bluuebunny/crossref_metadata_2025 huggingface dataset:
Control of Septoria tritici blotch by winter wheat cultivar mixtures: Meta-analysis of 19 years of cultivar trials
Authors: Kristoffersen Rose , Jørgensen Lise Nistrup , Eriksen Lars Bonde , Nielsen Ghita Cordsen , Kiær Lars Pødenphant
Published: June 2019

Wheat is the most commonly grown cereal crop in Europe and in major parts the most yield limiting disease is Septoria tritici blotch (STB). Currently, the control of the disease depends on cultivar resistance and significant input of fungicides. The impact of using mixtures of elite cultivars as an alternative was investigated through a meta-analysis based on trial data from the Danish national cultivar testing. The cultivar testing includes a four-way cultivar mixture every year and in these trials STB severity and yield have been monitored at multiple locations between 1995 and 2017. Results from 19 years of cultivar testing trials provided a data set for 406 trials from which the effect of mixtures was evaluated. The meta-analysis revealed that cultivar mixtures reduced STB severity with 10.6% and increased yields with 1.4% across all trials. The effects were greatest in untreated trials where STB severity was reduced with 17% and yields increased with 2.4%. The mixtures did not only perform better than the average of their component cultivars grown as pure stand, they also performed better than the average of the four most grown cultivars in a given year. No relationship was found between disease pressure or location and the performance of the mixtures. The mixtures included in the cultivar testing were not designed to control STB and the results are therefore perceived as a baseline to the attainable disease control from mixtures. The use of cultivar mixtures is relevant for low input farming systems, but can also contribute to disease control in intensive farming systems. Cultivar mixtures have the potential to minimise dependency on fungicides as an important element in integrated pest management.
Normal mammary gland development after MMTV-Cre mediated conditional PAK4 gene depletion
Authors: Rabieifar Parisa , Zhuang Ting , Costa Tânia D. F. , Zhao Miao , Strömblad Staffan
Published: June 2019

p21-activated protein kinases (PAKs) are serine/threonine kinases functioning as downstream effectors of the small GTPases Rac1 and Cdc42. Members of the PAK family are overexpressed in human breast cancer, but their role in mammary gland development is not fully explored. Here we examined the functional role of PAK4 in mammary gland development by creating a mouse model of MMTV-Cre driven conditional PAK4 gene depletion in the mammary gland. The PAK4 conditional knock-out mice were born healthy with no observed developmental deficits. Mammary gland whole-mounts revealed no defects in ductal formation or elongation of the mammary tree through the fat pad. PAK4 gene depletion also did not alter proliferation and invasion of the mammary epithelium in young virgin mice. Moreover, adult mice gave birth to healthy pups with normal body weight upon weaning. This implies that MMTV-Cre induced gene depletion of PAK4 in mice does not impair normal mammary gland development and thereby provides anin vivomodel for examination of the potential function of PAK4 in breast cancer.
Characteristics of University Students Supported by Counseling Services: Analysis of psychological tests and pulse rate variability
Authors: Adachi Yumi , Yoshikawa Hiroaki , Yokoyama Shigeru , Iwasa Kazuo
Published: June 2019

Objective

The number of students who use counseling services is increasing in universities. We clarified the characteristics of the students who access counseling services using both psychological tests and pulse rate variability (PRV).

Methods

We recruited the participants for this study from the students who had counseling sessions at Kanazawa University (Group S). As a control group, we also recruited students who had no experience in counseling sessions (Group H). We obtained health information from the database of annual health check-ups. Participants received the Wechsler Adult Intelligence Scale (WAIS) III, Autism-Spectrum Quotient (AQ), Sukemune-Hiew (S-H) Resilience Test, and State-Trait Anxiety Inventory-JYZ (STAI). We also studied the SF-12v2 Health Survey. We examined the spectral analyses of pulse rate variability (PRV) by accelerating plethysmography. We performed linear analysis of PRV for LF, HF, and LF/HF as indexes of autonomic nervous function. We also performed non-linear analysis of PRV for the largest Lyapunov exponent (LLE). We examined participants’ blood for autoantibodies against glutamate decarboxylase (GAD) 65.

Results

A total of 105 students participated in this study. Group S had 37 participants (Male: 26, Female: 11) and Group H had 68 participants (Male: 27, Female 41). There were 12 males and two females who had been diagnosed with autism spectrum disorder (ASD) in Group S. Group S had 1) lower Working Memory Index (WMI) despite relatively high Full-Scale IQ, 2) higher AQ scores, 3) lower resilience scores, 4) higher anxiety scores, 5)lower QOL in social health, and 6) shifting of autonomic nervous balance toward higher sympathetic activity. There were only two participants who had the anti-GAD65 antibody in Group S, and one participant had the anti-GAD65 antibody in Group H.

