bluuebunny/crossref_metadata_2025 huggingface dataset:
Perceptual decisions about object shape bias visuomotor coordination during rapid interception movements
Authors: Barany Deborah A. , Gómez-Granados Ana , Schrayer Margaret , Cutts Sarah A. , Singh Tarkeshwar
Published: October 2019

Visual processing in parietal areas of the dorsal stream facilitates sensorimotor transformations for rapid movement. This action-related visual processing is hypothesized to play a distinct functional role from the perception-related processing in the ventral stream. However, it is unclear how the two streams interact when perceptual identification is a prerequisite to executing an accurate movement. In the current study, we investigated how perceptual decision-making involving the ventral stream influences arm and eye movement strategies. Participants (N = 26) moved a robotic manipulandum using right whole-arm movements to rapidly reach a stationary object or intercept a moving object on an augmented-reality display. On some blocks of trials, participants needed to identify the shape of the object (circle or ellipse) as a cue to either hit the object (circle) or move to a pre-defined location away from the object (ellipse). We found that during perceptual decision-making, there was an increased urgency to act during interception movements relative to reaching, which was associated with more decision errors. Faster hand reaction times were correlated with a strategy to adjust the movement post-initiation, and this strategy was more prominent during interception. Saccadic reaction times were faster and initial gaze lags and gains greater during decisions, suggesting that eye movements adapt to perceptual demands for guiding limb movements. Together, our findings suggest that the integration of ventral stream information with visuomotor planning depends on imposed (or perceived) task demands.

New and Noteworthy

Visual processing for perception and for action are thought to be mediated by two specialized neural pathways. Using a visuomotor decision-making task, we show that participants differentially utilized online perceptual decision-making in reaching and interception, and that eye movements necessary for perception influenced motor decision strategies. These results provide evidence that task complexity modulates how pathways processing perception versus action information interact during the visual control of movement.
Bacterial metabolism rescues the inhibition of intestinal drug absorption by food and drug additives
Authors: Zou Ling , Spanogiannopoulos Peter , Chien Huan-Chieh , Pieper Lindsey M. , Cai Wenlong , Khuri Natalia , Pottel Joshua , Vora Bianca , Ni Zhanglin , Tsakalozou Eleftheria , Zhang Wenjun , Shoichet Brian K. , Giacomini Kathleen M. , Turnbaugh Peter J.
Published: October 2019

Food and drugs contain diverse small molecule additives (excipients) with unclear impacts on human physiology. Here, we evaluate their potential impact on intestinal absorption, screening 136 unique compounds for inhibition of the key transporter OATP2B1. We identified and validated 24 potent OATP2B1 transport inhibitors, characterized by higher molecular weight and hydrophobicity compared to poor or non-inhibitors. OATP2B1 inhibitors were also enriched for dyes, including 8 azo (R−N=N−R′) dyes. Pharmacokinetic studies in mice confirmed that FD&C Red No. 40, a common azo dye excipient, inhibited drug absorption; however, the human gut microbiome inactivated azo dye excipients, producing metabolites that no longer inhibit OATP2B1 transport. These results support a beneficial role for the microbiome in limiting the unintended effects of food and drug additives in the intestine.

One Sentence Summary

Food and drug additives inhibit intestinal drug transporters, although some are inactivated by gut bacterial metabolism.
An improved molecular tool for screening bacterial colonies using GFP expression enhanced by aDictyosteliumsequence
Authors: Kondo Tomo , Yumura Shigehiko
Published: October 2019

During molecular cloning, screening of bacterial transformants is a time-consuming and labor-intensive process. However, tractable tools that can be applied to various vectors for visual confirmation of desired colonies are limited. Recently, we reported that TED (translational enhancement by aDictyosteliumgene sequence) boosted protein expression even without an expression inducer inEscherichia coli. Here, we demonstrate a generally applicable molecular tool using the expression of green fluorescent protein (GFP) enhanced by TED. By inserting a module related to TED into the cloning site in advance, we effectively screenedE. colicolonies harboring the desired plasmid functions in a prokaryote (Magnetospirillum gryphiswaldense) or eukaryote (Dictyostelium discoideum). Thus, our system represents a user-friendly technique for cloning.
The stepwise endonuclease activity of a thermophilic Argonaute protein
Authors: Xun Guanhua , Liu Qian , Chong Yuesheng , Li Zhonglei , Guo Xiang , Li Yinhua , Fei He , Li Kai , Feng Yan
Published: October 2019

Thermophilic Argonaute proteins (Agos) can function as endonucleases via specific guide-target base-pairing cleavage for host defense. The ability to cleave target DNA sequences at any arbitrary sites endows them with reprogramed DNA capacity. Here, we identify that an Ago from the hyperthermophilic archaeon Pyrococcus furiosus (PfAgo) shows a stepwise endonuclease activity, which is demonstrated by the double strand DNA cleavage directed by a single guide DNA rather than canonical one pair of guide DNAs. We reveal that the cleavage products with 5’-phosphorylated ends can used as the renewed guide which is capable to induce next round of cleavage to complementary sequences of target DNA. By combining the PfAgo stepwise endonuclease activity followed by target DNA amplification, we establish a rapid and specific platform for the unambiguously multiplex gene detection, termed RADAR (Renewed-gDNA Assisted DNA-cleavage by Argonaute). In the end, RADAR was applied to distinguish of human papillomavirus of serotypes in patient samples in a single reaction, suggesting that our technique would be adopted for diagnosing application.
The methyltransferase DOT1L limits activation and the Th1 program in CD4+T cells during infection and inflammation
Authors: Scheer Sebastian , Runting Jessica , Bramhall Michael , Russ Brendan , Zaini Aidil , Ellemor Jessie , Rodrigues Grace , Ng Judy , Zaph Colby
Published: October 2019

