compression directly by HA filler. Further study is needed to examine other possible causes in order to eliminate this risk.
Complex Orbital Fractures: Three-Dimensional Planning and Combined Surgical Approach
Authors: Mici Elidon , Calvo Alessandro , Cicciù Marco , Cervino Gabriele , Belli Evaristo
Published: September 2018

Nowadays the development of diagnostic imaging, surgical techniques, alloplastic materials, and surgical instruments has made possible a more accurate management of orbital fractures. The aim of the present study was the management of orbital fractures and the solution of particular cases. The use of high-resolution computed tomography makes possible to gain a better understanding of the complex orbit anatomical structure. Also endoscopy is a valid alternative for medial orbital wall fractures treatment. It gives high control of the fracture site and its reduction. When this technology is combined with 3-dimensional (3D) reformatted images, it allows us to reconstruct more accurately the orbital defects. The authors present their experience in complex orbital fractures treated with the aim of the 3D navigation using a preformed orbital titanium plate. Endosopical approach was used to control plate positioning.
Comparison of Musculocutaneous and Fasciocutaneous Free Flaps for the Reconstruction of the Extensive Composite Scalp and Cranium Defects
Authors: Uzun Hakan , Bitik Ozan , Ersoy Umut Sinan , Bilginer Burçak , Aksu Ali Emre
Published: September 2018

Composite scalp and cranium defects, which require microsurgical reconstruction, result from tumor resection, radiation, trauma, severe burn injuries, and rarely vasculitic disorders. In the current study, the authors aim to compare the outcomes of the fasciocutaneous flaps and musculocutaneous free flaps used for the reconstruction of extensive composite scalp and cranium defects. From 2010 to 2017, 21 patients who underwent composite scalp and cranium defect reconstruction with a free flap were retrospectively identified. Eighteen patients had squamous cell carcinoma, 2 patients had meningioma, and 1 patient had Ewing sarcoma. Thirteen musculocutaneous free flaps including latissimus dorsi and vertical rectus abdominis flaps and 9 free fasciocutaneous flaps including radial forearm and anterolateral thigh flaps were used. Only 1 flap loss was encountered. No neurologic impairment in postoperative period was reported. The mean length of stay in the hospital, the duration of surgery, and total volume of blood transfusion for the fasciocutaneous flap group were significantly shorter than those for musculocutaneous flap group. No flap atrophy was reported in fasciocutaneous flap group. Reconstruction of the composite scalp and cranium defects with fasciocutaneous free flaps allows shorter hospitalization, less blood transfusion and less flap atrophy than those of musculocutaneous flaps. To this respect, their usage should be prioritized in such challenging patients.
A non-canonical JAGGED1 signal to JAK2 mediates osteoblast commitment in cranial neural crest cells
Authors: Kamalakar Archana , Oh Melissa S. , Stephenson Yvonne C. , Ballestas-Naissir Samir A. , Davis Michael E. , Willett Nick J. , Drissi Hicham M. , Goudy Steven L.
Published: September 2018

During craniofacial development, cranial neural crest (CNC) cells migrate into the developing face and form bone through intramembranous ossification. Loss of JAGGED1 (JAG1) signaling in the CNC cells is associated with maxillary hypoplasia or maxillary bone deficiency (MBD) in mice and recapitulates the MBD seen in humans with Alagille syndrome. JAGGED1, a membrane-bound NOTCH ligand, is required for normal craniofacial development, andJagged1mutations in humans are known to cause Alagille Syndrome, which is associated with cardiac, biliary, and bone phenotypes and these children experience increased bony fractures. Previously, we demonstrated deficient maxillary osteogenesis inWnt1-cre;Jagged1f/f(Jag1CKO) mice by conditional deletion ofJagged1in maxillary CNC cells. In this study, we investigated the JAG1 signaling pathways in a CNC cell line. Treatment with JAG1 induced osteoblast differentiation and maturation markers,Runx2andOcn, respectively, Alkaline Phosphatase (ALP) production, as well as classic NOTCH1 targets,Hes1andHey1.While JAG1-inducedHes1andHey1expression levels were predictably decreased after DAPT (NOTCH inhibitor) treatment, JAG1-inducedRunx2andOcnlevels were surprisingly constant in the presence of DAPT, indicating that JAG1 effects in the CNC cells are independent of the canonical NOTCH pathway. JAG1 treatment of CNC cells increased Janus Kinase 2 (JAK2) phosphorylation, which was refractory to DAPT treatment, highlighting the importance of the non-canonical NOTCH pathway during CNC cells osteoblast commitment. Pharmacologic inhibition of JAK2 phosphorylation, with and without DAPT treatment, upon JAG1 induction reduced ALP production and,Runx2andOcngene expression. Collectively, these data suggest that JAK2 is an essential component downstream of a non-canonical JAG1-NOTCH1 pathway through which JAG1 stimulates expression of osteoblast-specific gene targets in CNC cells that contribute to osteoblast differentiation and bone mineralization.
DksA controls the response of the Lyme disease spirochete Borrelia burgdorferi to starvation
Authors: Boyle William K. , Groshong Ashley M. , Drecktrah Dan , Boylan Julie A. , Gherardini Frank C. , Blevins Jon S. , Samuels D. Scott , Bourret Travis J.
Published: September 2018

