bluuebunny/crossref_metadata_2025 huggingface dataset:
Decomposing neural responses to melodic surprise in musicians and non-musicians: evidence for a hierarchy of predictions in the auditory system
Authors: Quiroga-Martinez D.R. , Hansen N.C. , Højlund A. , Pearce M. , Brattico E. , Vuust P.
Published: October 2019

Neural responses to auditory surprise are typically studied with highly unexpected, disruptive sounds. Consequently, little is known about auditory prediction in everyday contexts that are characterized by fine-grained, non-disruptive fluctuations of auditory surprise. To address this issue, we used IDyOM, a computational model of auditory expectation, to obtain continuous surprise estimates for a set of newly composed melodies. Our main goal was to assess whether the neural correlates of non-disruptive surprising sounds in a musical context are affected by musical expertise. Using magnetoencephalography (MEG), auditory responses were recorded from musicians and non-musicians while they listened to the melodies. Consistent with a previous study, the amplitude of the N1m component increased with higher levels of computationally estimated surprise. This effect, however, was not different between the two groups. Further analyses offered an explanation for this finding: Pitch interval size itself, rather than probabilistic prediction, was responsible for the modulation of the N1m, thus pointing to low-level sensory adaptation as the underlying mechanism. In turn, the formation of auditory regularities and proper probabilistic prediction were reflected in later components: the mismatch negativity (MMNm) and the P3am, respectively. Overall, our findings reveal a hierarchy of expectations in the auditory system and highlight the need to properly account for sensory adaptation in research addressing statistical learning.

Highlights

- In melodies, sound expectedness (modeled with IDyOM) is associated with the amplitude of the N1m.

- This effect is not different between musicians and non-musicians.

- Sensory adaptation related to melodic pitch intervals explains better the N1m effect.

- Auditory regularities and the expectations captured by IDyOM are reflected in the MMNm and P3am.

- Evidence for a hierarchy of auditory predictions during melodic listening.
An optimized procedure for robust volitional drug intake in mice
Authors: López Alberto J. , Johnson Amy R. , Kunnath Ansley J. , Zachry Jennifer E. , Thibeault Kimberly C. , Kutlu Munir G. , Siciliano Cody A. , Calipari Erin S.
Published: October 2019

Substance use disorder is a behavioral disorder characterized by volitional drug consumption, compulsive behavior, drug seeking, and relapse. Mouse models of substance use disorder allow for the use of molecular, genetic, and circuit level tools, which provide enormous potential for defining the underlying mechanisms of this disorder. However, the relevance of results depends entirely on the validity of the mouse models used. Self-administration models have long been considered the gold standard of preclinical addiction models, as they allow for volitional drug use, this providing strong face validity. In a series of experiments, we show that traditional mouse models of self-administration, where behavior is maintained on a fixed-ratio one schedule of reinforcement, show similar levels of responding in the presence and absence of drug delivery - demonstrating that it is impossible to determine when intake is and is not volitional. Further, when assessing inclusion criteria, we find a sex-bias in exclusion criteria where females that acquired food self-administration were eliminated when traditional criteria were applied. To address these issues, we have developed a novel mouse self-administration procedure where animals do not need to be pre-trained on food and behavior is maintained on a variable ratio schedule of reinforcement. This procedure increases rates of reinforcement behavior, increases levels of drug intake, and eliminates sex bias in inclusion criteria. Together, these data highlight a major issue with fixed-ratio models in mice that complicates subsequent analysis and provide a simple and novel approach to minimize these confounds with escalating variable-ratio schedules of reinforcement.
Evolution and development of male-specific leg brushes in Drosophilidae
Authors: Tanaka Kohtaro , Barmina Olga , Thompson Ammon , Massey Jonathan H. , Kim Bernard Y. , Suvorov Anton , Kopp Artyom
Published: October 2019

The origin, diversification, and secondary loss of sexually dimorphic characters are common in animal evolution. In some cases, structurally and functionally similar traits have evolved independently in multiple lineages. Prominent examples of such traits include the male-specific grasping structures that develop on the front legs of many dipteran insects. In this report, we describe the evolution and development of one of these structures, the male-specific “sex brush”. The sex brush is composed of densely packed, irregularly arranged modified bristles and is found in several distantly related lineages in the family Drosophilidae. Phylogenetic analysis using 250 genes from over 200 species provides modest support for a single origin of the sex brush followed by many secondary losses; however, independent origins of the sex brush cannot be ruled out completely. We show that sex brushes develop in very similar ways in all brush-bearing lineages. The dense packing of brush hairs is explained by the specification of bristle precursor cells at a near-maximum density permitted by the lateral inhibition mechanism, as well as by the reduced size of the surrounding epithelial cells. In contrast to the female and the ancestral male condition, where bristles are arranged in stereotypical, precisely spaced rows, cell migration does not contribute appreciably to the formation of the sex brush. The complex phylogenetic history of the sex brush can make it a valuable model for investigating coevolution of sex-specific morphology and mating behavior.
Motor training improves coordination and anxiety in symptomaticMecp2-null mice despite impaired functional connectivity within the motor circuit
Authors: Yue Yuanlei , Xu Pan , Liu Zhichao , Sun Xiaoqian , Su Juntao , Du Hongfei , Chen Lingling , Ash Ryan T. , Smirnakis Stelios , Simha Rahul , Kusner Linda , Zeng Chen , Lu Hui
Published: October 2019