CD4+T helper (Th) cell differentiation is controlled by lineage-specific expression of transcription factors and effector proteins, as well as silencing of lineage-promiscuous genes. Lysine methyltransferases (KMTs) comprise a major class of epigenetic enzymes that are emerging as important regulators of Th cell biology. Here, we show that the KMT DOT1L regulates Th cell function and lineage integrity. DOT1L-dependent dimethylation of lysine 79 of histone H3 (H3K79me2) is associated with lineage-specific gene expression. However, DOT1L-deficient Th cells overproduce IFN-γ under lineage-specific and lineage-promiscuous conditions. Consistent with the increased IFN-γ response, mice with a T cell-specific deletion of DOT1L are susceptible to infection with the helminth parasiteTrichuris murisand resistant to the development of allergic lung inflammation. These results identify a central role for DOT1L in Th cell lineage commitment and stability, and suggest that inhibition of DOT1L may provide a novel therapeutic strategy to limit type 2 immune responses.
Differential expression of deltaFosB in reward processing regions between binge eating prone and resistant female rats
Authors: Amissah Richard Quansah , Chometton Sandrine , Calvez Juliane , Guèvremont Genevieve , Timofeeva Elena , Timofeev Igor
Published: October 2019

Binge eating disorder (BED) is characterized by bingeing and compulsivity. Even though BED is the most prevalent eating disorder, little is known about its pathophysiology. We aimed to identify brain regions and neuron subtypes implicated in the development of binge-like eating in a female rat model. We separated rats into binge eating prone (BEP) and binge eating resistant (BER) phenotypes based on the amount of sucrose they consumed following foot-shock stress. We quantified deltaFosB (ΔFosB) expression to assess chronic neuronal activation during phenotyping. The number of ΔFosB-expressing neurons was: 1) higher in BEP than BER rats in reward processing areas (medial prefrontal cortex (mPFC), nucleus accumbens (Acb), and ventral tegmental area (VTA)); 2) similar in taste processing areas (insular cortex and parabrachial nucleus); 3) higher in the paraventricular nucleus of BEP than BER rats, but not different in the locus coeruleus, which are stress processing structures. To study subtypes of ΔFosB-expressing neurons in the reward system, we performed in situ hybridization for glutamate decarboxylase 65 and tyrosine hydroxylase mRNA after ΔFosB immunohistochemistry. In the mPFC and Acb, the proportions of gamma-aminobutyric acidergic (GABAergic) and non-GABAergic ΔFosB-expressing neurons were similar in BER and BEP rats. In the VTA, while the proportion of dopaminergic ΔFosB-expressing neurons was similar in both phenotypes, the proportion of GABAergic ΔFosB-expressing neurons was higher in BER than BEP rats. Our results suggest that reward processing brain regions, particularly the VTA, are important for the development of binge-like eating.

Significance

Because ΔFosB expression is associated with a reduction of activity in neurons, a higher expression of ΔFosB in the mPFC, Acb, and VTA of binge eating prone rats compared to binge eating resistant rats suggests a decrease in neuronal activity in these regions, which is consistent with results observed in neuroimaging studies in binge eating disorder patients. This decrease in activity due to ΔFosB expression may underlie the compulsivity and overconsumption of palatable food observed in both our rat model of binge-like eating and binge eating disorder patients.
The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death
Authors: Vanzyl Erin J. , Sayed Hadil , Blackmore Alex B. , Rick Kayleigh R.C. , Fernando Pasan , McKay Bruce C.
Published: October 2019

The spliceosome assembles on pre-mRNA in a stepwise manner through five successive pre-spliceosome complexes. The spliceosome functions to remove introns from pre-mRNAs to generate mature mRNAs that encode functional proteins. Many small molecule inhibitors of the spliceosome have been identified and they are cytotoxic. However, little is known about genetic determinants of cell sensitivity. Activating transcription factor 3 (ATF3) is a transcription factor that can stimulate apoptotic cell death in response to a variety of cellular stresses. Here, we used a genetic approach to determine if ATF3 was important in determining the sensitivity of mouse embryonic fibroblasts (MEFs) to two splicing inhibitors: pladienolide B (PB) and isoginkgetin (IGG), that target different pre-spliceosome complexes. Both compounds led to increased ATF3 expression and apoptosis in control MEFs while ATF3 null cells were significantly protected from the cytotoxic effects of these drugs. Similarly, ATF3 was induced in response to IGG and PB in the two human tumour cell lines tested while knockdown of ATF3 protected cells from both drugs. Taken together, ATF3 appears to contribute to the cytotoxicity elicited by these spliceosome inhibitors in both murine and human cells.
Social and endogenous infant vocalizations
Authors: Long Helen L. , Bowman Dale , Yoo Hyunjoo , Burkhardt-Reed Megan M. , Bene Edina R. , Oller D. Kimbrough
Published: October 2019