Conclusion

The results of our study revealed valuable information about the students who seek mental support in our university. Our results provide information that can be used in interventions for the university students who need counseling services.
Long-term influence of climate and experimental eutrophication regimes on phytoplankton blooms
Authors: Salk Kateri R. , Venkiteswaran Jason J. , Couture Raoul-Marie , Higgins Scott N. , Paterson Michael J. , Schiff Sherry L.
Published: June 2019

Phytoplankton blooms respond to multiple drivers, including climate change and nutrient loading. Here we examine a long-term dataset from Lake 227, a site exposed to a fertilization experiment (1969–present). Changes in nitrogen:phosphorus loading ratios (high N:P, low N:P, P-only) did not impact mean annual biomass, but blooms exhibited substantial inter- and intra-annual variability. We used a process-oriented lake model, MyLake, to successfully reproduce lake physics over 48 years and test if a P-limited model structure predicted blooms. The timing and magnitude of blooms was reproduced during the P-only period but not for the high and low N:P periods, perhaps due to N acquisition pathways not currently included in the model. A model scenario with no experimental fertilization confirmed P loading is the major driver of blooms, while a scenario that removed climate-driven temperature trends showed that increased spring temperatures have exacerbated blooms beyond the effects of fertilization alone.

Significance Statement

Harmful algal blooms and eutrophication are key water quality issues worldwide. Managing algal blooms is often difficult because multiple drivers, such as climate change and nutrient loading, act concurrently and potentially synergistically. Long-term datasets and simulation models allow us to parse the effects of interacting drivers of blooms. The performance of our model depended on the ratio of nitrogen to phosphorus inputs, suggesting that complex biological dynamics control blooms under variable nutrient loads. We found that blooms were dampened under a “no climate change” scenario, suggesting that the interaction of nutrient loading and increased temperature intensifies blooms. Our results highlight successes and gaps in our ability to model blooms, helping to establish future management recommendations.

Data Availability Statement

Data and metadata will be made available in a GitHub repository (https://github.com/biogeochemistry/Lake-227). Upon manuscript acceptance, the repository will be made publicly available and a DOI will be provided. We request that data users contact the Experimental Lakes Area directly, per their data use policy (http://www.iisd.org/ela/wp-content/uploads/2016/04/Data-Terms-And-Conditions.pdf).
Conditional, inducible gene silencing in dopamine neurons reveals a sex-specific role for Rit2 GTPase in acute cocaine response and striatal function
Authors: Sweeney Carolyn G. , Kearney Patrick J. , Fagan Rita R. , Smith Lindsey A. , Bolden Nicholas C. , Zhao-Shea Rubing , Rivera Iris V. , Kolpakova Jenya , Xie Jun , Gao Guangping , Tapper Andrew R. , Martin Gilles E. , Melikian Haley E.
Published: June 2019

Dopamine (DA) signaling is critical for movement, motivation, and addictive behavior. The neuronal GTPase, Rit2, is enriched in DA neurons (DANs), binds directly to the DA transporter (DAT), and is implicated in several DA-related neuropsychiatric disorders. However, it remains unknown whether Rit2 plays a role in either DAergic signaling and/or DA-dependent behaviors. Here, we leveraged the TET-OFF system to conditionally silence Rit2 in Pitx3IRES2-tTA mouse DANs. Following DAergic Rit2 knockdown (Rit2-KD), mice displayed an anxiolytic phenotype, with no change in baseline locomotion. Further, males exhibited increased acute cocaine sensitivity, whereas DAergic Rit2-KD suppressed acute cocaine sensitivity in females. DAergic Rit2-KD did not affect presynaptic TH and DAT protein levels in females, nor was TH was affected in males; however, DAT was significantly diminished in males. Paradoxically, despite decreased DAT levels in males, striatal DA uptake was enhanced, but was not due to enhanced DAT surface expression in either dorsal or ventral striatum. Finally, patch recordings in nucleus accumbens (NAcc) medium spiny neurons (MSNs) revealed reciprocal changes in spontaneous EPSP (sEPSP) frequency in male and female D1+ and D2+ MSNs following DAergic Rit2-KD. In males, sEPSP frequency was decreased in D1+, but not D2+, MSNs, whereas in females sEPSP frequency decreased in D2+, but not D1+, MSNs. Moreover, DAergic Rit2-KD abolished the ability of cocaine to reduce sEPSP frequency in D1+, but not D2+, male MSNs. Taken together, our studies are among the first to acheive AAV-mediated, conditional and inducible DAergic knockdown in vivo. Importantly, our results provide the first evidence that DAergic Rit2 expression differentially impacts striatal function and DA-dependent behaviors in males and females.
Shed skin as a source of DNA for genotyping-by-sequencing (GBS) in reptiles
Authors: Brekke Thomas D , Shier Liam , Hegarty Matthew J , Mulley John F
Published: June 2019

Over a fifth of reptile species are classified as ‘Threatened’ and conservation efforts, especially those aimed at recovery of isolated or fragmented populations, will require genetic and genomic data and resources. Shed skins of snakes and other reptiles contain DNA, are a safe and ethical way of non-invasively sampling large numbers of individuals, and provide a simple mechanism by which to involve the public in scientific research. Here we test whether the DNA in dried shed skin is suitable for reduced representation sequencing approaches, specifically genotyping-by-sequencing (GBS). Shed skin-derived libraries resulted in fewer sequenced reads than those from snap-frozen muscle samples, and contained slightly fewer variants (70,685 SNPs versus 97,724), but this issue can easily be rectified with deeper sequencing of shed skin-derived libraries. Skin-derived libraries also have a very slight (but significantly different) profile of transitions and transversions, most likely as a result of DNA damage, but the impact of this is minimal given the large number of single nucleotide polymorphisms (SNPs) involved. SNP density tends to scale with chromosome length, and microchromosomes have a significantly higher SNP density than macrochromosomes, most likely because of their higher GC content. Overall, shed skin provides DNA of sufficient quality and quantity for the identification of large number of SNPs, but requires greater sequencing depth, and consideration of the GC richness of microchromosomes when selecting restriction enzymes.
Termination of pre-mRNA splicing requires that the ATPase and RNA unwindase Prp43 acts on the catalytic snRNA U6
Authors: Toroney Rebecca , Nielsen Klaus H. , Staley Jonathan P.
Published: June 2019