The pathogenic spirocheteBorrelia burgdorferisenses and responds to diverse environmental challenges, including changes in nutrient availability, throughout its enzootic cycle inIxodesspp. ticks and vertebrate hosts. This study examined the role of DnaK suppressor protein (DksA) in the transcriptional response ofB. burgdorferito starvation. Wild-type anddksAmutantB. burgdorferistrains were subjected to starvation by shifting mid-logarithmic phase cultures grown in BSK II medium to serum-free RPMI medium for 6 h under microaerobic conditions (5% CO2, 3% O2). Microarray analyses of wild-typeB. burgdorferirevealed that genes encoding flagellar components, ribosomal proteins, and DNA replication machinery were downregulated in response to starvation. DksA mediated transcriptomic responses to starvation inB. burgdorferias thedksA-deficient strain differentially expressed only 47 genes in response to starvation compared to the 500 genes differentially expressed in wild-type strains. Consistent with a role for DksA in the starvation response ofB. burgdorferi, fewer CFUs were observed fordksAmutant after prolonged starvation in RPMI medium compared to wild-typeB. burgdorferi. Transcriptomic analyses revealed a partial overlap between the DksA regulon and the regulon of RelBbu, the guanosine tetraphosphate and guanosine pentaphosphate [(p)ppGpp] synthetase that controls the stringent response; the DksA regulon also included many plasmid-borne genes. Additionally, thedksAmutant strain exhibited constitutively elevated (p)ppGpp levels compared to the wild-type strain, implying a regulatory relationship between DksA and (p)ppGpp. Together, these data indicate that DksA along with (p)ppGpp direct the stringent response to effectB. burgdorferiadaptation to its environment.

IMPORTANCE

The Lyme disease bacteriumBorrelia burgdorferimust sense and respond to diverse environments as it cycles between its tick vectors and various vertebrate hosts.B. burgdorferimust withstand prolonged periods of starvation while it resides in unfedIxodesticks. In this study, the regulatory protein DksA is shown to play a pivotal role controlling the transcriptional responses ofB. burgdorferito starvation. The results of this study suggest that DksA gene regulatory activity impactsB. burgdorferimetabolism, virulence gene expression, and the ability of this bacterium to complete its natural life cycle.
Twin Study of Early-Onset Major Depression Finds DNA Methylation Enrichment for Neurodevelopmental Genes
Authors: Roberson-Nay Roxann , Wolen Aaron R. , Lapato Dana M. , Lancaster Eva E. , Webb Bradley T. , Verhulst Bradley , Hettema John M. , York Timothy P.
Published: September 2018

Major depression (MD) is a debilitating mental health condition with peak prevalence occurring early in life. Genome-wide examination of DNA methylation (DNAm) offers an attractive comple ment to studies of allelic risk given it can reflect the combined influence of genes and environment. The current study used a co-twin control design to identify differentially and variably methylated regions of the genome that distinguish monozygotic (MZ) twins with and without a lifetime history of early-onset MD. The sample included 150 Caucasian monozygotic twins (73% female;Mage=17.52SD=1.28) assessed during a developmental stage characterized by relatively dis tinct neurophysiological changes. All twins were generally healthy and currently free of medica tions with psychotropic effects. DNAm was measured in peripheral blood cells using the Infinium Human BeadChip 450K Array. MD associations were detected at 760 differentially and variably methylated probes/regions that mapped to 428 genes. Results indicated an association between early-onset MD and many genes and genomic regions involved in neural circuitry formation, pro jection, functioning, and plasticity. Gene enrichment analyses implicated genes related to neuron structures and neurodevelopmental processes including cell-cell adhesion genes (e.g.,CDHs, PCDHAs, PCDHA1C/2C). Genes previously implicated in mood and psychiatric disorders as well as chronic stress (e.g.,HDAC4, NRG1) also were identified. DNAm regions associated with MD where found to overlap genetic loci observed in the latest Psychiatric Genomics Consortium meta‐ analysis of depression. Understanding the time course of epigenetic influences during emerging adulthood may clarify developmental phases where genes modulate individual differences in MD risk.
Extrinsic Noise Suppression in Micro RNA mediated Incoherent Feedforward Loops
Authors: Carignano Alberto , Mukherjee Sumit , Singh Abhyudai , Seelig Georg
Published: September 2018