Research on infant vocal development has provided notable insights into vocal interaction with caregivers, elucidating growth in foundations for language through parental elicitation and reaction to vocalizations. A role for infant vocalizations produced endogenously, potentially providing raw material for interaction and a basis for growth in the vocal capacity itself, has received less attention. We report that in laboratory recordings of infants and their parents, the bulk of infant speech-like vocalizations, or “protophones”, were directed toward no one and instead appeared to be generated endogenously, mostly in exploration of vocal abilities. The tendency to predominantly produce protophones without directing them to others occurred both during periods when parents were instructed to interact with their infantsandduring periods when parents were occupied with an interviewer, with the infants in the room. The results emphasize the infant as an agent in vocal learning, even when not interacting socially and suggest an enhanced perspective on foundations for vocal language.
Screening of Tau Protein Kinase Inhibitors in a Tauopathy-relevant cell-based model of Tau Hyperphosphorylation and Oligomerization
Authors: Yadikar Hamad , Torres Isabel , Aiello Gabrielle , Kurup Milin , Yang Zhihui , Lin Fan , Kobeissy Firas , Yost Richard , Wang Kevin K.
Published: October 2019

Tauopathies are a class of neurodegenerative disorders characterized by abnormal deposition of post-translationally modified tau protein in the human brain. Tauopathies are associated with Alzheimer’s disease (AD), chronic traumatic encephalopathy (CTE), and other diseases. Hyperphosphorylation increases tau tendency to aggregate and forms neurofibrillary tangles (NFT), a pathological hallmark of AD. In this study, okadaic acid (OA, 100 nM), a protein phosphatase 1/2A inhibitor, was treated for 24h in mouse neuroblastoma (N2a) and differentiated rat primary neuronal cortical cell cultures (CTX) to induce tau-hyperphosphorylation and oligomerization as a cell-based tauopathy model. Following the treatments, the effectiveness of different kinase inhibitors was assessed using the tauopathy-relevant tau antibodies through tau-immunoblotting, including the sites: pSer202/pThr205 (AT8), pThr181 (AT270), pSer202 (CP13), pSer396/pSer404 (PHF-1), and pThr231 (RZ3). OA-treated samples induced tau phosphorylation and oligomerization at all tested epitopes, forming a monomeric band (46-67 kDa) and oligomeric bands (170 kDa and 240 kDa). We found that TBB (a casein kinase II inhibitor), AR and LiCl (GSK-3 inhibitors), cyclosporin A (calcineurin inhibitor), and Saracatinib (Fyn kinase inhibitor) caused robust inhibition of OA-induced monomeric and oligomeric p-tau in both N2a and CTX culture. Additionally, a cyclin-dependent kinase 5 inhibitor (Roscovitine) and a calcium chelator (EGTA) showed conflicting results between the two neuronal cultures.This study provides a comprehensive view of potential drug candidates (TBB, CsA, AR, and Saracatinib), and their efficacy against tau hyperphosphorylation and oligomerization processes. These findings warrant further experimentation, possibly including animal models of tauopathies, which may provide a putative Neurotherapy for AD, CTE, and other forms of tauopathy-induced neurodegenerative diseases.
Divergent excitation two photon microscopy for 3D random access mesoscale imaging at single cell resolution
Authors: Janiak FK , Bartel P , Bale MR , Yoshimatsu T , Komulainen E , Zhou M , Staras K , Prieto-Godino LL , Euler T , Maravall M , Baden T
Published: October 2019

ABSTACT

In neuroscience, diffraction limited two-photon (2P) microscopy is a cornerstone technique that permits minimally invasive optical monitoring of neuronal activity. However, most conventional 2P microscopes impose significant constraints on the size of the imaging field-of-view and the specific shape of the effective excitation volume, thus limiting the scope of biological questions that can be addressed and the information obtainable. Here, employing ‘divergent beam optics’ (DBO), we present an ultra-low-cost, easily implemented and flexible solution to address these limitations, offering a several-fold expanded three-dimensional field of view that also maintains single-cell resolution. We show that this implementation increases both the space-bandwidth product and effective excitation power, and allows for straight-forward tailoring of the point-spread-function. Moreover, rapid laser-focus control via an electrically tunable lens now allows near-simultaneous imaging of remote regions separated in three dimensions and permits the bending of imaging planes to follow natural curvatures in biological structures. Crucially, our core design is readily implemented (and reversed) within a matter of hours, and fully compatible with a wide range of existing 2P customizations, making it highly suitable as a base platform for further development. We demonstrate the application of our system for imaging neuronal activity in a variety of examples in mice, zebrafish and fruit flies.
Biosynthesis of the redox cofactor mycofactocin comprises oligoglycosylation by MftF in Mycolicibacterium smegmatis
Authors: Peña-Ortiz Luis , Graça Ana Patrícia , Guo Huijuan , Braga Daniel , Köllner Tobias G. , Regestein Lars , Beemelmanns Christine , Lackner Gerald
Published: October 2019