The termination of pre-mRNA splicing functions to discard suboptimal substrates, thereby enhancing fidelity, and to release excised introns in a manner coupled to spliceosome disassembly, thereby allowing recycling. The mechanism of termination, including the RNA target of the DEAH-box ATPase Prp43, remains ambiguous. We discovered a critical role for nucleotides at the 3’-end of the catalytic U6 small nuclear RNA in splicing termination. Though conserved sequence at the 3’-end is not required, 2’ hydroxyls are, paralleling requirements for Prp43 biochemical activities. While the 3’-end of U6 is not required for recruiting Prp43 to the spliceosome, the 3’ end crosslinks directly to Prp43 in an RNA-dependent manner. Our data indicate a mechanism of splicing termination in which Prp43 translocates along U6 from the 3’ end to disassemble the spliceosome and thereby release suboptimal substrates or excised introns. This mechanism reveals that the spliceosome becomes primed for termination at the same stage it becomes activated for catalysis, implying a requirement for stringent control of spliceosome activity within the cell.
The Evolution of Fluoroquinolone-Resistance inMycobacterium tuberculosisis Modulated by the Genetic Background
Authors: Castro Rhastin A. D. , Ross Amanda , Kamwela Lujeko , Reinhard Miriam , Loiseau Chloé , Feldmann Julia , Borrell Sonia , Trauner Andrej , Gagneux Sebastien
Published: June 2019

Fluoroquinolones (FQ) form the backbone in experimental treatment regimens against drug-susceptible tuberculosis. However, little is known on whether the genetic variation present in natural populations ofMycobacterium tuberculosis(Mtb) affects the evolution of FQ-resistance (FQ-R). To investigate this question, we used a set ofMtbstrains that included nine genetically distinct drug-susceptible clinical isolates, and measured their frequency of resistance to the FQ ofloxacin (OFX)in vitro. We found that theMtbgenetic background led to differences in the frequency of OFX-resistance (OFX-R) that spanned two orders of magnitude and substantially modulated the observed mutational profiles for OFX-R. Furtherin vitroassays showed that the genetic background also influenced the minimum inhibitory concentration and the fitness effect conferred by a given OFX-R mutation. To test the clinical relevance of ourin vitrowork, we surveyed the mutational profile for FQ-R in publicly available genomic sequences from clinicalMtbisolates, and found substantialMtblineage-dependent variability. Comparison of the clinical and thein vitromutational profiles for FQ-R showed that 45% and 19% of the variability in the clinical frequency of FQ-RgyrAmutations in Lineage 2 and Lineage 4 strains, respectively, can be attributed to howMtbevolves FQ-Rin vitro. As theMtbgenetic background strongly influenced the evolution of FQ-Rin vitro, we conclude that the genetic background ofMtbalso impacts the evolution of FQ-R in the clinic.

Significance

Newer generations of fluoroquinolones form the backbone in many experimental treatment regimens againstM. tuberculosis(Mtb). While the genetic variation in natural populations ofMtbcan influence resistance evolution to multiple different antibiotics, it is unclear whether it modulates fluoroquinolone-resistance evolution as well. Using a combination ofin vitroassays coupled with genomic analysis of clinical isolates, we provide the first evidence illustrating theMtbgenetic background’s substantial role in fluoroquinolone-resistance evolution, and highlight the importance of bacterial genetics when studying the prevalence of fluoroquinolone-resistance inMtb. Our work may provide insights into how to maximize the timespan in which fluoroquinolones remain effective in clinical settings, whether as part of current standardized regimens, or in new regimens againstMtb.
“A distinct neutrophil population invades the central nervous system during pancreatic cancer”
Authors: Burfeind Kevin G. , Zhu Xinxia , Norgard Mason A. , Levasseur Peter R. , Olson Brennan , Michaelis Katherine A. , Torres Eileen Ruth S. , Patel Esha M. , Jeng Sophia , McWeeney Shannon , Raber Jacob , Marks Daniel L.
Published: June 2019

Weight loss, fatigue, and cognitive dysfunction are common symptoms in cancer patients that occur prior to initiation of cancer therapy. Inflammation in the brain is a driver of these symptoms, yet cellular sources of neuroinflammation during malignancy are unknown. In a mouse model of pancreatic ductal adenocarcinoma (PDAC), we observed early and robust myeloid cell infiltration into the brain. Infiltrating immune cells were predominately neutrophils, which accumulated at a unique central nervous system entry portal called the velum interpositum, where they expressed CCR2. CCR2 knockout mice had significantly decreased brain-infiltrating neutrophils as well as attenuated anorexia and muscle catabolism during PDAC, without any changes in neutrophils in other organs. Lastly, intracerebroventricular blockade of the purinergic receptor P2RX7 during PDAC abolished neutrophil recruitment to the brain and attenuated anorexia. Our data demonstrate a novel function for the CCR2/CCL2 axis in recruiting neutrophils to the brain, which drives anorexia and muscle catabolism.
Asymmetrical cleavages ofSleeping Beautytransposons generate multiple excised transposon fragments during transposition
Authors: Gu Qilin , Yang Xiaojie , Li Qing , Long Yong , Song Guili , Pei Desheng , Hackett Perry B. , Chen Jun , Peng Jinrong , Cui Zongbin
Published: June 2019