Rett Syndrome (RTT) is a severe neurodevelopmental disorder caused by loss of function of the X-linked Methyl-CpG-binding protein 2 (MECP2). Several case studies report that gross motor function can be improved in children with RTT through treadmill walking, but whether the MeCP2-deficient motor circuit can support actual motor learning remains unclear. We used two-photon calcium imaging to simultaneously observe layer (L) 2/3 and L5a excitatory neuronal activity in the motor cortex (M1) while mice adapted to changing speeds on a computerized running wheel. Despite circuit hypoactivity and weakened functional connectivity across L2/3 and L5a, theMecp2-null circuit’s firing pattern evolved with improved performance over two weeks. Moreover, trained mice became less anxious and lived 20% longer than untrained mice. Since motor deficits and anxiety are core symptoms of Rett, which is not diagnosed until well after symptom onset, these results underscore the benefit of motor learning.
Dynamic evolution of de novo DNA methyltransferases in rodent and primate genomes
Authors: Molaro Antoine , Malik Harmit S. , Bourc’his Deborah
Published: October 2019

Transcriptional silencing of retrotransposons via DNA methylation is paramount for mammalian fertility and reproductive fitness. During germ cell development, most mammalian species utilize the de novo DNA methyltransferases DNMT3A and DNMT3B to establish DNA methylation patterns. However, many rodent species deploy a third enzyme, DNMT3C, to selectively methylate the promoters of young retrotransposon insertions in their germline. The evolutionary forces that shaped DNMT3C’s unique function are unknown. Using a phylogenomic approach, we confirm here that Dnmt3C arose through a single duplication of Dnmt3B that occurred between 45-71Mya in the last common ancestor of muroid rodents. Most importantly, we reveal that DNMT3C is composed of two independently evolving segments: the latter two-thirds has undergone recurrent gene conversion with Dnmt3B, whereas the N-terminus has not undergone gene conversion and has evolved under strong diversifying selection. We hypothesize that positive selection of Dnmt3C is the result on an ongoing evolutionary arms race with young retrotransposon lineages in muroid genomes. Interestingly, although primates lack DNMT3C, we find that the N-terminus of DNMT3A has also evolved under diversifying selection. Thus, the N-termini of two independent de novo DNMT enzymes have evolved under diversifying selection in rodents and primates. We hypothesize that repression of young retrotransposons might be driving the recurrent innovation of a functional domain in the N-termini on germline DNMTs in mammals.
Human neutrophil response to Pseudomonas bacteriophages
Authors: Roach Dwayne R. , Chollet-Martin Sylvie , Noël Benoît , Granger Vanessa , Debarbieux Laurent , de Chaisemartin Luc
Published: October 2019

The immune system offers several mechanisms of response to remove harmful microbes that invade the human body. As a first line of defense, neutrophils can remove pathogens by phagocytosis, inactivate them by the release of reactive oxygen species (ROS) or immobilize them by neutrophil extracellular traps (NETs). Although, recent studies have shown that bacteriophages (phages) make up a large portion of human microbiomes and are currently being explored as human antibacterial therapeutics, neutrophilic responses to phages are still elusive. Here, we show that exposure of isolated human resting neutrophils to high concentration of thePseudomonasphage PAK_P1 led to a 2.8 fold increase in interleukin-8 (IL-8) secretion. Importantly, phage exposure did not further affect resting neutrophil apoptosis or induce necrosis, CD11 expression, oxidative burst, and NETs. Similarly, inflammatory stimuli activated neutrophil effector responses were unaffected by phage exposure. Our work suggest that phages are unlikely to inadvertently cause excessive neutrophil responses that could damage tissues and worsen disease. Because IL-8 functions as a chemoattractant directing immune cells to sites of infection and inflammation, phage-stimulated IL-8 production may boost host immune responses.
Donor monocyte-derived macrophages promote human acute graft versus host disease
Authors: Jardine Laura , Cytlak Urszula , Gunawan Merry , Reynolds Gary , Green Kile , Wang Xiao-Nong , Pagan Sarah , Pradnya Maharani , Lamb Christopher A , Long Anna K , Hurst Erin , Nair Smeera , Jackson Graham , Publicover Amy , Bigley Venetia , Haniffa Muzlifah , Simpson A. John , Collin Matthew
Published: October 2019

Myelopoiesis is invariably present, and contributes to pathology, in animal models of graft versus host disease (GVHD). In humans, a rich inflammatory infiltrate bearing macrophage markers has also been described in histological studies. In order to determine the origin, functional properties and role in pathogenesis of these cells, we isolated single cell suspensions from acute cutaneous GVHD and subjected them to genotype, transcriptome andin vitrofunctional analysis. A donor-derived population of CD11c+CD14+ cells was the dominant population of all leukocytes in GVHD. Surface phenotype and nanostring gene expression profiling indicated the closest steady-state counterpart of these cells to be monocyte-derived macrophages. In GVHD, however, there was upregulation of monocyte antigens SIRPα and S100A8/9, and transcripts associated with leukocyte trafficking, pattern recognition, antigen presentation, and co-stimulation. Isolated GVHD macrophages stimulated greater proliferation and activation of allogeneic T cells, and secreted higher levels of inflammatory cytokines than their steady-state counterparts. In HLA-matched mixed leukocyte reactions, we also observed differentiation of activated macrophages with a similar phenotype. These exhibited cytopathicity to a cell line and mediated pathological damage to skin explants, independently of T cells. Together, these results define the origin, functional properties and potential pathogenic roles of human GVHD macrophages.
The insertion of a mitochondrial selfish element into the nuclear genome and its consequences
Authors: Dutheil Julien Y. , Münch Karin , Schotanus Klaas , Stukenbrock Eva H. , Kahmann Regine
Published: October 2019