Mycofactocin (MFT) is a redox cofactor involved in alcohol metabolism of mycobacteria including Mycobacterium tuberculosis. In recent years, a preliminary biosynthetic model of MFT has been established by in-vitro studies, while the final structure of MFT remained elusive. Here, we report the discovery of MFT by metabolomics and establish a model of its biosynthesis in Mycolicibacterium smegmatis. Structure elucidation revealed that MFT is decorated with up to nine β-1,4-linked glucose residues. Dissection of biosynthetic genes demonstrated that the oligoglycosylation is catalyzed by the glycosyltransferase MftF. Furthermore, we confirm the cofactor function of MFT by activity-based metabolic profiling using the carveol dehydrogenase LimC and show that the MFT pool expands during cultivation on ethanol. Our results close an important gap of knowledge, will guide future studies into the physiological roles of MFT in bacteria and may inspire its utilization as a biomarker or potential drug target to combat mycobacterial diseases.
Ten-eleven translocation 1 Mediated-DNA Hydroxymethylation is Required for Myelination and Remyelination in the Mouse Brain
Authors: Zhang Ming , Wang Jian , Zhang Kaixiang , Lu Guozhen , Liu Yuming , Ren Keke , Wang Wenting , Xin Dazhuan , Xu Lingli , Mao Honghui , Xing Junlin , Gao Xingchun , Jin Weilin , Berry Kalen , Mikoshiba Katsuhiko , Wu Shengxi , Lu Q. Richard , Zhao Xianghui
Published: October 2019

Ten-eleven translocation (TET) proteins, the dioxygenase for DNA hydroxymethylation, are important players in nervous system development and diseases. However, their role in myelination and remyelination after injury remains elusive. Here, we identify a genome-wide and locus-specific DNA hydroxymethylation landscape shift during differentiation of oligodendrocyte-progenitor cells (OPC). Ablation of Tet1 results in stage-dependent defects in oligodendrocyte (OL) development and myelination in the mouse brain. The mice lacking Tet1 in the oligodendrocyte lineage develop behavioral deficiency. We also show that TET1 is required for remyelination in adulthood. Transcriptomic, genomic occupancy, and DNA hydroxymethylation profiling reveal a critical TET1-regulated epigenetic program for oligodendrocyte differentiation that includes genes associated with myelination, cell division, and calcium transport. Tet1-deficient OPCs exhibit reduced calcium activity, increasing calcium activity rescues the differentiation defects in vitro. Deletion of a TET1-5hmC target gene, Itpr2 impairs the onset of OPC differentiation. Together, our results suggest that stage-specific TET1-mediated epigenetic programming and intracellular signaling are important for proper myelination and remyelination in mice.
Dual Histone Methyl Reader ZCWPW1 Facilitates Repair of Meiotic Double Strand Breaks
Authors: Mahgoub Mohamed , Paiano Jacob , Bruno Melania , Wu Wei , Pathuri Sarath , Zhang Xing , Ralls Sherry , Cheng Xiaodong , Nussenzweig Andre , Macfarlan Todd
Published: October 2019

Meiotic crossovers result from homology-directed repair of double strand breaks (DSBs). Unlike yeast and plants, where DSBs are generated near gene promoters, in many vertebrates, DSBs are enriched at hotspots determined by the DNA binding activity of the rapidly evolving zinc finger array of PRDM9 (PR domain zinc finger protein 9). PRDM9 subsequently catalyzes tri-methylation of lysine 4 and lysine 36 of Histone H3 in nearby nucleosomes. Here, we identify the dual histone methylation reader ZCWPW1, which is tightly co-expressed during spermatogenesis withPrdm9and co-evolved withPrdm9in vertebrates, as an essential meiotic recombination factor required for efficient synapsis and repair of PRDM9-dependent DSBs. In sum, our results indicate that the evolution of a dual histone methylation writer/reader system in vertebrates facilitated a shift in genetic recombination away from a static pattern near genes towards a flexible pattern controlled by the rapidly evolving DNA binding activity of PRDM9.
Prostaglandins regulate invasive, collective border cell migration
Authors: Fox Emily F. , Lamb Maureen C. , Mellentine Samuel Q. , Tootle Tina L.
Published: October 2019

While prostaglandins (PGs), short-range lipid signals, regulate cell migration, their mechanisms of action are poorly understood in collective migration. To address this, we useDrosophilaborder cell migration during Stage 9 of oogenesis. The border cells delaminate from the epithelium, and migrate collectively and invasively between the nurse cells. Pxt is theDrosophilacyclooxygenase-like enzyme responsible for all PG synthesis. Loss of Pxt results in both a significant delay in border cell migration during Stage 9 and an increase in cluster length compared to wild-type controls. Contributing to these phenotypes is altered integrin localization. Integrins are enriched on the border cell membranes, and this enrichment is lost inpxtmutants. Active integrins require interaction with the actin cytoskeleton. As we previously found PGs regulate the actin bundler Fascin and Fascin is required for border cell migration, we hypothesized PGs regulate Fascin to control integrins. Supporting this, loss of Fascin results in apxt-like integrin localization, and dominant genetic interaction studies reveal that co-reduction of Pxt and Fascin results in delayed and elongated border cell clusters. Together these data lead to the model that PG signaling controls Fascin, and thereby integrins, to mediate on-time border cell migration and maintain cluster cohesion.
EEG state-trajectory instability and speed reveal global rules of intrinsic spatiotemporal neural dynamics
Authors: Menceloglu Melisa , Grabowecky Marcia , Suzuki Satoru
Published: October 2019