Although theSleeping Beauty(SB) transposon is the most validated DNA transposon used as a gene delivery vehicle in vertebrates, many details of the excision and integration steps in the transposition process are unclear. We have probed in detail the products of the excision step and apparent selective integration of a subset of those products during transposition. The standard model of SB transposase-mediated transposition includes symmetrical cleavages at both ends of the transposon for excision and re-integration in another DNA sequence. In our analysis of excised transposon fragments (ETFs), we found evidence for the requirement of certain flanking sequences for efficient cleavage and a significant rate of asymmetrical cleavage during the excision process that generates multiple ETFs. Our results suggest that the cleavage step by SB transposase is not as precise as indicated in most models. Repair of the donor ends can produce eight footprint sequences (TACTGTA, TACAGTA, TACATA, TACGTA, TATGTA, TACTA, TAGTA and TATA). Our data also suggest that mismatch repair (MMR) is not an essential requirement for footprint formation. Among the twenty liberated ETFs, only eight appear to effectively re-integrate into TA sites distributed across the genome, supporting earlier findings of unequal rates of excision and reintegration during SB transposition. These findings may be important in considerations of efficiency of SB transposon remobilization, selection of TA integration sites and detection of SB excision and integration loci, all of which may be important in human gene therapy.
Variations and expression features of CYP2D6 contribute to schizophrenia risk
Authors: Ma Liang , Chetty Sundari
Published: June 2019

Objective

Genome-wide association studies (GWAS) have successfully identified 145 loci implicated in schizophrenia (SCZ). However, the underlying mechanisms remain largely unknown.

Methods

Here, we analyze 1,479 RNA-seq data from 13 postmortem brain regions in combination with their genotype data and identify SNPs that are associated with expression throughout the genome by dissecting expression features to genes (eGene) and exon-exon junctions (eJunction). Then, we co-localize eGene and eJunction with SCZ GWAS using SMR and mapping. Multiple ChIP-seq data and DNA methylation data generated from brain were used for identifying the causative variants. Finally, we used a hypothesis-free (no SCZ risk loci considered) enrichment analysis to determine implicated pathways.

Results

We identified 171 genes and eight splicing junctions located within four genes (SNX19, ARL6IP4, APOPT1 and CYP2D6) that potentially contribute to SCZ susceptibility. Among the genes, CYP2D6 is significantly associated with SCZ SNPs in both eGene and eJunction across the 13 brain regions. In-depth examination of the CYP2D6 region revealed that a non-synonymous single nucleotide variant (SNV) rs16947 is strongly associated with a higher abundance of CYP2D6 exon 3 skipping junctions. While we found rs133377 and two other SNPs in high linkage disequilibrium (LD) with rs16947 (r2 = 0.9539), histone acetylation analysis showed they are located within active transcription start sites. Furthermore, our data-driven enrichment analysis showed CYP2D6 is significantly involved in drug metabolism of tamoxifen, codeine and citalopram.

Conclusions

Our study facilitates an understanding of the genetic architecture of SCZ and provides new drug targets.
Molecular pathway analysis indicates a distinct metabolic and immune phenotype in women with right-sided colon cancer
Authors: Sun Yazhi , Mironova Varvara , Chen Ying , Lundh Elliott P.F. , Zhang Qian , Cai Yuping , Vasiliou Vasilis , Zhang Yawei , Garcia-Milian Rolando , Khan Sajid A. , Johnson Caroline H.
Published: June 2019

Colon cancer is the third most commonly diagnosed cancer in the United States. Recent reports have shown that the location of the primary tumor is of clinical importance. Patients with right-sided cancers (RCCs) (tumors arising between the cecum and proximal transverse colon) have poorer clinical outcomes than those with left-sided colon cancers (LCCs) (tumors arising between the distal transverse colon and sigmoid colon, excluding the rectum). Interestingly, women have a lower incidence of colon cancer than men do. However, women have a higher propensity for RCC than men. Identification of gene expression differences between RCC and LCC is considered a potential means of prognostication. Furthermore, studying colon cancer sidedness could reveal important predictive markers for response to various treatments. This study provides a comprehensive bioinformatic analysis of various genes and molecular pathways that correlated with sex and anatomical location of colon cancer using four publicly available annotated datasets housed in the National Center for Biotechnology Information’s Gene Expression Omnibus (GEO). We identified differentially expressed genes in tumor tissues from women with RCC, which showed attenuated energy and nutrient metabolism when compared to women with LCC. Specifically, we showed that the downregulation of 5’ AMP-activated protein kinase alpha subunit (AMPKα) and downregulated anti-tumor immune response in women with RCC. This difference was not seen when comparing tumor tissues from men with RCC to men with LCC. Therefore, women with RCC may have a specific metabolic and immune phenotype which accounts for differences in prognosis and treatment response.
Ribosomal protein RACK1 facilitates efficient translation of poliovirus and other viral IRESs
Authors: LaFontaine Ethan , Miller Clare M. , Permaul Natasha , Johnson Alex G. , Martin Elliot T. , Fuchs Gabriele
Published: June 2019