MicroRNA mediated incoherent feed forward loops (IFFLs) are recurrent network motifs in mammalian cells and have been a topic of study for their noise rejection and buffering properties. Previous work showed that IFFLs can adapt to varying promoter activity and are less prone to noise than similar circuits without the feed forward loop. Furthermore, it has been shown that microRNAs are better at rejecting extrinsic noise than intrinsic noise. This work studies the biological mechanisms that lead to extrinsic noise rejection for microRNA mediated feed forward network motifs. Specifically, we compare the effects of microRNA-induced mRNA degradation and translational inhibition on extrinsic noise rejection, and identify the parameter regimes where noise is most efficiently rejected. In the case of static extrinsic noise, we find that translational inhibition can expand the regime of extrinsic noise rejection. We then analyze rejection of dynamic extrinsic noise in the case of a single-gene feed forward loop (sgFFL), a special case of the IFFL motif where the microRNA and target mRNA are co-expressed. For this special case, we demonstrate that depending on the time-scale of fluctuations in the extrinsic variable compared to the mRNA and microRNA decay rates, the feed forward loop can both buffer or amplify fluctuations in gene product copy numbers.
Sexual selection rewires reproductive protein networks
Authors: Karr Timothy L. , Southern Helen , Rosenow Matthew , Gossmann Toni I. , Snook Rhonda R.
Published: September 2018

Polyandry drives postcopulatory sexual selection (PCSS), resulting in rapid evolution of male ejaculate traits. Critical to male and female fitness, the ejaculate is known to contain rapidly evolving seminal fluid proteins (SFPs) produced by specialized male secretory accessory glands. The evidence that rapid evolution of some SFPs is driven by PCSS, however, is indirect, based on either plastic responses to changes in the sexual selection environment or correlative macroevolutionary patterns. Moreover, such studies focus on SFPs that represent but a small component of the accessory gland proteome. Neither how SFPs function with other reproductive proteins, nor how PCSS influences the underlying secretory tissue adaptations and content of the accessory gland, has been addressed at the level of the proteome. Here we directly test the hypothesis that PCSS results in rapid evolution of the entire male accessory gland proteome and protein networks by taking a system-level approach, combining divergent experimental evolution of PCSS inDrosophila pseudoobscura (Dpse), high resolution mass spectrometry (MS) and proteomic discovery, bioinformatics and population genetic analyses. We demonstrate that PCSS influences the abundance of over 200 accessory gland proteins, including SFPs. A small but significant number of these proteins display molecular signatures of positive selection. Divergent PCSS also results in fundamental and remarkably compartmentalized evolution of accessory gland protein networks in which males subjected to strong PCSS invest in protein networks that serve to increase protein production whereas males subjected to relaxed PCSS alters protein networks involved in protein surveillance and quality. These results directly demonstrate that PCSS is a key evolutionary driver that shapes not only individual reproductive proteins, but rewires entire reproductive protein networks.

The abbreviations used are:

BLAST

Basic Local Alignment Search Tool

Dpse

Drosophila pseudoobscura

PCSS

postcopulatory sexual selection

SFPs

seminal fluid proteins

Dmel

D. melanogaster

SDS

sodium dodecylsulfate

SDS-PAGE

sodium dodecylsulfate polyacrylamide gel electrophoresis

MS

mass spectrometry

LC-MS/MS

liquid chromatography-MS/MS

AcgP

accessory gland proteome

FDRs

False Discovery Rates

AcgS

accessory gland secretome

exoP

exoproteome

LFQ

label-free quantitation

P

polyandry

M

monandry

GO

gene ontology

CC

cellular component

MF

molecular function

BP

biological process

STRING

Search Tool for the Retrieval of Interacting Genes/Proteins

DIOPT

DRSC Integrative Ortholog Prediction Tools

ER

endoplasmic reticulum
Genome wide association study in 3,173 outbred rats identifies multiple loci for body weight, adiposity, and fasting glucose
Authors: Chitre Apurva S. , Polesskaya Oksana , Holl Katie , Gao Jianjun , Cheng Riyan , Bimschleger Hannah , Martinez Angel Garcia , George Tony , Gileta Alexander F. , Han Wenyan , Horvath Aidan , Hughson Alesa , Ishiwari Keita , King Christopher P. , Lamparelli Alexander , Versaggi Cassandra L. , Martin Connor , Pierre Celine L. St. , Tripi Jordan A. , Wang Tengfei , Chen Hao , Flagel Shelly B. , Meyer Paul , Richards Jerry , Robinson Terry E. , Palmer Abraham A. , Solberg Woods Leah C.
Published: September 2018

Objective

Obesity is influenced by genetic and environmental factors. Despite success of human genome wide association studies (GWAS), the specific genes that confer obesity remain largely unknown. The objective of this study was to use outbred rats to identify genetic loci underlying obesity and related morphometric and metabolic traits.