Homing endonucleases (HE) are enzymes capable of cutting DNA at highly specific target sequences, the repair of the generated double-strand break resulting in the insertion of the HE-encoding gene (“homing” mechanism). HEs are present in all three domains of life and viruses; in eukaryotes, they are mostly found in the genomes of mitochondria and chloroplasts, as well as nuclear ribosomal RNAs. We here report the case of a HE that accidentally integrated into a telomeric region of the nuclear genome of the fungal maize pathogenUstilago maydis. We show that the gene has a mitochondrial origin, but its original copy is absent from theU. maydismitochondrial genome, suggesting a subsequent loss or a horizontal transfer from a different species. The telomeric HE underwent mutations in its active site and lost its original start codon. A potential other start codon was retained downstream, but we did not detect any significant transcription of the newly created open reading frame, suggesting that the inserted gene is not functional. Besides, the insertion site is located in a putative RecQ helicase gene, truncating the C-terminal domain of the protein. The truncated helicase is expressed during infection of the host, together with other homologous telomeric helicases. This unusual mutational event altered two genes: the integrated HE gene subsequently lost its homing activity, while its insertion created a truncated version of an existing gene, possibly altering its function. As the insertion is absent in other field isolates, suggesting that it is recent, theU. maydis521 reference strain offers a snapshot of this singular mutational event.
Developmental onset of enduring long-term potentiation in mouse hippocampus
Authors: Ostrovskaya Olga I. , Cao Guan , Eroglu Cagla , Harris Kristen M.
Published: October 2019

Analysis of long-term potentiation (LTP) provides a powerful window into cellular mechanisms of learning and memory. Prior work shows late LTP (L-LTP), lasting >3 hours, occurs abruptly at postnatal day 12 (P12) in rat hippocampus. The goal here was to determine the developmental profile of synaptic plasticity leading to L-LTP in the mouse hippocampus. Two mouse strains and two mutations known to affect synaptic plasticity were chosen: C57BL/6 and Fmr1−/y on the C57BL/6 background, and 129SVE and Hevin−/− (Sparcl1−/−) on the 129SVE background. Like rats, hippocampal slices from all of the mice showed test pulse-induced depression early during development that was gradually resolved with maturation by 5 weeks. All the mouse strains showed a gradual progression between P10-P35 in the expression of short-term potentiation (STP), lasting ≤ one hour. In the 129SVE mice, L-LTP onset (>25% of slices) occurred by 3 weeks, reliable L-LTP (>50% slices) was achieved by 4 weeks, and Hevin−/− advanced this profile by one week. In the C57BL/6 mice, L-LTP onset occurred significantly later, over 3-4 weeks, and reliability was not achieved until 5 weeks. Although some of the Fmr1−/y mice showed L-LTP before 3 weeks, reliable L-LTP also was not achieved until 5 weeks. Two bouts of TBS separated by ≥90 minutes advanced the onset age of L-LTP in rats from P12 to P10. In contrast, L-LTP onset was not advanced in any of the mouse genotypes by multiple bouts of TBS at 90 or 180 minute intervals. These findings show important species differences in the onset of STP and L-LTP, which occur at the same age in rats but are sequentially acquired in mice.

SIGNIFICANCE STATEMENT

Long-term potentiation (LTP) is a cellular mechanism of learning and memory. Knowing the developmental profile for LTP provides a basis for investigating developmental abnormalities leading to intellectual disabilities and other neurodevelopmental disorders. Here we explore the developmental profile of LTP onset in two wild type mouse strains, C57BL/6 and 129SVE, together with Fmr1−/y and Hevin−/− (Sparcl1−/−) mutations that produce abnormalities in synaptic structure, plasticity, and development. Our data provide a foundation for future investigations into connections between structural and functional plasticity leading to developmental anomalies in the brain.
Assessing the specificity of the relationship between brain alpha oscillations and tonic pain
Authors: Valentini Elia , Halder Sebastian , McInnersey Daisy , Cooke Jason , Romei Vincenzo
Published: October 2019

Recent research has pointed to alpha brain oscillations as a potential clinical biomarker for sensitivity to pain. In particular, researchers claimed that the slowing of individual alpha frequency (IAF) could be an objective marker of pain during prolonged nociceptive stimulation. However, prolonged pain has been also associated with increased IAF. To date, there is insufficient evidence to conclude that IAF can be a neural marker of pain.

