bluuebunny/crossref_metadata_2025 huggingface dataset:
Polyphyly of theNiphargus stygiusspecies group (Crustacea, Amphipoda, Niphargidae) in the Southern Limestone Alps
Authors: Stoch Fabio , Salussolia Alice , Flot Jean-François
Published: May 2022

Abstract

TheNiphargus stygiusspecies complex is a groundwater group of large-sized, sexually dimorphic species inhabiting mainly caves and, less frequently, wells and springs. According to the taxonomists of the last century, this species complex was supposed to be present in the whole Southern Limestone Alps of Italy as well as in peninsular Italy, Slovenia, and Croatia. Considering the large, presumed distribution area, we tested the contrasting hypotheses of monophyly versus paraphyly of this subterranean species complex, taking in account the presence of putative cryptic species. For this reason, we sampled the type localities of all the described species in the complex present in the Italian Southern Limestone Alps and neighbouring areas, and used nuclear rDNA (28S, ITS region) and mtDNA (COI) markers to assess the phylogenetic relationships and species richness. Phylogenetic analysis confirmed that theNiphargus stygiuscomplex in the Southern Limestone Alps is polyphyletic comprising an eastern clade (theN. juliusclade, present in NW Italy, northern Slovenia, and southern Austria) and two western clades (theN. brixianusandN. montellianusclades). These two clades are not closely related to the eastern one but rather form a monophyletic group together with a widely distributed Apennine clade (N. speziaeclade). None of these clades is closely related to typicalN. stygius. Three different molecular species delimitation methods applied to COI and rDNA sequences recognized slighlty different numbers of putative species, suggesting that each clade is a species complex. Bayesian time-calibrated phylogeny revealed that most clades began to split up during Miocene and Pliocene, ruling out the effect of Pleistocene glaciations, evidenced only by the COI marker, in explaining their speciation process and justifying the presence of several putative cryptic or pseudocryptic species.
Tau seeds translocate across the cell membrane to initiate aggregation
Authors: Dodd Dana A. , LaCroix Michael , Valdez Clarissa , Knox Gregory M. , Vega Anthony R. , Kumar Ashwani , Xing Chao , White Charles L. , Diamond Marc I.
Published: May 2022

Neurodegenerative tauopathies, including Alzheimer’s disease and related disorders, are caused by intracellular aggregation of tau protein in ordered assemblies. Experimental evidence suggests that tau assemblies propagate pathology across brain networks. Tau seeds enter cells through endocytosis but must access the cytoplasm to serve as templates for their own replication. The mechanism by which this occurs is unknown. To study tau uptake, we began with a whole-genome CRISPR knockout screen, which indicated a requirement vacuolar H+ ATPase (v-ATPase) components. Treatment with Bafilomycin A1, an inhibitor of the v-ATPase, also reduced tau entry. We next tested direct modifiers of endolysosomal trafficking. Dominant-negative Rab5a expression uniquely decreased tau uptake, as did temporary cold temperature during tau exposure, consistent with a primary role of endocytosis in tau uptake. However, despite reducing tau uptake, these interventions all paradoxically increased intracellular seeding. Consequently, we generated giant plasma membrane vesicles (GPMVs), which cannot undergo endocytosis, and observed that tau fibrils and monomer translocated into the vesicles, in addition to TAT peptide, whereas transferrin and albumin did not. In every case, tau required binding to heparan sulfate proteoglycans (HSPGs) for cell uptake, seeding, or GPMV entry. These findings are most consistent with direct translocation of tau seeds across the lipid bilayer, a novel mechanism of entry into the cytoplasm.
Agency as a Bridge to Form Associative Memories
Authors: Ruiz Nicholas A. , DuBrow Sarah , Murty Vishnu P.
Published: May 2022