Spatiotemporal dynamics of EEG/MEG (electro-/magneto-encephalogram) have typically been investigated by applying time-frequency decomposition and examining amplitude-amplitude, phase-phase, or phase-amplitude associations between combinations of frequency bands and scalp sites, primarily to identify neural correlates of behaviors and traits. Instead, we directly extracted global EEG spatiotemporal dynamics as trajectories of k-dimensional state vectors (k = the number of estimated current sources) to investigate potential global rules governing neural dynamics. We chose timescale-dependent measures of trajectory instability (approximately the 2nd temporal derivative) and speed (approximately the 1st temporal derivative) as state variables, that succinctly characterized trajectory forms. We compared trajectories across posterior, central, anterior, and lateral scalp regions as the current sources under those regions may serve distinct functions. We recorded EEG while participants rested with their eyes closed (likely engaged in spontaneous thoughts) to investigate intrinsic neural dynamics. Some potential global rules emerged. Time-averaged trajectory instability from all five regions tightly converged (with their variability minimized) at the level of generating nearly unconstrained but slightly conservative turns (∼100° on average) on the timescale of ∼25 ms, suggesting that spectral-amplitude profiles are globally adjusted to maintain this convergence. Further, within-frequency and cross-frequency phase relations appear to be independently coordinated to reduce average trajectory speed and increase the variability in trajectory speed and instability in a relatively timescale invariant manner, and to make trajectories less oscillatory. Future research may investigate the functional relevance of these intrinsic global-dynamics rules by examining how they adjust to various sensory environments and task demands or remain invariant. The current results also provide macroscopic constraints for quantitative modeling of neural dynamics as the timescale dependencies of trajectory instability and speed are relatable to oscillatory dynamics.
Nanog safeguards early embryogenesis against global activation of maternal β-catenin activity by interfering with TCF factors
Authors: He Mudan , Zhang Ru , Zhang Fenghua , Jiao Shengbo , Ye Ding , Wang Houpeng , Sun Yonghua
Published: October 2019

Maternal β-catenin activity is essential and critical for dorsal induction and its dorsal activation has been thoroughly studied. However, how the maternal β-catenin activity is suppressed in the non-dorsal cells remains poorly understood. Nanog is known to play a central role for maintenance of the pluripotency and maternal-to-zygotic transition. Here we reveal a novel role of Nanog as a strong repressor of maternal Wnt/β-catenin signaling to safeguard the embryo against hyper-activation of maternal β-catenin activity and hyper-dorsalization. Knockdown ofnanogat different levels led to either posteriorization or dorsalization, mimicking zygotic or maternal activation of Wnt/β-catenin activities, and the maternal-zygotic mutant ofnanog(MZnanog) showed strong activation of maternal β-catenin and hyper-dorsalization. Although a constitutive-activator-type Nanog (Vp16-Nanog, lacking the N-terminal) perfectly rescued the defects of maternal to zygotic transition in MZnanog, it did not rescue the phenotypes resulting from β-catenin activation. Mechanistically, the N-terminal of Nanog directly interacts with TCF and interferes with the binding of β-catenin to TCF, thereby attenuating the transcriptional activity of β-catenin. Therefore, our study establishes a novel role for Nanog in repressing maternal β-catenin activity and demonstrates a transcriptional switch between β-catenin/TCF and Nanog/TCF complexes, which safeguards the embryo from global activation of maternal β-catenin activity.
Neuronal transcriptome analyses reveal novel neuropeptide modulators of excitation and inhibition imbalance in C. elegans
Authors: McCulloch Katherine A. , Zhou Kingston , Jin Yishi
Published: October 2019

Neuropeptides are secreted molecules that have conserved roles modulating many processes, including mood, reproduction, and feeding. Dysregulation of neuropeptide signaling is also implicated in neurological disorders such as epilepsy. However, much is unknown about the mechanisms regulating specific neuropeptides to mediate behavior. Here, we report that the expression levels of dozens of neuropeptides are up-regulated in response to circuit activity imbalance in C. elegans. acr-2 encodes a homolog of human nicotinic receptors, and functions in the cholinergic motoneurons. A hyperactive mutation, acr-2(gf), causes an activity imbalance in the motor circuit. We performed cell-type specific transcriptomic analysis and identified genes differentially expressed in acr-2(gf), compared to wild type. The most over-represented class of genes are neuropeptides, with insulin-like-peptides (ILPs) the most affected. Moreover, up-regulation of neuropeptides occurs in motoneurons, as well as sensory neurons. In particular, the induced expression of the ILP ins-29 occurs in the BAG neurons, which are previously shown to function in gas-sensing. We also show that this up-regulation of ins-29 in acr-2(gf) animals is activity-dependent. Our genetic and molecular analyses support cooperative effects for ILPs and other neuropeptides in promoting motor circuit activity in the acr-2(gf) background. Together, this data reveals that a major transcriptional response to motor circuit dysregulation is in up-regulation of multiple neuropeptides, and suggests that BAG sensory neurons can respond to intrinsic activity states to feedback on the motor circuit.