The current study aimed at elucidating the conflicting findings by assessing the specificity of the relationship between brain alpha oscillations and tonic pain. We recorded electroencephalography (EEG) on healthy volunteers during exposure to consecutive 5-minute sessions of painful hot water immersion, innocuous warm water immersion and an aversive, non-painful auditory stimulus, matched by unpleasantness to the painful condition. Participants rated stimulus unpleasantness throughout each condition. We also asked participants to sit still with eyes closed and eyes open right before and after the three experimental conditions in order to obtain a robust estimate of baseline alpha. Our findings revealed both increased and decreased IAF during tonic hot stimulation depending on the alpha range targeted (7-13 Hz vs. 8-10 Hz). In addition, they provide mild evidence for a negative relationship between IAF and the unpleasantness of the experience. Finally, we could not identify a difference between IAF during tonic hot temperature and during tonic auditory experience. Altogether, these findings emphasize a twofold frequency pattern (increase vs. decrease) for IAF during tonic thermal pain, thus indicating the need for robust methodological scrutiny of IAF as a neural marker of pain.
Genetic variation at 27 y-strs in four regions of bahrain
Authors: Al-Snan Noora R. , Messaoudi Safia A. , Khubrani Yahya M. , Wetton Jon H. , Jobling Mark A. , Bakhiet Moiz
Published: October 2019

Bahrain location in the Arabian Gulf contributed to the diversity of its indigenous population descended from Christian Arabs, Persians (Zoroastrians), Jews, and Aramaic-speaking agriculturalists. The aim of this study was to examine population substructure within Bahrain using the 27 Y-STRs (short tandem repeats) in the Yfiler Plus kit and to characterize the haplotypes of 562 unrelated Bahraini nationals, sub-divided into the four geographical regions - North, Capital, South and Muharraq. Yfiler Plus provided a significant improvement over the earlier 17-locus Yfiler kit in discrimination capacity, increasing it from 77% to 87.5%, but this value differed widely between regions from 98.4% in Muharraq to 75.2% in the Northern region, an unusually low value possibly as a consequence of the very rapid expansion in population size in the last 80 years. Clusters of closely related male lineages were seen, with only 79.4% of donors displaying unique haplotypes and 59% of instances of shared haplotypes occurring within, rather than between, regions. Haplogroup prediction indicated diverse origins of the population with a predominance of haplogroups J2 and J1, both typical of the Arabian Peninsula, but also haplogroups such as B2 and E1b1a originating in Africa and H, L and R2 indicative of migration from the east. Haplogroup frequencies differed significantly between regions with J2 significantly more common in the Northern region compared with the Southern possibly as a result of differential settlement with Baharna (descended from populations in which J2 predominates) and Arabs (both indigenous and migrant Huwala who are expected to have a higher frequency of J1). Our study illustrated the importance of encompassing geographical and social variation when constructing population databases and the need for highly discriminating multiplexes where rapid expansions have occurred within tightly bounded populations.
Size reductions and genomic changes associated with harvesting within two generations in wild walleye populations
Authors: Bowles Ella , Marin Kia , Mogensen Stephanie , Macleod Pamela , Fraser Dylan J.
Published: October 2019

The extent and rate of harvest-induced genetic changes in natural populations may impact population productivity, recovery and persistence. While there is substantial evidence for phenotypic changes in harvested fishes, knowledge of genetic change in the wild remains limited, as phenotypic and genetic data are seldom considered in tandem, and the number of generations needed for genetic changes to occur is not well understood. We quantified changes in size-at-age, sex-specific changes in body size, and genomic metrics in three harvested walleye (Sander vitreus) populations and a fourth reference population with low harvest levels over a 15-year period in Mistassini Lake, Quebec. We also collected Traditional Ecological Knowledge (TEK) surrounding concerns about these populations over time. Using ∼9000 SNPs, genomic metrics included changes in population structure, neutral genomic diversity, effective population size and signatures of selection. TEK revealed concerns about overall reductions in body size and number of fish caught. Smaller body size, smaller size-at-age, changing population structure (population differentiation within one river and homogenization between two others), and signatures of selection between historical and contemporary samples reflected coupled phenotypic and genomic change in the three harvested populations in both sexes, while no change occurred in the reference population. Sex-specific analyses revealed differences in both body size and genomic metrics but were inconclusive about whether one sex was disproportionately affected. Our results support that harvest-induced genetic changes can arise within 1-2.5 generations in long-lived wild fishes, demonstrating the need to investigate concerns about harvest-induced evolution quickly once they have been raised.
Organic management promotes natural pest control through enhanced plant resistance to insects
Authors: Blundell Robert , Schmidt Jennifer E. , Igwe Alexandria , Cheung Andrea L. , Vannette Rachel L. , Gaudin Amélie C.M. , Casteel Clare L.
Published: October 2019

Lower insect pest populations found on long-term organic farms have largely been attributed to increased biodiversity and abundance of beneficial predators. However, potential induction of plant defenses has largely been ignored. This study aims to determine whether host plant resistance mediates decreased pest populations in organic systems, and to identify the underpinning mechanisms. We demonstrate that greater numbers of leafhoppers (Circulifer tenellus) settle on tomatoes (Solanum lycopersicum) grown using conventional management as compared to organic. Soil microbiome sequencing, chemical analysis, and transgenic approaches, coupled with multi-model inference, suggest that changes in leafhopper settling between organically and conventionally-grown tomatoes are dependent on salicylic acid accumulation in the plant, likely mediated by rhizosphere microbial communities. These results suggest that organically-managed soils and microbial communities may play an unappreciated role in reducing plant attractiveness to pests by increasing plant resistance.
Complete chloroplast genomes of 14 mangroves: phylogenetic and genomic comparative analyses
Authors: Shi Chengcheng , Han Kai , Li Liangwei , Seim Inge , Lee Simon Ming-Yuen , Xu Xun , Yang Huanming , Fan Guangyi , Liu Xin
Published: October 2019