The perception of agency occurs when individuals feel their decisions exert control over their environment. While agency can increase memory for items, most real-life situations are more complex. The decisions we make not only affect the item we act upon, but all the other items in direct proximity of our decisions. Here, we examined how an individual’s agency to influence a situation affects their ability to learn associations between items that occur prior to and after making a decision. In our paradigm, participants were told they were playing a game show where they had to help a trial unique ‘contestant’ choose between three doors. On ‘agency’ trials, participants were allowed to pick any door they wanted. On ‘forced-choice’ trials, participants were instructed to select a door that was highlighted. They then saw the outcome, a ‘prize’ that was behind the selected door. Across two studies, participants show enhanced memory for contestants they saw in agency vs forced-choice trials. Memory benefits also extended to contestant - door and door - prize associations in both studies. Study 2 found this effect in the contestant - prize association. Notably, we found that agency also shaped the representation of memories such that they were stored as integrated sequences rather than individual relational pairs. Together, these data suggest agency over a situation leads to enhanced memory for all items in that situation. This enhanced binding for items may be occurring by the formation of causal links when an individual has agency over their learning environment.
Improved methods for the large-scale cultivation ofGiardia lambliatrophozoites in the academic laboratory
Authors: Wimberly Brian T. , Bilodeau Danielle , Rissland Olivia S. , Kieft Jeffrey S.
Published: May 2022

The parasitic protistGiardia lambliacauses giardiasis, one of the leading diarrheal diseases worldwide. As a phylogenetically divergent eukaryote,Giardiais also an emerging model organism for exploring the diversity of core eukaryotic metabolic pathways and important molecular structures. To date, methods for the cultivation of large numbers (>109) ofGiardiatrophozoites have been either expensive or cumbersome, hampering structural and biochemical studies. Here, we present two improved strategies for the laboratory-scale growth of billions of adherent trophozoites, with suggestions for the optimization of media components, media preparation, and harvesting methods.
Chimera States among Synchronous Fireflies
Authors: Sarfati Raphaël , Peleg Orit
Published: May 2022

Systems of oscillators, whether animate or inanimate, often converge to a state of collective synchrony, when sufficiently interconnected. Twenty years ago, the mathematical study of models of coupled oscillators revealed the possibility for complex phases which exhibit the coexistence of synchronous and asynchronous clusters, since then referred to as “chimera states”. Beyond their recurrence in theoretical models, chimera states have been observed in specifically-designed, non-biological experimental conditions, yet their emergence in nature has remained elusive. Here, we report robust evidence for the occurrence of chimera states in a celebrated realization of natural synchrony: fireflies. In video recordings of collective displays of Photuris frontalis fireflies, we observe, within a single swarm, the spontaneous emergence of different groups flashing with the same periodicity but with a constant time delay between them. From the three-dimensional reconstruction of the swarm, we demonstrate that these states are stable over time and spatially intertwined, but find no evidence of enhanced correlations in their spatial dynamics. We discuss the implications of these findings on the synergy between mathematical models and firefly collective behavior.
The Human Dendritic Cell Atlas: An integrated transcriptional tool to study human dendritic cell biology
Authors: Elahi Zahra , Angel Paul W. , Butcher Suzanne , Rajab Nadia , Choi Jarny , Mintern Justine D. , Radford Kristen J. , Wells Christine A.
Published: May 2022

Dendritic cells (DCs) are functionally diverse and are present in most adult tissues, however progress in understanding human DC biology is hampered by a relatively small number of these in circulation and by limited access to human tissues. We built a transcriptional atlas of human DCs by combining samples from 14 expression profiling studies derived from 10 laboratories. We identified significant gene expression variation of DC subset-defining markers across tissue-type and upon viral or bacterial stimulation. We further highlight critical gaps between in vitro-derived DC subsets and their in vivo counterparts and provide evidence that monocytes or cord blood progenitor in vitro-differentiated DCs fail to capture the repertoire of primary DC subsets or behaviours. In constructing a reference DC atlas, we provide an important resource for the community wishing to identify and annotate tissue-specific DC subsets from single-cell datasets, or benchmark new in vitro models of DC biology.

Key Points

A reference atlas of human DC that allows benchmarking of in vitro DC models

Meta-analysis of 14 integrated studies demonstrate that human conventional dendritic cells have distinct tissue-of-origin phenotypes

User uploads allow tissue-relevant annotation of human DC subsets from single cell datasets

Key subset markers are altered by tissue or activation status

Gaps between in vitro-differentiated DC and in vivo counterparts are partially rescued by humanized mouse models, or coculture with NOTCH-ligands.
Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission
Authors: Stern Shani , Zhang Lei , Wang Meiyan , Wright Rebecca , Cordeiro Diogo , Peles David , Hang Yuqing , Mendes Ana P. D. , Baul Tithi , Roth Julien , Coorapati Shashank , Boks Marco , Pol Hilleke Hulshoff , Brennand Kristen J. , Réthelyi Janos M , Kahn René S. , Marchetto Maria C. , Gage Fred H.
Published: May 2022