Viruses have evolved various strategies to ensure efficient translation using host cell ribosomes and translation factors. In addition to cleaving translation initiation factors required for host cell translation, poliovirus (PV) uses an internal ribosome entry site (IRES) to bypass the need for these translation initiation factors. Recent studies also suggest that viruses have evolved to exploit specific ribosomal proteins to enhance translation of their viral proteins. The ribosomal protein receptor for activated C kinase 1 (RACK1), a protein of the 40S ribosomal subunit, was previously shown to mediate translation of the 5′ cricket paralysis virus and hepatitis C virus IRESs. Here we found that while translation of a PV dual-luciferase reporter shows only a moderate dependence on RACK1, PV translation in the context of a viral infection is drastically reduced. We observed significantly reduced poliovirus plaque size and a delayed host cell translational shut-off suggesting that loss of RACK1 increases the length of the virus life cycle. Our findings further illustrate the involvement of the cellular translational machinery in PV infection and how viruses usurp the function of specific ribosomal proteins.
Space is the Place: Effects of Continuous Spatial Structure on Analysis of Population Genetic Data
Authors: Battey C.J. , Ralph Peter L. , Kern Andrew D.
Published: June 2019

Real geography is continuous, but standard models in population genetics are based on discrete, well-mixed populations. As a result many methods of analyzing genetic data assume that samples are a random draw from a well-mixed population, but are applied to clustered samples from populations that are structured clinally over space. Here we use simulations of populations living in continuous geography to study the impacts of dispersal and sampling strategy on population genetic summary statistics, demographic inference, and genome-wide association studies. We find that most common summary statistics have distributions that differ substantially from that seen in well-mixed populations, especially when Wright’s neighborhood size is less than 100 and sampling is spatially clustered. Stepping-stone models reproduce some of these effects, but discretizing the landscape introduces artifacts which in some cases are exacerbated at higher resolutions. The combination of low dispersal and clustered sampling causes demographic inference from the site frequency spectrum to infer more turbulent demographic histories, but averaged results across multiple simulations were surprisingly robust to isolation by distance. We also show that the combination of spatially autocorrelated environments and limited dispersal causes genome-wide association studies to identify spurious signals of genetic association with purely environmentally determined phenotypes, and that this bias is only partially corrected by regressing out principal components of ancestry. Last, we discuss the relevance of our simulation results for inference from genetic variation in real organisms.
Amplifying the Neural Power Spectrum
Authors: Doyle J. Andrew , Toussaint Paule-Joanne , Evans Alan C.
Published: June 2019

We introduce a novel method that employs a parametric model of human electroen-cephalographic (EEG) brain signal power spectra to evaluate cognitive science experiments and test scientific hypotheses. We develop the Neural Power Amplifier (NPA), a data-driven approach to EEG pre-processing that can replace current filtering strategies with a principled method based on combining filters with log-arithmic and Gaussian magnitude responses. Presenting the first time domain evidence to validate an increasingly popular model for neural power spectra [1], we show that filtering out the 1/f background signal and selecting peaks improves a time-domain decoding experiment for visual stimulus of human faces versus random noise.
Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines
Authors: Ali Farhan , Gerhard Danielle M. , Sweasy Katherine , Pothula Santosh , Pittenger Christopher , Duman Ronald S. , Kwan Alex C.
Published: June 2019

A subanesthetic dose of ketamine causes acute psychotomimetic symptoms and then more sustained antidepressant effects. A key targeted brain region is the prefrontal cortex, and the prevailing disinhibition hypothesis posits that N-methyl-d-aspartate receptor (NMDAR) antagonists such as ketamine may act preferentially on GABAergic neurons. However, cortical GABAergic neurons are heterogeneous. In particular, somatostatin-expressing (SST) interneurons selectively inhibit dendrites and regulate synaptic inputs, yet their response to systemic NMDAR antagonism is unknown. Here, we report that administration of ketamine acutely suppresses the activity of SST interneurons in the medial prefrontal cortex of the awake mouse. The deficient dendritic inhibition leads to greater synaptically evoked calcium transients in the apical dendritic spines of pyramidal neurons. By manipulating NMDAR signaling via GluN2B knockdown, we show that ketamine’s actions on the dendritic inhibitory mechanism has ramifications for frontal cortex-dependent behaviors and cortico-cortical connectivity. Collectively, these results demonstrate dendritic disinhibition and elevated calcium levels in dendritic spines as important local-circuit alterations driven by the administration of subanesthetic ketamine.
Neuropilin 2 signaling mediates corticostriatal transmission, spine maintenance, and goal-directed learning in mice
Authors: Assous Maxime , Martinez Edward , Eisenberg Carol , Kosc Aleksandra , Varghese Kristie , Espinoza Diego , Bhimani Shaznaan , Shah Fulva , Tepper James M. , Shiflett Michael W. , Tran Tracy S.
Published: June 2019