Mangroves are main components of an ecosystem which connect land and ocean and is of significant ecological importance. They are found around the world and taxonomically distributed in 17 families. Until now there has been no evolutionary phylogenetic analyses on mangroves based on complete plastome sequences. In order to infer the relationship between mangroves and terrestrial plants at the molecular level, we generated chloroplast genomes of 14 mangrove species from eight families, spanning six orders: Fabales (Pongamia pinnata), Lamiales (Avicennia marina), Malpighiales (Excoecaria agallocha, Bruguiera sexangula, Kandelia obovata, Rhizophora stylosa, Ceriops tagal), Malvales (Hibiscus tiliaceus, Heritiera littoralis, Thespesia populnea), Myrtales (Laguncularia racemose, Sonneratia ovata, Pemphis acidula), and Sapindales (Xylocarpus moluccensis). The whole-genome length of these chloroplasts is from 149kb to 168kb. They have a conserved structure, with two Inverted Repeat (IRa and IRb, ~25.8kb), a large single-copy region (LSC, ~89.0kb), a short single-copy (SSC, ~18.9kb) region, as well as ~130 genes (85 protein-coding, 37 tRNA, and 8 rRNA). The number of simple sequence repeats (SSRs) varied between mangrove species. Phylogenetic analysis using complete chloroplast genomes of 71 mangrove and land plants, confirmed the previously reported phylogeny within rosids, including the positioning of obscure families such as Linaceae within Malpighiales. Most mangrove chloroplast genes are conserved and we found six genes subjected to positive or neutral selection. Genomic comparison showed IR regions have lower divergence than other regions. Our study firstly reported several plastid genetic resource for mangroves, and the determined evolutionary locations as well as comparative analyses of these species provid insights into the mangrove genetic and phylogenetic research.
Flexibility of intrinsically disordered degrons in AUX/IAA proteins reinforces auxin co-receptor assemblies
Authors: Niemeyer Michael , Castillo Elena Moreno , Ihling Christian H. , Iacobucci Claudio , Wilde Verona , Hellmuth Antje , Hoehenwarter Wolfgang , Samodelov Sophia L. , Zurbriggen Matias D. , Kastritis Panagiotis L. , Sinz Andrea , Calderón Villalobos Luz Irina A.
Published: October 2019

Cullin RING-type E3 ubiquitin ligases SCFTIR1/AFB1-5and their ubiquitylation targets, AUX/IAAs, sense auxin concentrations in the nucleus. TIR1 binds a surface-exposed degron in AUX/IAAs promoting their ubiquitylation and rapid auxin-regulated proteasomal degradation. Here, we resolved TIR1·auxin·IAA7 and TIR1·auxin·IAA12 complex topology, and show that flexible intrinsically disordered regions (IDRs) in the degron’s vicinity, cooperatively position AUX/IAAs on TIR1. The AUX/IAA PB1 interaction domain also assists in non-native contacts, affecting AUX/IAA dynamic interaction states. Our results establish a role for IDRs in modulating auxin receptor assemblies. By securing AUX/IAAs on two opposite surfaces of TIR1, IDR diversity supports locally tailored positioning for targeted ubiquitylation, and might provide conformational flexibility for adopting a multiplicity of functional states. We postulate IDRs in distinct members of the AUX/IAA family to be an adaptive signature for protein interaction and initiation region for proteasome recruitment.
Distinct molecular processes in placentae involved in two major subtypes of preeclampsia
Authors: Ren Zhonglu , Gao Yunfei , Gao Yue , Liang Guanmei , Chen Qian , Jiang Sijia , Yang Xiaoxue , Fan Cuixia , Wang Haizhen , Wang Jing , Shi Yi-Wu , Xiao Chaoqun , Zhong Mei , Yu Yanhong , Yang Xinping
Published: October 2019

Patients with preeclampsia display a spectrum of onset time and severity of clinical presentation, yet the underlying molecular bases for the early-onset and late-onset clinical subtypes are not known. Since the root cause of PE is thought to be located in the placentae, we carried out RNA-seq on 65 high-quality placenta samples, including 33 from 30 patients and 32 from 30 control subjects, to search for molecular features. We identified two functionally distinct sets of dysregulated genes in two major subtypes: metabolism-related genes, notably transporter genes, in early-onset severe preeclampsia and immune-related genes in late-onset severe preeclampsia, while the late-onset mild preeclampsia could not be distinguished from normal controls. A small number of dysregulated transcription factors may drive the widespread gene dysregulation in both early-onset and late-onset patients. These results suggest that early-onset and late-onset severe preeclampsia have different molecular mechanisms, whereas the late-onset mild preeclampsia may have no placenta-specific causal factors.
The actin binding protein α-adducin modulates desmosomal turnover and plasticity
Authors: Hiermaier Matthias , Kliewe Felix , Schinner Camilla , Stüdle Chiara , Maly I. Piotr , Wanuske Marie-Therèse , Rötzer Vera , Endlich Nicole , Vielmuth Franziska , Waschke Jens , Spindler Volker
Published: October 2019