AUTHOR SUMMARY

Neuropeptides are secreted small molecules that regulate a variety of neuronal functions and are also implicated in many diseases. However, it remains poorly understood how expression of neuropeptides is regulated, particularly in disease states. Using a genetic animal model that mimics epilepsy, we identified dozens of neuropeptides that are up-regulated when neuronal activities are altered. Some of these neuropeptides share similarity to insulin-like properties (ILPs). Strikingly, one of these ILPs is expressed in sensory neurons that normally respond to acute carbon dioxide exposure. We show that the mis-regulation of this ILP expression is activity-dependent. Moreover, these neuropeptides act in concert to modulate animal behaviors. The findings in this study provide further evidence that neuropeptides are key mediators of aberrant cholinergic signaling, and suggest complex neural network effects from sensory neurons onto motor function.
Land productivity dynamics in and around protected areas globally from 1999 to 2013
Authors: de la Fuente Begoña , Weynants Mélanie , Bertzky Bastian , Delli Giacomo , Mandrici Andrea , Bendito Eduardo Garcia , Dubois Grégoire
Published: October 2019

Tracking changes in total biomass production or land productivity is an essential part of monitoring land transformations and long-term alterations of the health and productive capacity of land that are typically associated with land degradation. Persistent declines in land productivity impact many terrestrial ecosystem services that form the basis for sustainable livelihoods of human communities. Protected areas (PAs) are a key strategy in global efforts to conserve biodiversity and ecosystem services that are critical for human well-being, and cover about 15% of the land worldwide. Here we globally assess the trends in land productivity in PAs of at least 10 km2and in their unprotected surroundings (10 km buffers) from 1999 to 2013. We quantify the percentage of the protected and unprotected land that shows stable, increasing or decreasing trends in land productivity, quantified as long-term (15 year) changes in above-ground biomass derived from satellite-based observations with a spatial resolution of 1 km. We find that 44% of the land in PAs globally has retained the productivity at stable levels from 1999 to 2013, compared to 42% of stable productivity in the unprotected land around PAs. Persistent increases in productivity are more common in the unprotected lands around PAs (32%) than within PAs (18%) globally, which may be related to more active management and vegetation cover changes in some of these unprotected lands. About 14% of the protected land and 12% of the unprotected land around PAs has experienced declines in land productivity from 1999 to 2013 globally. Oceania has the highest percentage of land with stable productivity in PAs (57%) followed by Asia (52%). Europe is the continent with the lowest percentage of land with stable productivity levels in PAs (38%) and with the largest share of protected land with increasing land productivity (32%), which may be related to the high population density and share of agricultural land within PAs as well as to rural land abandonment processes in many regions of Europe. In conclusion, we provide a relevant indicator and assessment of land productivity dynamics that contributes to characterise the state, pressures and changes in and around protected areas globally. Further research may focus on more detailed analyses to disentangle the relative contribution of specific drivers (from climate change to land use change) and their interaction with land productivity dynamics and potential land degradation in different regions of the world.
Anlotinib overcomes multiple drug resistant of the colorectal cancer cells via inactivating PI3K/AKT pathway
Authors: Lan Weilan , Zhao Jinyan , Shang Haixia , Peng Jun , Chen Wujin , Lin Jiumao
Published: October 2019

Background

Anlotinib is a multi-tyrosine kinase inhibitor that has been reported to have activity against colorectal cancer. However, the functional mechanisms whereby anlotinib mediates against deadly drug-resistant colorectal cancer (CRC) has not been fully described-specifically, the potential mechanisms that inhibit proliferation and induce apoptosis remain largely unknown.

Methods

MTT assays were used to detect cell viability and calculate the resistance index. Colony formation was used to evaluate the proliferation of resistant cells. DAPI staining was used to detect cell apoptosis morphologically. Annexin V-FITC with PI staining was used to detect early and late-stage apoptosis of cells. Cell cycle distribution was determined by Flow cytometry. Transwell assays were performed to examine the ability of migration and invasion. Cyclin D1 Survivin, CDK4, Bcl-2, Bax and changes of PI3K/AKT pathway were detected by Western blotting. Compared as a single agent or combined with anlotinib or LY294002, PI3K inhibitor (LY294002) was used to verify whether it inhibited drug-resistant CRC cells by lowering PI3K/AKT.

Results

HCT-8/5-FU cells showed multiple drug resistance. Drug resistance index of 5-FU, ADM and DDP were 390.27, 2.55 and 4.57, respectively. Anlotinib was shown to inhibit cell viability on HCT-8/5-FU and HCT-8 cells for 24 h and 48 h in a dosage- and time-dependent pattern. Compared with 48 h, intervened with anlotinib (0 μM, 10 μM, 20 μM and 40 μM) for 24 h, the HCT-8/5-FU cells were sensitive to anlotinib, and their sensitivity was greater than that of the parent cell line (HCT-8) at 24 h. Further, anlotinib inhibited the number of cloned cells significantly and had a significant inhibitory effect on cell cycle, mainly by blocking G1 transferring to S phase. Moreover, anlotinib could down-regulate the expression of survivin, cyclin D1, CDK4, caspase-3, Bcl-2, MMP-2, vimentin, MMP-9, and N-cadherin, while up-regulating cleaved-caspase-3, Bax and E-cadherin. Anlotinib inhibited the activity of the PI3K/AKT pathway and induced apoptosis in HCT-8/5-FU cells. Using LY294002, a specific PI3K inhibitor, our experiment found anlotinib can inhibit drug-resistant CRC cells by reducing PI3K and p-AKT activity-induce apoptosis.