The striatum represents the main input structure of the basal ganglia, receiving massive excitatory input from the cortex and the thalamus. The development and maintenance of cortical input to the striatum is crucial for all striatal function including many forms of sensorimotor integration, learning and action control. The molecular mechanisms regulating the development and maintenance of corticostriatal synaptic transmission are unclear. Here we show that the guidance cue, Semaphorin 3F and its receptor Neuropilin 2 (Nrp2), influence dendritic spine maintenance, corticostriatal short-term plasticity, and learning in adult male and female mice. We found that Nrp2 is enriched in adult layer V pyramidal neurons, corticostriatal terminals, and in developing and adult striatal spiny projection neurons (SPNs). Loss of Nrp2 increases SPN excitability and spine number, reduces short-term facilitation at corticostriatal synapses, and impairs goal-directed learning in an instrumental task. Acute deletion of Nrp2 selectively in adult layer V cortical neurons produces a similar increase in the number of dendritic spines and presynaptic modifications at the corticostriatal synapse in the Nrp2-/- mouse, but does not affect the intrinsic excitability of SPNs. Furthermore conditional loss of Nrp2 impairs sensorimotor learning on the accelerating rotarod without affecting goal-directed instrumental learning. Collectively, our results identify Nrp2 signaling as essential for the development and maintenance of the corticostriatal pathway and may shed novel insights on neurodevelopmental disorders linked to the corticostriatal pathway and semaphorin signaling.

Significance Statement

The corticostriatal pathway controls sensorimotor, learning and action control behaviors and its dysregulation is linked to neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here we demonstrate that neuropilin 2 (Nrp2), a receptor for the axon-guidance cue semaphorin 3F, has important and previously unappreciated functions in the development and adult maintenance of dendritic spines on striatal spiny projection neurons (SPNs), corticostriatal short-term plasticity, intrinsic physiological properties of SPNs and learning in mice. Our findings, coupled with Nrp2’s association with ASD in human populations, suggest that Nrp2 may play an important role in ASD pathophysiology. Overall, our work demonstrates Nrp2 as a key regulator of corticostriatal development, maintenance and function, and may lead to better understanding of neurodevelopmental disease mechanisms.
Baseline Semantic Fluency Is Associated with Six-Year Progression to Mild Cognitive Impairment in Middle-Aged Men
Authors: Gustavson Daniel E. , Elman Jeremy A. , Panizzon Matthew S. , Franz Carol E. , Zuber Jordan , Sanderson-Cimino Mark , Reynolds Chandra A. , Jacobson Kristen C. , Xian Hong , Jak Amy J. , Toomey Rosemary , Lyons Michael J. , Kremen William S.
Published: June 2019

Objective

Test the hypothesis that individual differences in episodic memory and verbal fluency in cognitively normal middle-aged adults will predict progression to amnestic MCI after 6 years.

Method

The analysis sample included 842 male twins who were cognitively normal at baseline (M=56 years), completed measures of episodic memory and verbal fluency at baseline and again 6 years later (M=62 years).

Results

Poor episodic memory predicted progression to both amnestic MCI (OR=4.42, 95% CI [2.44, 10.60]) and non-amnestic MCI (OR=1.92, 95% CI [1.32, 3.44]). Poor semantic verbal fluency also independently predicted progression to amnestic MCI (OR=1.86, 95% CI [1.12, 3.52]). In the full sample, a semantic-specific fluency latent variable at wave 1 (which controls for letter fluency) predicted change in episodic memory at wave 2 (β=.13), but not vice-versa (β=.04). Associations between episodic memory and verbal fluency factors were primarily explained by genetic, rather than environmental, correlations.

Conclusions

Among individuals who were cognitively normal at wave 1, episodic memory moderately-to-strongly predicted progression to MCI at average age 62, emphasizing the fact that there is still meaningful variability even among cognitively normal individuals. Episodic memory, which is typically a primary focus for AD risk, declined earlier and more quickly than fluency. However, semantic fluency at average age 56 predicted 6-year change in memory as well as progression to amnestic MCI even after accounting for baseline memory performance. These findings emphasize the utility of memory and fluency measures in early identification of AD risk.
Glioblastoma utilizes fatty acids and ketone bodies for growth allowing progression during ketogenic diet therapy
Authors: Sperry Jantzen , Condro Michael C. , Guo Lea , Braas Daniel , Vanderveer-Harris Nathan , Kim Kristen K.O. , Pope Whitney B. , Divakaruni Ajit S. , Lai Albert , Christofk Heather , Castro Maria G. , Lowenstein Pedro R. , Le Belle Janel E. , Kornblum Harley I.
Published: June 2019

Glioblastoma (GBM) metabolism has traditionally been characterized by a primary dependence on aerobic glycolysis, prompting the use of the ketogenic diet (KD) as a potential therapy. In this study we evaluated the effectiveness of the KD in GBM and assessed the role of fatty acid oxidation (FAO) in promoting GBM propagation. In vitro assays revealed FA utilization throughout the GBM metabolome, and growth inhibition in nearly every cell line in a broad spectrum of patient-derived glioma cells treated with FAO inhibitors. In vivo assessments revealed that knockdown of carnitine palmitoyltransferase 1A (CPT1A), the rate limiting enzyme for FAO, reduced the rate of tumor growth and increased survival. However, the unrestricted ketogenic diet did not reduce tumor growth, and for some models significantly reduced survival. Altogether, these data highlight important roles for FA and ketone body metabolism that could serve to improve targeted therapies in GBM.
Developmental myelination is modified by microglial pruning
Authors: Hughes Alexandria N. , Appel Bruce
Published: June 2019