Intercellular adhesion is essential for tissue integrity and homeostasis. Desmosomes are especially abundant in the epidermis and the myocardium, tissues, which are under constantly changing mechanical stresses. Yet, it is largely unclear whether desmosomal adhesion can be rapidly adapted to changing demands and the mechanisms underlying desmosome turnover are only partially understood. We here show that loss of the actin-binding protein α-adducin prevented the ability of cultured keratinocytes or murine epidermis to withstand mechanical stress paralleled with reduced desmosome number. This effect was not caused by decreased levels or impaired adhesive properties of desmosomal molecules but rather by altered desmosome turnover. Mechanistically, reduced cortical actin density in α-adducin knockout keratinocytes resulted in increased mobility of the desmosomal adhesion molecule desmoglein 3 (Dsg3) and impaired interactions with E-cadherin, a crucial step in desmosome formation. Accordingly, loss of α-adducin prevented increased membrane localization of Dsg3 in response to cyclic stretch or shear stress. Our data demonstrate plasticity of desmosomal molecules in response to mechanical stimuli and unravel a mechanism how the actin cytoskeleton indirectly shapes intercellular adhesion by restricting the mobility of desmosomal molecules.
Electron Microscopic Identification of Distant Metastatic Cell in Human Prostate Cancer in Tissue section
Authors: Sinha Akhouri A.
Published: October 2019

Mutation in chromatin/DNA/genes of stem cells is a prerequisite for the development of cancer in the benign prostate. Mutation imparts chronic proliferation advantage to invasive and metastatic cancer cells, but not in benign prostate. We hypothesize that identification of metastatic prostatic cancer (PC) cells in tissue sections can lead to an early diagnosis and treatment of patients, hopefully, reducing death due to this disease. We have tested our hypothesis using biopsy and/or radical prostatectomy specimens of untreated and DES (diethylstilbestrol)-treated prostate cancer and transmission electron microscopy. Materials and methods: Tissue samples embedded in Epon were thin sectioned and examined on RCA EMU 3 or 4 transmission electron microscope. Results: We have identified two types of PC stem cells. Invasive stem cell invades the adjacent stroma whereas metastatic cell, a lineage of stem cell, is dedifferentiated columnar/cuboidal cells. Metastatic cell is identified by nuclear plasticity (pleomorphic nucleus), loss of nuclear membranes, loss of boundary between nucleus and cytoplasm and presence of electron dense molecules. Nuclear chromatin/DNA appears as electron dense molecules which readily pass plasma and basement membranes and enter the capillary before adhering to the red cell surface. Electron dense molecules are found in capillary, undoubtedly, reach metastatic site (s). Discussion and conclusion: Chromatin/DNA are small molecules that can readily cross many barriers, unlike an individual cancer cell. We show that invasive a cell is stem cell and metastasis develops from dedifferentiated columnar/cuboidal nuclear electron dense molecules. This is the first study to cells characterize metastatic cell in tissue sections.
Evidence that stress-induced changes in surface temperature serve a thermoregulatory function
Authors: Robertson Joshua K. , Mastromonaco Gabriela , Burness Gary
Published: October 2019

Changes in body temperature following exposure to stressors have been documented for nearly two millennia, however, the functional value of this phenomenon is poorly understood. We tested two competing hypotheses to explain stress-induced changes in temperature, with respect to surface tissues. Under the first hypothesis, changes in surface temperature are a consequence of vasoconstriction that occurs to attenuate blood-loss in the event of injury and serves no functional purposeper se;defined as the Haemoprotective Hypothesis. Under the second hypothesis, changes in surface temperature reduce thermoregulatory burdens experienced during activation of a stress response, and thus hold a direct functional value; here, the Thermoprotective Hypothesis. To understand whether stress-induced changes in surface temperature have functional consequences, we tested predictions of the Haemoprotective and Thermoprotective hypotheses by exposing Black-capped Chickadees (n = 20) to rotating stressors across an ecologically relevant ambient temperature gradient, while non-invasively monitoring surface temperature (eye region temperature) using infrared thermography. Our results show that individuals exposed to rotating stressors reduce surface temperature and dry heat loss at low ambient temperature and increase surface temperature and dry heat loss at high ambient temperature, when compared to controls. These results support the Thermoprotective Hypothesis and suggest that changes in surface temperature following stress exposure have functional consequences and are consistent with an adaptation. Such findings emphasize the importance of the thermal environment in shaping physiological responses to stressors in vertebrates, and in doing so, raise questions about their suitability within the context of a changing climate.

Summary Statement

We provide empirical evidence for a functional value to stress-induced changes in surface temperature that is consistent with an adaptation, using a temperate endotherm (Black-capped Chickadee) as a model species.
Pervasively thinner neocortex as a transdiagnostic feature of general psychopathology
Authors: Romer Adrienne L. , Elliott Maxwell L. , Knodt Annchen R. , Sison Maria L. , Ireland David , Houts Renate , Ramrakha Sandhya , Poulton Richie , Keenan Ross , Melzer Tracy R. , Moffitt Terrie E. , Caspi Avshalom , Hariri Ahmad R.
Published: October 2019

Objective

Neuroimaging research has revealed that structural brain alterations are common across broad diagnostic families of disorders rather than specific to a single psychiatric disorder. Such overlap in the structural brain correlates of mental disorders mirrors already well-documented phenotypic comorbidity of psychiatric symptoms and diagnoses, which can be indexed by a general psychopathology orpfactor. We hypothesized that if general psychopathology drives the convergence of structural alterations common across disorders then 1) there should be few associations unique to any one diagnostic family of disorders, and 2) associations with thepfactor should overlap with those for the broader diagnostic families.