Methods

We measured obesity-relevant traits including body weight, body length, body mass index, fasting glucose, and retroperitoneal, epididymal, and parametrial fat pad weight in 3,173 male and female adult N/NIH heterogeneous stock (HS) rats across three institutions, providing data for the largest rat GWAS to date. Genetic loci were identified using a linear mixed model that accounted for the complex family relationships of the HS and covariate to account for differences among the three phenotyping centers.

Results

We identified 32 independent loci, several of which contained only a single gene (e.g. Epha5, Nrg1 and Klhl14) or obvious candidate genes (Adcy3, Prlhr). There were strong phenotypic and genetic correlations among obesity-related traits, and extensive pleiotropy at individual loci.

Conclusions

These studies demonstrate utility of HS rats for investigating the genetics of obesity related traits across institutions and identify several candidate genes for future functional testing.
Rapid and highly-specific generation of targeted DNA sequencing libraries enabled by linking capture probes with universal primers
Authors: Pel Joel , Leung Amy , Choi Wendy W. Y. , Despotovic Milenko , Ung W. Lloyd , Shibahara Gosuke , Gelinas Laura , Marziali Andre
Published: September 2018

Targeted Next Generation Sequencing (NGS) is being adopted increasingly broadly in many research, commercial and clinical settings. Currently used target capture methods, however, typically require complex and lengthy (sometimes multi-day) workflows that complicates their use in certain applications. In addition, small panels for high sequencing depth applications such as liquid biopsy typically have low on-target rates, resulting in unnecessarily high sequencing cost.

We have developed a novel targeted sequencing library preparation method, named Linked Target Capture (LTC), which replaces typical multi-day target capture workflows with a single-day, combined ‘target-capture-PCR’ workflow. This approach uses physically linked capture probes and PCR primers and is expected to work with panel sizes from 100 bp to >10 Mbp. It reduces the time and complexity of the capture workflow, eliminates long hybridization and wash steps and enables rapid library construction and target capture. High on-target read fractions are achievable due to repeated sequence selection in the target-capture-PCR step, thus lowering sequencing cost.

We have demonstrated this technology on sample types including cell-free DNA (cfDNA) and formalin-fixed, paraffin-embedded (FFPE) derived DNA, capturing a 35-gene pan-cancer panel, and therein detecting single nucleotide variants, copy number variants, insertions, deletions and gene fusions. With the integration of unique molecular identifiers (UMIs), variants as low as 0.25% abundance were detected, limited by input mass and sequencing depth. Additionally, sequencing libraries were prepared in less than eight hours from extracted DNA to loaded sequencer, demonstrating that LTC holds promise as a broadly applicable tool for rapid, cost-effective and high performance targeted sequencing.
STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pigmentation pathway
Authors: Swoboda Alexander , Soukup Robert , Kinslechner Katharina , Wingelhofer Bettina , Schörghofer David , Sternberg Christina , Pham Ha T. T. , Vallianou Maria , Horvath Jaqueline , Stoiber Dagmar , Kenner Lukas , Larue Lionel , Poli Valeria , Beermann Friedrich , Yokota Takashi , Kubicek Stefan , Krausgruber Thomas , Rendeiro André F. , Bock Christoph , Zenz Rainer , Kovacic Boris , Aberger Fritz , Hengstschläger Markus , Petzelbauer Peter , Mikula Mario , Moriggl Richard
Published: September 2018

Metastatic melanoma is hallmarked by its ability to switch oncogenic MITF expression. Here we tested the impact of STAT3 on melanoma onset and progression in association with MITF expression levels. We established a mouse melanoma model for deleting Stat3 specifically in melanocytes with specific expression of human hyperactive NRASQ61K in an Ink4a deficient background. Mice with tissue specific Stat3 deletion showed an early onset of disease, but displayed significantly diminished lung metastases. Whole genome expression profiling also revealed a reduced invasion phenotype, which was functionally confirmed in 3D melanoma model systems. Notably, loss or knockdown of STAT3 in mouse or human cells resulted in up-regulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3 induced CEBPa/b expression was sufficient to suppress MITF transcription. Epigenetic analysis by ATAC-seq confirmed that STAT3 enabled CEBPa/b binding to the MITF enhancer region thereby silencing it. We conclude that STAT3 is a metastasis driver in melanoma able to antagonize the MITF oncogene via direct induction of CEBP family member transcription facilitating RAS-RAF-driven melanoma metastasis.