During development, oligodendrocytes contact and wrap neuronal axons with myelin. Similar to neurons and synapses, excess myelin sheaths are produced and selectively eliminated. However, unlike these other structures, almost nothing is known about myelin sheath elimination. Microglia, the resident immune cells of the CNS, refine the developing CNS by engulfing surplus neurons and synapses. To determine if microglia also prune myelin sheaths, we used zebrafish to visualize and manipulate interactions between microglia, oligodendrocytes, and neurons during development. We found that microglia closely associate with oligodendrocytes and specifically phagocytose myelin sheaths. Silencing neuronal activity with botulinum toxin (BoNT/B) increased myelin engulfment by microglia. Furthermore, oligodendrocytes maintained excessive myelin sheaths following microglial ablation. Our work reveals a neuronal activity-regulated role for microglia in regulating myelination by oligodendrocytes.
Y-chromosome haplotypes of varying differentiation to the X are not associated with male fitness in common frogs
Authors: Veltsos Paris , Rodrigues Nicolas , Studer Tania , Ma Wen-Juan , Sermier Roberto , Leuenberger Julien , Perrin Nicolas
Published: June 2019

The canonical model of sex-chromosome evolution assigns a key role to sexually antagonistic (SA) genes on the arrest of recombination and ensuing degeneration of Y chromosomes. This assumption cannot be tested in organisms with highly differentiated sex chromosomes, such as mammals or birds, owing to the lack of polymorphism. Fixation of SA alleles, furthermore, might be the consequence rather than the cause of recombination arrest. Here we focus on a population of common frogs (Rana temporaria) where XY males with genetically differentiated Y chromosomes (non-recombinant Y haplotypes) coexist with both XY° males with proto-Y chromosomes (only differentiated from X chromosomes in the immediate vicinity of the candidate sex-determining locus Dmrt1) and XX males with undifferentiated sex chromosomes (genetically identical to XX females). Our study shows no effect of sex-chromosome differentiation on male phenotype, mating success or fathering success. Our conclusions rejoin genomic studies that found no differences in gene expression between XY, XY° and XX males. Sexual dimorphism in common frogs seems to result from the differential expression of autosomal genes rather than sex-linked SA genes. Among-male variance in sex-chromosome differentiation is better explained by a polymorphism in the penetrance of alleles at the sex locus, resulting in variable levels of sex reversal (and thus of X-Y recombination in XY females), independent of sex-linked SA genes.

Impact Summary

Humans, like other mammals, present highly differentiated sex chromosomes, with a large, gene-rich X chromosome contrasting with a small, gene-poor Y chromosome. This differentiation results from a process that started approximately 160 Mya, when the Y first stopped recombining with the X. How and why this happened, however, remain controversial. According to the canonical model, the process was initiated by sexually antagonistic selection; namely, selection on the proto-Y chromosome for alleles that were beneficial to males but detrimental to females. The arrest of XY recombination then allowed such alleles to be only transmitted to sons, not to daughters. Although appealing and elegant, this model can no longer be tested in mammals, as it requires a sex-chromosome system at an incipient stage of evolution. Here we focus on a frog that displays within-population polymorphism is sex-chromosome differentiation, where XY males with differentiated chromosomes coexist with XX males lacking Y chromosomes. We find no effect of sex-chromosome differentiation on male phenotype or mating success, opposing expectations from the standard model. Sex linked genes do not seem to have a disproportionate effect on sexual dimorphism. From our results, sexually antagonistic genes show no association with sex-chromosome differentiation in frogs, which calls for alternative models of sex-chromosome evolution.
Fungal Feature Tracker (FFT): A tool for quantitatively characterizing the morphology and growth of filamentous fungi
Authors: de Ulzurrun Guillermo Vidal-Diez , Huang Tsung-Yu , Chang Ching-Wen , Lin Hung-Che , Hsueh Yen-Ping
Published: June 2019

Filamentous fungi are ubiquitous in nature and serve as important biological models in various scientific fields including genetics, cell biology, ecology, evolution, and chemistry. A significant obstacle in studying filamentous fungi is the lack of tools for characterizing their growth and morphology in an efficient and quantitative manner. Consequently, assessments of the growth of filamentous fungi are often subjective and imprecise. In order to remedy this problem, we developed Fungal Feature Tracker (FFT), a user-friendly software comprised of different image analysis tools to automatically quantify different fungal characteristics, such as spore number, spore morphology, and measurements of total length, number of hyphal tips and the area covered by the mycelium. In addition, FFT can recognize and quantify specialized structures such as the traps generated by nematode-trapping fungi, which could be tuned to quantify other distinctive fungal structures in different fungi. We present a detailed characterization and comparison of a few fungal species as a case study to demonstrate the capabilities and potential of our software. Using FFT, we were able to quantify various features at strain and species level, such as mycelial growth over time and the length and width of spores, which would be difficult to track using classical approaches. In summary, FFT is a powerful tool that enables quantitative measurements of fungal features and growth, allowing objective and precise characterization of fungal phenotypes.