Methods

Analyses were conducted on structural MRI and psychopathology data collected from 861 members of the population representative Dunedin Study at age 45.

Results

Study members with high scores across three broad diagnostic families of disorders (Externalizing, Internalizing, Thought Disorder) exhibited highly overlapping patterns of reduced global and widely distributed parcel-wise neocortical thickness. Study members with highpfactor scores exhibited patterns of reduced global and parcel-wise neocortical thickness nearly identical to those associated with the three broad diagnostic families.

Conclusions

A pattern of pervasively reduced neocortical thickness appears common across all forms of mental disorders and may represent a transdiagnostic feature of general psychopathology. As has been documented with regard to symptoms and diagnoses, the underlying brain structural correlates of mental disorders may not exhibit specificity, the continued pursuit of which may limit progress toward more effective strategies for etiological understanding, prevention, and intervention.
Fast searches of large collections of single cell data using scfind
Authors: Lee Jimmy Tsz Hang , Patikas Nikolaos , Kiselev Vladimir Yu , Hemberg Martin
Published: October 2019

Single cell technologies have made it possible to profile millions of cells, but for these resources to be useful they must be easy to query and access. To facilitate interactive and intuitive access to single cell data we have developed scfind, a search engine for cell atlases. Using transcriptome data from mouse cell atlases we show how scfind can be used to evaluate marker genes, to perform in silico gating, and to identify both cell-type specific and housekeeping genes. Moreover, we have developed a subquery optimization routine to ensure that long and complex queries return meaningful results. To make scfind more user friendly and accessible, we use indices of PubMed abstracts and techniques from natural language processing to allow for arbitrary queries. Finally, we show how scfind can be used for multi-omics analyses by combining single-cell ATAC-seq data with transcriptome data.
Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia
Authors: Colombo Alessio , Dinkel Lina , Müller Stephan A. , Monasor Laura Sebastian , Schifferer Martina , Cantuti-Castelvetri Ludovico , König Jasmin , Vidatic Lea , Bremova-Ertl Tatiana , Hecimovic Silva , Simons Mikael , Lichtenthaler Stefan F. , Strupp Michael , Schneider Susanne A. , Tahirovic Sabina
Published: October 2019

Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations inNpc1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, consequences of NPC1 loss on microglial function remain uncharacterized. Here, we provide an in-depth characterization of microglial proteomic signatures and phenotypes in a NPC1-deficient (Npc1-/-) murine model and patient blood-derived macrophages. We demonstrate enhanced phagocytic uptake and impaired lipid trafficking inNpc1-/-microglia that precede neuronal death. Loss of NPC1 compromises microglial developmental functions as revealed by increased synaptic pruning and deficient myelin turnover. Undigested myelin accumulates within multi-vesicular bodies ofNpc1-/-microglia while lysosomal degradation remains preserved. To translate our findings to human disease, we generated novelex vivoassays using patient macrophages that displayed similar proteomic disease signatures and lipid trafficking defects as murineNpc1-/-microglia. Thus, peripheral macrophages provide a novel promising clinical tool for monitoring disease progression and therapeutic efficacy in NPC patients. Our study underscores an essential role for NPC1 in immune cells and implies microglial therapeutic potential.
Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities
Authors: Rambow Florian , Marine Jean-Christophe , Goding Colin R.
Published: October 2019

An incomplete view of the mechanisms that drive metastasis, the primary cause of cancer-related death, has been a major barrier to development of effective therapeutics and prognostic diagnostics. Increasing evidence indicates that the interplay between microenvironment, genetic lesions, and cellular plasticity drives the metastatic cascade and resistance to therapies. Here, using melanoma as a model, we outline the diversity and trajectories of cell states during metastatic dissemination and therapy exposure, and highlight how understanding the magnitude and dynamics of nongenetic reprogramming in space and time at single-cell resolution can be exploited to develop therapeutic strategies that capitalize on nongenetic tumor evolution.
Pedigree-based estimation of human mobile element retrotransposition rates
Authors: Feusier Julie , Watkins W. Scott , Thomas Jainy , Farrell Andrew , Witherspoon David J. , Baird Lisa , Ha Hongseok , Xing Jinchuan , Jorde Lynn B.
Published: October 2019