List of Abbreviations

ATAC-seq, Assay for Transposase-Accessible Chromatin using sequencing; CEBP, CAAT Box Enhancer Binding Protein; CRE, Cre recombinase; EGF, Epidermal Growth Factor; GEO, Gene Expression Omnibus; GSEA, Gene Set Enrichment Analysis; HSC70, Heat Shock 70 kDa protein; IHC, Immunohistochemistry; IL-6, Interleukin-6; JAK, Janus Kinase; MITF, Microphthalmia-Associated Transcription Factor; NSG, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice; OSM, Oncostatin M; PDGF, Platelet-Derived Growth Factor; pS, phosphoserine; pY, phosphotyrosine; RAS, Rat Sarcoma; RAF, Rapidly Accelerated Fibrosarcoma; RTK, Receptor Tyrosine Kinase; RT-PCR, Reverse Transcription Polymerase Chain Reaction; S100b, Calcium Binding Protein S100 beta; shRNA, short hairpin RNA; SOX10, Sex Determining Region Y-10; STAT, Signal Transducer and Activator of Transcription; TCGA, The Cancer Genome Atlas; TMA, Tissue Micro Array
Eco-evolutionary processes underlying early warning signals of population declines
Authors: Baruah Gaurav , Clements Christopher F. , Ozgul Arpat
Published: September 2018

Environmental change can impact the stability of populations and can cause rapid declines in abundance. Abundance-based warning signals have been proposed to predict such declines, but these have been shown to have limited success, leading to the development of warning signals based on the distribution of fitness-related traits such as body size.

The dynamics of such traits in response to external environmental perturbations are controlled by a range of underlying factors such as reproductive rate, genetic variation, and plasticity. However, it remains unknown how such ecological and evolutionary factors affect the stability landscape of populations and the detectability of abundance and trait-based warning signals of population decline.

Here, we apply a trait-based demographic approach and investigate both trait and population dynamics in response to gradual changes in the environment. We explore a range of ecological and evolutionary constraints under which the stability of a population may be affected.

We show both analytically and with model-based simulations that strength of abundance-based early warning signals is significantly affected by ecological and evolutionary factors.

Finally, we show that a unified approach, combining trait- and abundance-based information, significantly improves our ability to predict population declines. Our study suggests that the inclusion of trait dynamic information alongside generic warning signals should provide more accurate forecasts of the future state of biological systems.
Patient-specific logic models of signaling pathways from screenings on cancer biopsies to prioritize personalized combination therapies
Authors: Eduati Federica , Jaaks Patricia , Merten Christoph A. , Garnett Mathew J. , Rodriguez Julio Saez-
Published: September 2018

Mechanistic modeling of signaling pathways mediating patient-specific response to therapy can help to unveil resistance mechanisms and improve therapeutic strategies. Yet, creating such models for patients, in particular for solid malignancies, is challenging. A major hurdle to build these models is the limited material available, that precludes the generation of large-scale perturbation data. Here, we present an approach that couples ex vivo high-throughput screenings of cancer biopsies using microfluidics with logic-based modeling to generate patient-specific dynamic models of extrinsic and intrinsic apoptosis signaling pathways. We used the resulting models to investigate heterogeneity in pancreatic cancer patients, showing dissimilarities especially in the PI3K-Akt pathway. Variation in model parameters reflected well the different tumor stages. Finally, we used our dynamic models to efficaciously predict new personalized combinatorial treatments. Our results suggest our combination of microfluidic experiments and mathematical model can be a novel tool toward cancer precision medicine.
Characteristics of Interactions at Protein Segments External to Globular Domains in the Protein Data Bank
Authors: Kasahara Kota , Minami Shintaro , Aizawa Yasunori
Published: September 2018

The principle of three-dimensional protein structure formation is a long-standing conundrum in structural biology. A globular domain of a soluble protein is formed by a network of atomic contacts among amino acid residues, but regions external to globular domains, like loop and linker, often do not have intramolecular contacts with globular domains. Although these regions can play key roles for protein function as interfaces for intermolecular interactions, their nature remains unclear. Here, we termed protein segments external to globular domains as floating segments and sought for them in tens of thousands of entries in the Protein Data Bank. As a result, we found that 0.72 % of residues are in floating segments. Regarding secondary structural elements, coil structures are enriched in floating segments, especially for long segments. Interactions with polypeptides and polynucleotides, but not small compounds, are enriched in floating segments. The amino acid preferences of floating segments are similar to those of surface residues, with exceptions; the small side chain amino acids, Gly and Ala, are preferred, and some charged side chains, Arg and His, are disfavored for floating segments compared to surface residues. Our comprehensive characterization of floating segments may provide insights into understanding protein sequence-structure-function relationships.
Chemerin Induced byTreponema pallidumPredicted Membrane Protein Tp0965 Mediates Endothelial Dysfunction via Activating MAPK Signaling Pathway
Authors: Zhang Rui-Li , Yang Li-Jia , Wang Qian-Qiu
Published: September 2018

Chemerin, a chemoattractant protein, is involved in endothelial dysfunction and vascular inflammation in pathological conditions. In a recent study, we observed the upregulation of chemerin in endothelial cells followingin vitrotreatment withT. pallidum. Here, we investigated the role of chemerin in endothelial cells dysfunction induced by theT. pallidumpredicted membrane protein Tp0965. Following stimulation of human umbilical vein endothelial cells (HUVECs) with Tp0965, chemerin and its ChemR23 receptor were up-regulated, companied with elevated expression of TLR2. Furthermore, chemerin from HUVECs activated endothelial cells via chemerin/ChemR23 signaling in an autocrine/paracrine manner, characterized by upregulated expression of ICAM-1, E-selectin and MMP-2. Activation of endothelial cells depended on the MAPK signaling pathway. In addition, Tp0965-induced chemerin promoted monocytes migration to endothelial cells, also via chemerin/ChemR23 pathway. The RhoA/ROCK signaling pathway was also involved in monocytes migration in response to chemerin/ChemR23. Our results highlight the role of Tp0965-induced chemerin in endothelial cells dysfunction, which contributes to the immunopathogenesis of vascular inflammation of syphilis.