Author Summary

One of the main obstacles to study filamentous fungi is the lack of tools for characterizing fungal phenotypes in an efficient and quantitative manner. Assessment of cell growth and numbers rely on tedious manual techniques that often result in subjective and imprecise measurements. In response to those limitations, we developed Fungal Feature Tracker (FFT), a user-friendly software that allows researchers to characterize different phenotypic features of filamentous fungi such as sporulation, spore morphology and mycelial growth. In addition, FFT can recognize and quantify other fungal structures including the fungal traps developed by nematode-trapping fungi. In order to show the capabilities and potential of our software, we conducted a detailed characterization and comparison of different fungal species. Our comparison relies on a series of experimental set-ups using standard and easily accessible equipment to ensure reproducibility in other laboratories. In summary, FFT is an easy to use and powerful tool that can quantitatively characterize fungal morphology, cell number and quantitatively measures the filamentous growth, which will allow advance our understanding of the growth and biology of filamentous fungi.
Biophysical principles of choanoflagellate self-organization
Authors: Larson Ben T. , Ruiz-Herrero Teresa , Lee Stacey , Kumar Sanjay , Mahadevan L. , King Nicole
Published: June 2019

Inspired by the patterns of multicellularity in choanoflagellates, the closest living relatives of animals, we quantify the biophysical processes underlying the morphogenesis of rosette colonies in the choanoflagellateSalpingoeca rosetta. We find that rosettes reproducibly transition from an early stage of 2D growth to a later stage of 3D growth, despite the underlying stochasticity of the cell lineages. We postulate that the extracellular matrix (ECM) exerts a physical constraint on the packing of proliferating cells, thereby sculpting rosette morphogenesis. Our perturbative experiments coupled with biophysical simulations demonstrates the fundamental importance of a basally-secreted ECM for rosette morphogenesis. In addition, this yields a morphospace for the shapes of these multicellular colonies, consistent with observations of a range of choanoflagellates. Overall, our biophysical perspective on rosette development complements previous genetic perspectives and thus helps illuminate the interplay between cell biology and physics in regulating morphogenesis.

Significance statement

Comparisons among animals and their closest living relatives, the choanoflagellates, have begun to shed light on the origin of animal multicellularity and development. Here we complement previous genetic perspectives on this process by focusing on the biophysical principles underlying colony morphology and morphogenesis. Our study reveals the crucial role of the extracellular matrix in shaping the colonies and leads to a phase diagram that delineates the range of morphologies as a function of the biophysical mechanisms at play.
Yeast growth responses to environmental perturbations are associated with rewiring of large epistatic networks
Authors: Zan Yanjun , Carlborg Örjan
Published: June 2019

The phenotypic effects of genetic polymorphisms often depend on the genetic and environmental context. Here, we explore how polymorphic loci in large interaction networks contribute to complex trait variation and in particular how genetic effects and network topologies are influenced by environmental perturbations. This was done by reanalysing a dataset of >4,000 haploid yeast segregants grown on 20 different media. In total, 130 epistatic loci were associated with growth in at least one environment. The across-environment interaction network defined by these loci explained 69 - 100% of the narrow sense heritability in the individual environments. Environmental changes often resulted in network hubs being connected and disconnected from their interactors, leading to changes in additive effects of individual loci, epistatic effects of multi-locus interactions and the total level of genetic variance in growth. The largest variation in genetic effects across environments was found for epistatic loci that were highly connected network hubs in some environments but not in others. In environments where loci were highly connected, the segregating alleles epistatically suppressed or released genetic effects from their interactors. In environments where they were lowly connected, the same alleles made small or no contributions to growth. Hub-loci thus often serve as modulators, influencing the phenotypic effects of environmentally specific sets of interacting effector genes, rather than being effectors themselves. These findings illustrate the importance of the interplay between large genetic interactions networks and the living environment, both for individual phenotypes and population level metrics of genetic variation.
Isolation and characterization of toxic Cyanobacterial Communities distribution in Lake Tana, Amhara Regional state, Ethiopia
Authors: Admas Adugnaw , Agida Aklilue , Melese Smegnew , Genetu Amare
Published: June 2019

Lake Tana is the second largest lake next to Victoria Lake in Africa. This Lake is exsposed to agriculture run off, industrial and Urban waste since it has not buffer zone to protect any invading materials to the water body. The accumulation and growth of blue-green algae in water body call public attention because of its health concern. Some cyanobacterial species produce toxin microcystins and anatoxin molecules can affect the liver, kideney and nervous system of animals because the toxic molecules of released from some toxic cyanobacteria may lead the organs to fail the metabolice system. The major exposure pathways of these toxins are through drinking water and recreations including swimming. In addition, these problems happen through food web. Those cyanobacteria’a are spread and growth in diffrent water body via agriculture run off, industrial and urban wastes and other nutrient source of N and P. The main goal of this scientific study was to assess the distribution of potential toxic cyanobacteria in Lake Tana. Cyano bacterial distributions were studied in different water bodies of Lake Tana. From the water bodies that have visible algal blooms and not observed algal blooms were investigated. Identification of cyano bacteria was conducted using microscope by following appropriate procedures. In the present studied area Anabaena sp, Nostoc sp., Chlorella sp., and Microcystis aeruginosa sp. were dominantly exist. Therefore, Maybe the numbers of fishe depleted in Lake Tana due to the presence of microcystine molcule source, those are Anabaena sp.,Nostoc sp. and Microcystis aeruginosa sp.