Germline mutation rates in humans have been estimated for a variety of mutation types, including single-nucleotide and large structural variants. Here, we directly measure the germline retrotransposition rate for the three active retrotransposon elements: L1, Alu, and SVA. We used three tools for calling mobile element insertions (MEIs) (MELT, RUFUS, and TranSurVeyor) on blood-derived whole-genome sequence (WGS) data from 599 CEPH individuals, comprising 33 three-generation pedigrees. We identified 26 de novo MEIs in 437 births. The retrotransposition rate estimates for Alu elements, one in 40 births, is roughly half the rate estimated using phylogenetic analyses, a difference in magnitude similar to that observed for single-nucleotide variants. The L1 retrotransposition rate is one in 63 births and is within range of previous estimates (1:20–1:200 births). The SVA retrotransposition rate, one in 63 births, is much higher than the previous estimate of one in 900 births. Our large, three-generation pedigrees allowed us to assess parent-of-origin effects and the timing of insertion events in either gametogenesis or early embryonic development. We find a statistically significant paternal bias in Alu retrotransposition. Our study represents the first in-depth analysis of the rate and dynamics of human retrotransposition from WGS data in three-generation human pedigrees.
Calcium Phosphate-Mediated Transfection of Adherent Cells or Cells Growing in Suspension: Variations on the Basic Method
Authors: Kumar Priti , Nagarajan Arvindhan , Uchil Pradeep D.
Published: October 2019

This protocol describes two variations of the calcium phosphate-mediated transfection method. The first can be used with all types of adherent cells, but is particularly useful for polarized epithelial cells, which do not efficiently take up material by endocytosis through the apical plasma membrane. To improve transfection efficiency, adherent cells are trypsinized and collected by centrifugation. The cells are resuspended in the calcium phosphate–DNA coprecipitate and then plated again on tissue culture dishes. Most lines of cells grown in suspension are resistant to calcium phosphate-mediated transfection methods; however, a few cell lines grown as suspension cultures (e.g., HeLa cells) can be transfected using the second modified calcium phosphate procedure described here.
POWGEN: rebuild of a third-generation powder diffractometer at the Spallation Neutron Source
Authors: Huq Ashfia , Kirkham Melanie , Peterson Peter F. , Hodges Jason P. , Whitfield Pamela S. , Page Katharine , Hűgle Thomas , Iverson Erik B. , Parizzi Andre , Rennich George
Published: October 2019

The neutron powder diffractometer POWGEN at the Spallation Neutron Source has recently (2017–2018) undergone an upgrade which resulted in an increased detector complement along with a full overhaul of the structural design of the instrument. The current instrument has a solid angular coverage of 1.2 steradians and maintains the original third-generation concept, providing a single-histogram data set over a wide d-spacing range and high resolution to access large unit cells, detailed structural refinements and in situ/operando measurements.
Atomic structures and migration mechanisms of interphase boundaries during body- to face-centered cubic phase transformations
Authors: Huang Yunhao , Wang Jincheng , Wang Zhijun , Li Junjie
Published: October 2019

Atomic structures and migration mechanisms of interphase boundaries have been of scientific interest for many years owing to their significance in the field of phase transformations. Though the interphase boundary structures can be deduced from crystallographic investigations, the detailed atomic structures and migration mechanisms of interphase boundaries during phase transformations are still poorly understood. In this study, a systematic study on atomic structures and migration mechanisms of interphase boundaries in a body-centered cubic (b.c.c.) to face-centered cubic (f.c.c.) massive transformation was carried out using the phase-field crystal model. Simulation results show that the f.c.c./b.c.c. interphase boundaries can be classified into faceted interphase boundaries and side surfaces. The faceted interphase boundaries are semi-coherent with a group of dislocations, leading to a ledge migration mechanism, while the side surfaces are incoherent and thus migrate in a continuous way. After a careful analysis of the simulated migration process of interphase boundaries at atomic scales, a detailed description of the ledge mechanism based on the motion and nucleation of interphase boundary dislocations is presented. The ledge-forming process is accompanied by the nucleation of new heterogeneous dislocations and motions of original dislocations, and thus the barrier of ledge formation comes from the hindrance of these two dislocation behaviors. Once the ledge is formed, the original dislocations continue to advance until the ledge height reaches 1/|Δg|, where Δg represents the difference in reciprocal lattice vectors between two phases. The new heterogeneous dislocation moves along the radial direction of the interphase boundary, resulting in ledge extension. The interface dislocation behaviors greatly affect the migration of the interphase boundary, leading to different migration kinetics of faceted interphase boundaries under the Kurdjumov–Sachs and the Nishiyama–Wasserman orientation relationships. This study revealed the mechanisms and kinetics of complex structure transition during a b.c.c.–f.c.c. massive phase transformation and can shed some light on the process of solid phase transformations.
Electron backscatter diffraction study of variant selection during ordering phase transformation in L10-type red gold alloy
Authors: Larcher Margaux N. D. , Cayron Cyril , Blatter Andreas , Soulignac Raphaëlle , Logé Roland E.
Published: October 2019

A shape-memory effect is known to appear in red gold alloys with compositions close to Au–Cu. The aim of this paper is to study by electron backscatter diffraction (EBSD) the variant selection in the A1 → L10transformation occurring under stress, in bending conditions. The L10domains are successfully identified by this technique despite thec/aratio being close to unity. The orientation relationship between the cubic and tetragonal phases is determined by a careful analysis of the EBSD data. The distortion of the lattice for each variant is then modelled and calculated from the experimental orientations. The mechanical work associated with the transformation is computed from the lattice distortion by neglecting the obliquity. Finally, the distribution of this mechanical work is compared with the case of a uniform distribution of all variants, in order to evaluate the extent of variant selection. The maximal work criterion, often used for martensitic transformations, enabled quantification of the variant selection phenomenon.