Author summary

Treponema pallidumis the spirochete of syphilis, which causes a chronic system inflammation. Endothelium damage caused by this bacterium is the key step in the systemic dissemination and pathophysiology of syphilis, particularly cardiovascular syphilis and neurosyphilis. In this study, we show a novel molecular mechanism of endothelium damage induce byTreponema pallidumpredicted membrane protein Tp0965. Chemerin is a recently identified adipocytokine and chemoattractant protein with a crucial role in endothelial dysfunction and vascular inflammation in pathological conditions. Our data show that Tp0965 up-regulated the expression of chemerin and its ChemR23 receptor by endothelial cells in vitro. Furthermore, chemerin from HUVECs activated endothelial cells via chemerin/ChemR23 signaling in an autocrine/paracrine manner and depended on the MAPK signaling pathway. In addition, Tp0965-induced chemerin promoted monocytes migration to endothelial cells, also via chemerin/ChemR23 pathway. The RhoA/ROCK signaling pathway was also involved in monocytes migration in response to chemerin/ChemR23. These findings contribute to the immunopathogenesis of vascular inflammation of syphilis.
Keratinocyte desmoglein 1 regulates the epidermal microenvironment and tanning response
Authors: Arnette Christopher R. , Koetsier Jennifer L. , Broussard Joshua A. , Gerami Pedram , Johnson Jodi L. , Green Kathleen J.
Published: September 2018

Coordinated responses to environmental stimuli within the keratinocyte:melanocyte niche are poorly understood. Desmoglein 1 (Dsg1), a keratinocyte-specific desmosomal cell-cell adhesion protein with emerging signaling roles, is reduced by ultraviolet light radiation. Loss-of-function Dsg1 mutations elevate keratinocyte cytokines in Severe dermatitis, multiple Allergies, and Metabolic wasting (SAM) syndrome. We asked whether Dsg1 regulates keratinocyte:melanocyte paracrine communication to induce the tanning response. Dsg1-silenced keratinocytes increasedPro-opiomelanocortinmRNA and cytokine secretion. Melanocytes treated with conditioned media from Dsg1-silenced keratinocytes exhibited increasedMitfandTrp1mRNA, melanin secretion, and dendrite length. Inhibiting the melanocyte pigment-associated melanocortin 1 receptor reduced pigment secretion in response to Dsg1-deficient conditioned media. Melanocytes incorporated into Dsg1-deficient human skin equivalents relocalized suprabasally, reminiscent of early melanoma pagetoid behavior. Dsg1 decreased in keratinocytes surrounding dysplastic nevi and early melanoma, but not benign nevi. We posit Dsg1 controls keratinocyte:melanocyte communication through paracrine signaling, which goes awry upon Dsg1 loss in melanoma development.
Dissociating refreshing and elaboration and their impacts on memory
Authors: Bartsch Lea M. , Loaiza Vanessa M. , Jäncke Lutz , Oberauer Klaus , Lewis-Peacock Jarrod A.
Published: September 2018

Maintenance of information in working memory (WM) is assumed to rely on refreshing and elaboration, but clear mechanistic descriptions of these cognitive processes are lacking, and it is unclear whether they are simply two labels for the same process. This fMRI study investigated the extent to which refreshing, elaboration, and repeating of items in WM are distinct neural processes with dissociable behavioral outcomes in WM and long-term memory (LTM). Multivariate pattern analyses of fMRI data revealed differentiable neural signatures for these processes, which we also replicated in an independent sample of older adults. In some cases, the degree of neural separation within an individual predicted their memory performance. Elaboration improved LTM, but not WM, and this benefit increased as its neural signature became more distinct from repetition. Refreshing had no impact on LTM, but did improve WM, although the neural discrimination of this process was not predictive of the degree of improvement. These results demonstrate that refreshing and elaboration are separate processes that differently contribute to memory performance.

Highlights

Repeated reading, refreshing, and elaboration are differentiable in brain activation patterns in both young and older adults.

Elaboration selectively improved long-term memory for young adults, and the size of the benefit was related to the neural separability of elaboration from other processes.

Older adults implemented a sub-optimal form of elaboration, and this may be a factor contributing to age-related deficits in long-term memory.