Conclusions

Anlotinib inhibited the proliferation, metastasis and induced apoptosis of HCT-8 / 5-FU cells; and the mechanism could be that anlotinib overcomes multiple drug resistant of the colorectal cancer cells via inactivating PI3K/AKT pathway.
Torsin ATPases are required to complete nuclear pore complex biogenesis in interphase
Authors: Rampello Anthony J. , Laudermilch Ethan , Vishnoi Nidhi , Prohet Sarah M. , Shao Lin , Zhao Chenguang , Lusk C. Patrick , Schlieker Christian
Published: October 2019

Nuclear envelope herniations (blebs) containing FG-nucleoporins and ubiquitin are the phenotypic hallmark of Torsin ATPase manipulation. Both the dynamics of blebbing and the connection to nuclear pore biogenesis remain poorly understood. We employ a proteomics-based approach to identify MLF2 as a luminal component of the bleb. Using an MLF2-based live cell imaging platform, we demonstrate that NE blebbing occurs rapidly and synchronously immediately after nuclear envelope reformation during mitosis. Bleb formation is independent of ubiquitin conjugation within the bleb, but strictly dependent on POM121, a transmembrane nucleoporin essential for interphase nuclear pore biogenesis. Nup358, a late marker for interphase nuclear pore complex (NPC) biogenesis, is underrepresented relative to FG nucleoporins in nuclear envelopes of Torsin-deficient cells. The kinetics of bleb formation, its dependence on POM121, and a reduction of mature NPCs in Torsin deficient cells lead us to conclude that the hallmark phenotype of Torsin manipulation represents the accumulation of stalled NPC assembly intermediates.
Low-cost open hardware system for behavioural experiments simultaneously with electrophysiological recordings
Authors: Aguiar Leandro A. A. , de Vasconcelos Nivaldo A P , Tunes Gabriela Chiuffa , Fontenele Antonio J. , de Albuquerque Nogueira Romildo , Reyes Marcelo Bussotti , Carelli Pedro V.
Published: October 2019

A major frontier in neuroscience is to find neural correlates of perception, learning, decision making, and a variety of other types of behavior. In the last decades, modern devices allow simultaneous recordings of different operant responses and the electrical activity of large neuronal populations. However, the commercially available instruments for studying operant conditioning are expensive, and the design of low-cost chambers has emerged as an appealing alternative to resource-limited laboratories engaged in animal behavior. In this article, we provide a full description of a platform that records the operant behavior and synchronizes it with the electrophysiological activity. The programming of this platform is open source, flexible and adaptable to a wide range of operant conditioning tasks. We also show results of operant conditioning experiments with freely moving rats with simultaneous electrophysiological recordings.

Specifications table
Quantitative modeling of the function of kinetically driven transcriptional riboswitches
Authors: Parra-Rojas César , Fürtig Boris , Schwalbe Harald , Hernandez-Vargas Esteban A.
Published: October 2019

We propose a generalized modeling framework for the kinetic mechanisms of transcriptional riboswitches. The formalism accommodates time-dependent transcription rates and changes of metabolite concentration and permits incorporation of variations in transcription rate depending on transcript length. We derive explicit analytical expressions for the fraction of transcripts that determine repression or activation of gene expression, pause site location and its slowing down of transcription for the case of the (2’dG)-sensing riboswitch fromMesoplasma florum. Our modeling challenges the current view on the exclusive importance of metabolite binding to transcripts containing only the aptamer domain. Numerical simulations of transcription proceeding in a continuous manner under time-dependent changes of metabolite concentration further suggest that rapid modulations in concentration result in a reduced dynamic range for riboswitch function regardless of transcription rate, while a combination of slow modulations and small transcription rates ensures a wide range of finely tuneable regulatory outcomes.
Metabolic cross-feeding allows a gut microbial community to overcome detrimental diets and alter host behaviour
Authors: Henriques Sílvia F. , Serra Lúcia , Francisco Ana Patrícia , Carvalho-Santos Zita , Baltazar Célia , Elias Ana Paula , Anjos Margarida , Zhang Tong , Maddocks Oliver D. K. , Ribeiro Carlos
Published: October 2019

The impact of commensal bacteria on the host arises from complex microbial-diet-host interactions. Mapping metabolic interactions in gut microbial communities is therefore key to understand how the microbiome influences the host. Here we use an interdisciplinary approach including isotope-resolved metabolomics to show that inDrosophila melanogaster, Aceto-bacter pomorum(Ap) andLactobacillus plantarum(Lp) establish a syntrophic relationship to overcome detrimental host diets and identifyApas the bacterium altering the host’s feeding decisions. Specifically, we show thatLpgenerates lactate which is used byApto produce and provide amino acids that are essential toLpallowing it to grow in imbalanced diets. Lactate is also necessary and sufficient forApto alter the fly’s protein appetite. Our data show that gut bacterial communities use metabolic interactions to become resilient to detrimental host diets and to ensure the constant flow of metabolites used by effector bacteria to alter host behaviour.
PTP-MEG2 regulates quantal size and fusion pore opening through two distinct structural bases and substrates
Authors: Xu Yun-Fei , Chen Xu , Yang Zhao , Xiao Peng , Liu Chun-Hua , Li Kang-Shuai , Yang Xiao-Zhen , Wang Yi-Jing , Zhu Zhong-Liang , Xu Zhi-Gang , Zhang Sheng , Wang Chuan , Song You-Chen , Zhao Wei-Dong , Wang Chang-He , Ji Zhi-Liang , Zhang Zhong-Yin , Cui Min , Sun Jin-Peng , Yu Xiao
Published: October 2019