Schizophrenia affects approximately 1% of the world population. Genetics, epigenetics, and environmental factors are known to play a role in this psychiatric disorder. While there is a high concordance in monozygotic twins, about half of twin pairs are discordant for schizophrenia. We characterized human-induced pluripotent stem cell (iPSC)-derived hippocampal neurons from two pairs of monozygotic twins that are discordant for a schizophrenia diagnosis. We compared the affected and the non-affected siblings and compared all of them to twin sets where none of the siblings suffered from schizophrenia. We found that the neurons derived from the schizophrenia patients were less arborized, were hypoexcitable with immature spike features, and exhibited a significant reduction in synaptic activity with dysregulation in synapse-related genes. Interestingly, the neurons derived from the co-twin siblings who did not have schizophrenia formed another distinct group that was different from the neurons in the group of the affected twin siblings but also different from the neurons in the group of the control twins. The neurons in the unaffected co-twin group were also less arborized than the neurons from controls but more arborized than those from affected siblings. Some of their spike features were immature (but less immature than neurons derived from the affected siblings). Importantly, their synaptic activity was not affected. Since schizophrenia is a genetically complex disorder, our twin study allows the measurement of neuronal phenotypes with a similar genetic background. The differences between the siblings may arise due to changes that occurred after the split of the egg into twins. Therefore, our study confirms that dysregulation of synaptic pathways, as well as changes in the rate of synaptic events, distinguishes between individuals affected with schizophrenia and unaffected individuals, even in those having a very similar genetic background.
Translational Activity Controls Ribophagic Flux and Turnover of Distinct Ribosome Pools
Authors: Trendel Jakob , Aleksić Milan , Bertolini Matilde , Jochem Marco , Kramer Günter , Pfeffer Stefan , Bukau Bernd , Krijgsveld Jeroen
Published: May 2022

Ribosomes are among the most abundant and complex machineries in the cell, however, the turnover of their subunits remains poorly understood. Here, we apply proteomic flux and cryo-electron microscopy analyses to interrogate the ribosome life cycle in human cells. We show that subpopulations of ribosomal subunits coexist, which vary in turnover kinetics and structure. Specifically, 80S ribosomes have a much longer half-life than free 40S and 60S ribosomal subunits, indicating that they represent distinct subunit pools that poorly intermix. Translation inhibition starkly increases the pool-size of 80S ribosomes in a translationally idle state and induces ribophagy of old ribosomes, ultimately rejuvenating the ribosome fleet. Our findings provide a comprehensive model for ribosome turnover and its regulation via translational activity.
Single-cell characterisation of the hematopoietic bone marrow interactome in health and disease
Authors: Ennis Sarah , Conforte Alessandra , O’Reilly Eimear , Cichocka Tatiana , Pal Dhami Sukhraj , Nicholson Pamela , Krebs Philippe , Ó Broin Pilib , Szegezdi Eva
Published: May 2022

1

The bone marrow (BM) is a complex microenvironment and the primary site of hematopoiesis, coordinating the production of billions of blood cells every day. Despite the essential role of the hematopoietic niche in maintaining hemostasis and its relevance to hematopoietic diseases, many aspects of this environment remain poorly characterised due to experimental hurdles. Here we present a high-resolution characterisation of the niche in health and acute myeloid leukemia (AML) by establishing a comprehensive single-cell gene expression database of nearly 340,000 BM constituent cells encompassing all disease stages (healthy BM, AML at diagnosis, remission and relapse). We characterised the cell type composition of the BM and found that the proportions of both myeloid and lymphoid lineage cell types are significantly altered in AML. We also determined broadscale dysregulation of gene expression in almost all BM cell types upon establishment of AML, indicating that the entire niche is disrupted by the disease. Given the importance of interactions between hematopoietic cells and their microenvironment in regulating their function and properties, we determined all possible ligand-receptor interactions between hematopoietic stem and progenitor cells (HSPC) and every other BM constituent cell type. This analysis revealed a remarkable expansion of HSPC interactions in AML involving multiple BM constituent cells that can drive dysregulated HSPC-cell adhesion, immunosuppression and enhanced cytokine signalling. In particular, we found that interactions involving TGFB1 become widespread in AML and present evidence that these interactions can drive AML cell quiescence in vitro, thus highlighting TGFB1 signalling as a potential target for increasing drug sensitivity and preventing relapse. Our results shed light on potential mechanisms of enhanced competitiveness of AML HSPCs and an overall skewed microenvironment that fosters AML growth.
High-resolution kinetic gene expression analysis of T helper cell differentiation reveals a STAT-dependent, unique transcriptional program in Th1/2 hybrid cells
Authors: Burt Philipp , Peine Michael , Peine Caroline , Borek Zuzanna , Serve Sebastian , Floßdorf Michael , Hegazy Ahmed N. , Höfer Thomas , Löhning Max , Thurley Kevin
Published: May 2022