Ethics statement

The study was approved by the ethical review board of the canton of Zurich (BASEC-No. 2017-00190) and all subjects gave informed written consent in accordance with the Declaration of Helsinki.

Data and code availability statement

All behavioral data and analysis scripts can be assessed on the Open Science Framework (osf.io/p2h8b/). The fMRI data that support the findings of this study are available on request from the corresponding author, LMB. The fMRI data are not publicly available due to restrictions of the Swiss Ethics Committees on research involving humans regarding data containing information that could compromise the privacy of research participants.
Microbial communities across a hillslope-riparian transect shaped by proximity to the stream, groundwater table, and weathered bedrock
Authors: Lavy Adi , McGrath David Geller , Matheus Carnevali Paula B. , Wan Jiamin , Dong Wenming , Tokunaga Tetsu , Thomas Brian C. , Williams Kenneth H. , Hubbard Susan , Banfield Jillian F.
Published: September 2018

Watersheds are important suppliers of freshwater for human societies. Within mountainous watersheds, microbial communities impact water chemistry and element fluxes as water from precipitation events discharges through soils and underlying weathered rock, yet there is limited information regarding the structure and function of these communities. Within the East River, CO watershed, we conducted a depth-resolved, hillslope to riparian zone transect study to identify factors that control how microorganisms are distributed and their functions. Metagenomic and geochemical analyses indicate that distance from the East River and proximity to groundwater and underlying weathered shale strongly impact microbial community structure and metabolic potential. Riparian zone microbial communities are compositionally distinct from all hillslope communities. Bacteria from phyla lacking isolated representatives consistently increase in abundance with increasing depth, but only in the riparian zone saturated sediments did we find Candidate Phyla Radiation bacteria. Riparian zone microbial communities are functionally differentiated from hillslope communities based on their capacities for carbon and nitrogen fixation and sulfate reduction. Selenium reduction is prominent at depth in weathered shale and saturated riparian zone sediments. We anticipate that the drivers of community composition and metabolic potential identified throughout the studied transect will predict patterns across the larger watershed hillslope system.
Conversion of graded presynaptic climbing fiber activity into graded postsynaptic Ca2+ signals by Purkinje cell dendrites
Authors: Gaffield Michael A. , Christie Jason M.
Published: September 2018

The brain must make sense of external stimuli to generate relevant behavior. We used a combination of in vivo approaches to investigate how the cerebellum processes sensory-related information. We found that the inferior olive encodes contexts of sensory-associated external cues in a graded manner, apparent in the presynaptic activity of their axonal projections in the cerebellar cortex. Further, individual climbing fibers were broadly responsive to different sensory modalities but relayed sensory-related information to the cortex in a lobule-dependent manner. Purkinje cell dendrites faithfully transformed this climbing fiber activity into dendrite-wide Ca2+ signals without a direct contribution from the mossy fiber pathway. These results demonstrate that the size of climbing fiber-evoked Ca2+ signals in Purkinje cell dendrites is largely determined by the firing level of climbing fibers. This coding scheme emphasizes the overwhelming role of the inferior olive in generating salient signals useful for instructing plasticity and learning.
miRNA analysis with Prost! reveals evolutionary conservation of organ-enriched expression and post-transcriptional modifications in three-spined stickleback and zebrafish
Authors: Desvignes Thomas , Batzel Peter , Sydes Jason , Eames B. Frank , Postlethwait John
Published: September 2018

MicroRNAs (miRNAs) can have tissue-specific expression and functions; they can originate from dedicated miRNA genes, from non-canonical miRNA genes, or from mirror-miRNA genes and can also experience post-transcriptional variations. It remains unclear, however, which mechanisms of miRNA production or modification are tissue-specific and the extent of their evolutionary conservation. To address these issues, we developed the software Prost! (PRocessing Of Short Transcripts), which, among other features, allows accurate quantification of mature miRNAs, takes into account post-transcriptional processing, such as nucleotide editing, and helps identify mirror-miRNAs. Here, we applied Prost! to annotate and analyze miRNAs in three-spined stickleback (Gasterosteus aculeatus), a model fish for evolutionary biology reported to have a miRNome larger than most teleost fish. Zebrafish (Danio rerio), a distantly related teleost with a well-known miRNome, served as comparator. Despite reports suggesting that stickleback had a large miRNome, results showed that stickleback has 277 evolutionary-conserved mir genes and 366 unique mature miRNAs (excluding mir430 gene replicates and the vaultRNA-derived mir733), similar to zebrafish. In addition, small RNA sequencing data from brain, heart, testis, and ovary in both stickleback and zebrafish identified suites of mature miRNAs that display organ-specific enrichment, which is, for many miRNAs, evolutionarily-conserved. These data also supported the hypothesis that evolutionarily-conserved, organ-specific mechanisms regulate miRNA post-transcriptional variations. In both stickleback and zebrafish, miR2188-5p was edited frequently with similar nucleotide editing patterns in the seed sequence in various tissues, and the editing rate was organ-specific with higher editing in the brain. In summary, Prost! is a critical new tool to identify and understand small RNAs and can help clarify a species’ miRNA biology, as shown here for an important fish model for the evolution of developmental mechanisms, and can provide insight into organ-specific expression and evolutionary-conserved miRNA post-transcriptional mechanisms.
The Population Genetic Variation Analysis of Bitter Gourd Wilt Caused byFusarium oxysporumf. sp.momordicaein China by Inter Simple Sequence Repeats (ISSR) Molecular Marker
Authors: Zang Rui , Zhao Ying , Guo Kangdi , Hong Kunqi , Xi Huijun , Wen Caiyi
Published: September 2018