Tyrosine phosphorylation of secretion machinery proteins is a crucial regulatory mechanism for exocytosis. However, the participation of protein tyrosine phosphatases (PTPs) in different exocytosis stages has not been defined. Here we demonstrated that PTP-MEG2 controls multiple steps of catecholamine secretion. Biochemical and crystallographic analyses revealed key residues that the interactions between govern the PTP-MEG2 and NSF-pY83 site, specify PTP-MEG2 substrate selectivity and modulate the fusion of catecholamine-containing vesicles. Unexpectedly, delineation of PTP-MEG2 mutants along with the NSF binding interface revealed that PTP-MEG2 controls the fusion pore opening through non-NSF dependent mechanisms. Utilizing bioinformatics search and biochemical and electrochemical screening approaches, we discovered that PTP-MEG2 regulates the opening and extension of the fusion pore by dephosphorylating the DYNAMIN2-pY125 and MUNC18-1-pY145 site. Further structural and biochemical analysis confirmed the interaction of PTP-MEG2 with MUNC18-1-pY145 or DYNAMIN2-pY125 through a distinct structural basis compared with that of the NSF-pY83 site. Our studies extended mechanistic insights in complex exocytosis processes.

HIGHLIGHTS

PTP-MEG2 regulates multiple steps of exocytosis.

A crystal structure of the PTP-MEG2/phosphor-NSF-pY83 segment was obtained.

Functional delineation of the PTP-MEG2/NSF interface led to the discovery of new PTP-MEG2 substrates.

PTP-MEG2 regulates fusion pore opening and extension through the DYNAMIN2-pY125 site and MUNC18-1 pY145 site.

The distinct structural basis of the recognition of substrates by PTP-MEG2 allows selective inhibitor design.
Roles of adenine methylation and genetic mutations in adaptation to different temperatures in Serratia marcescens
Authors: Bruneaux Matthieu , Kronholm Ilkka , Ashrafi Roghaieh , Ketola Tarmo
Published: October 2019

Epigenetic modifications can contribute to adaptation, but the relative contributions of genetic and epigenetic variation are unknown. Previous studies on the role of epigenetic changes in adaptation in eukaryotes have nearly exclusively focused on cytosine methylation (m5C), while prokaryotes exhibit a richer system of methyltransferases targetting adenines (m6A) or cytosines (m4C, m5C). DNA methylation in prokaryotes has many roles, but its potential role in adaptation still needs further investigation. We collected phenotypic, genetic, and epigenetic data using single molecule real-time sequencing of clones of the bacterium Serratia marcescens that had undergone experimental evolution in contrasting temperatures to investigate the relationship between environment and genetic, epigenetic, and phenotypic changes. This data provided a detailed description of the methylation landscape of S. marcescens and allowed us to examine the potential contributions of genetic and epigenetic changes to phenotypic adaptation. The genomic distribution of GATC motifs, which are the main target for m6A methylation, and of partially methylated epiloci pointed to a link between m6A methylation and regulation of gene expression in S. marcescens. Evolved strains, while genetically homogeneous, exhibited many polymorphic m6A epiloci. There was no strong support for a genetic control of methylation changes in our experiment, and no clear evidence of parallel environmentally-induced or environmentally-selected methylation changes at specific epiloci was found. Both some genetic and epigenetic variants were associated with some phenotypic traits. Overall, our results suggest that both genetic and adenine methylation changes have potential to contribute to phenotypic adaptation in S. marcescens, but that any environmentally-induced epigenetic change occurring in our experiment would probably have been quite labile.
Optimizing the Accuracy of Cortical Volumetric Analysis in Traumatic Brain Injury
Authors: Diamond Bram R. , Mac Donald Christine L. , Snider Samuel B. , Fischl Bruce , Dams-O’Connor Kristen , Edlow Brian L.
Published: October 2019

Cortical volumetric analysis is widely used to study the anatomic basis of neurological deficits in patients with traumatic brain injury (TBI). However, patients with TBI-related lesions are often excluded from analysis, because cortical lesions may compromise the accuracy of reconstructed surfaces upon which volumetric measurements are based. Here, we propose a novel FreeSurfer-based lesion correction method and illustrate its impact on cortical volume measures in patients with chronic moderate-to-severe TBI. We performed MRI in 87 patients at mean+/−SD 10.9+/−9.1 years post-injury using a T1-weighted multi-echo MPRAGE sequence at 1 mm resolution. Following surface reconstruction, we parcellated the cerebral cortex into seven functional networks using FreeSurfer’s standard pipeline. Next, we manually labeled vertices on the cortical surface where lesions caused inaccuracies and removed them from network-based cortical volumetric measures. After performing this lesion correction procedure, we measured the surface area of lesion overlap with each network and the percent volume of each network affected by lesions. We identified 120 lesions that caused inaccuracies in the cortical surface in 46 patients. In these 46 patients, the most commonly lesioned networks were the limbic and default mode networks (95.7% each), followed by the executive control (78.3%), and salience (71.7%) networks. The limbic network had the largest average surface area of lesion overlap (4.4+/−3.7%) and the largest percent volume affected by lesions (12.7+/−9.7%). The lesion correction method has the potential to improve the accuracy of cortical volumetric measurements and permit inclusion of patients with lesioned brains in quantitative analyses, providing new opportunities to elucidate network-based mechanisms of neurological deficits in patients with TBI.