The bitter gourd fusarium wilt caused byFusarium oxysporumf.sp.momordicae(FOM) was a devastating disease in China and leading to great economic losses every year. A total of 152 isolates, which have the typicalFusarium oxysporumcharacteristics with abundant microconidia and macroconidia on the white or ruby colonies, were obtained from diseased plant tissues with typical fusarium wilt symptoms. The BLASTn analysis of rDNA-ITS showed 99% identity withF.oxysporumspecies. Among the tested isolates, three isolates infected tower gourd, and five isolates were pathogenic to bottle gourd. However, they were all pathogenic to bitter gourd. Based on the molecular and morphologic results, the isolates were identified as FOM. For genetic variation analysis, forty ISSR primers were screened and eleven primers were used in PCR amplification. Totally, 121 loci were detected, of which 52 loci were polymorphic at rate of 42.98%. The POPGENE analysis showed that Nei’s gene diversity index (H) and Shannon’s information index (I) were 0.0902 and 0.1478, respectively, which indicated that the genetic diversity for the tested 152 isolates was relatively low. It also means that each geographical population was a relatively independent unit. While the value of coefficient of gene differentiation (Gst=0.4929 > 0.15) pointed to the genetic differentiation was mainly among populations. The strength of gene flow (Nm=0.5143<1.0) was weaker, indicating that gene exchanges were blocked to some degree. The dendrogram based on ISSR markers showed that the eight geographical populations were clustered into four groups at the threshold of genetic similar coefficient 0.96. Fujian, Jiangxi and Guangdong populations were clustered into Group I. Group II contained Hunan and Guangxi populations. Group III only had Hainan population. GroupIVconsisted Shandong and Henan populations. The geographical populations closer to each other grouped together, suggesting a correlationship between geographical origin and genetic differentiation. Two hybridization events were observed between Hainan and Hunan populations and between Guangdong and Guangxi by Structure analysis. Our findings enrich the knowledge on genetic variation characteristics of the FOM populations with helpful of development of effective disease management programs and disease resistance breeding.
2-(4-Aminophenyl)-3-[3,4-bis(pyridin-2-ylmethoxy)phenyl]acrylonitrile
Authors: Liu Gang , Liu Qingsong , Zhang Huihui , Yu Jianhua
Published: September 2018

The crystal structure of C27H22N4O2 is characterized by N—H...N hydrogen bonds, which connect the molecules into zigzag chains running along the b-axis direction. The central ring subtends dihedral angles of 17.89 (6)° with the aminophenyl ring and of 8.75 (9) and 28.77 (7)° with the two pyridyl rings.
2-(2-Fluorophenyl)-3-hydroxy-4H-chromen-4-one
Authors: Koh Dongsoo
Published: September 2018

The asymmetric unit of the title compound, C15H9FO3, contains two independent molecules in which the fluorine-substituted benzene ring is twisted by 47.64 (3) and 56.02 (4)° relative to the 4H-chromenon skeleton. The hydroxyl group in each molecule is tilted from 4H-chromenon skeleton by 24.5 (1) and 16.1 (1)°, respectively. In the crystal, pairs of O—H...O hydrogen bonds form inversion dimers with an R
2
2(10) graph-set motif.
Individual unlearning, organizational unlearning and strategic flexibility
Authors: Wang Xiangyang , Qi Ying , Zhao Yingxin
Published: September 2018

Purpose

The purpose of this paper is to explore the relationship between unlearning and strategic flexibility from the down-up change perspective.

Design/methodology/approach

Drawing on the routine-updating process, this study builds a theoretical model and examines it using survey data from 233 firms in China.

Findings

Unlearning is the enabler to strategic flexibility. Specifically, individual unlearning and organizational unlearning both have positive effects on strategic flexibility. Organizational unlearning exerts a partly mediating effect on the relationship between individual unlearning and strategic flexibility.

Originality/value

The paper examines the different mechanisms of individual and organizational unlearning on strategic flexibility and suggests that unlearning is a useful method or approach for strategic flexibility. In addition, this study is useful to help managers or practitioners determine how to embrace strategic flexibility by unlearning.