Selective differentiation of CD4+ T helper (Th) cells into specialized subsets such as Th1 and Th2 cells is a key element of the adaptive immune system driving appropriate immune responses. Besides those canonical Th cell lineages, hybrid phenotypes such as Th1/2 cells arise in vivo, and their generation could be reproduced in vitro. While master-regulator transcription factors like T-bet for Th1 and GATA-3 for Th2 cells drive and maintain differentiation into the canonical lineages, the transcriptional architecture of hybrid phenotypes is less well understood. In particular, it has remained unclear whether a hybrid phenotype implies a mixture of the effects of several canonical lineages for each gene, or rather a bimodal behavior across genes. Th cell differentiation is a dynamic process in which the regulatory factors are modulated over time, but longitudinal studies of Th cell differentiation are sparse. Here, we present a dynamic transcriptome analysis following Th cell differentiation into Th1, Th2 and Th1/2 hybrid cells. We identified an early bifurcation point in gene expression programs, and we found that only a minority of ∼20% of Th cell-specific genes showed mixed effects from both Th1 and Th2 cells on Th1/2 hybrid cells. While most genes followed either Th1 or Th2 cell gene expression, another fraction of ∼20% of genes followed a Th1 and Th2 cell-independent transcriptional program under control of the transcription factors STAT1 and STAT4. Overall, our results emphasize the key role of high-resolution longitudinal data for the characterization of cellular phenotypes.
Echolocation-like model of directed cell migration within growing tissues
Authors: Loo Tricia Y. J. , Mahabaleshwar Harsha , Carney Tom , Saunders Timothy E.
Published: May 2022

During development and regeneration, cells migrate to specific locations within growing tissues. These cells can respond to both biochemical signals and mechanical cues, resulting in directed migration. Such migration is often highly stereotypic. Yet, how cells respond to migratory signals in a robust manner within a growing domain remains an open problem. Here, we propose a model of directed migration in growing tissues motivated by echolocation. The migrating cells generate a signaling gradient that induces a response signal from the moving system boundary. This response signal mediates cellular adhesion to the surrounding matrix and hence modulates the cell migration. We find that such a mechanism can align a series of cells at stable positions within growing systems and can effectively scale to system size. Finally, we discuss the relevance of such a model to fibroblast migration and location within the developing zebrafish caudal fin, which may be regulated by opposing signaling gradients of Slit-Robo pathway components.

Significance Statement

How do cells reliably migrate within growing environments? Here, we show that cells can take advantage of an echolocation-like process, whereby they induce a response from the tissue boundary. As they approach the boundary, the response signal strengthens and brings the cell to a fixed position from the boundary. This simple system may be applicable to fibroblast migration in the fin.
Structural Basis of Mutation-Dependent p53 Tetramerization Deficiency
Authors: Rigoli Marta , Spagnolli Giovanni , Lorengo Giulia , Monti Paola , Potestio Raffaello , Biasini Emiliano , Inga Alberto
Published: May 2022

The formation of a tetrameric assembly is essential for the ability of the tumor suppressor protein p53 to act as a transcription factor. Such a quaternary conformation is driven by a specific tetramerization domain, separated from the central DNA binding domain by a flexible linker. Despite the distance, functional crosstalk between the two domains has been reported. This phenomenon can explain the pathogenicity of some inherited or somatically acquired mutations in the tetramerization domain, including the widespread R337H missense mutation occurring in the population of south Brazil. In this work, we have combined computational predictions through extended all-atom molecular dynamics simulations with functional assays in a genetically defined yeast-based model system to reveal structural features of p53 tetramerization domains and their transactivation capacity and specificity. Besides the germline and cancer-associated R337H and R337C, other rationally designed missense mutations targeting a significant salt bridge interaction that stabilizes the p53 tetramerization domain were studied (R337D, D352R, and the double mutation R337D plus D352R). Simulations revealed a destabilizing effect of pathogenic mutations within the p53 tetramerization domain and highlighted the importance of electrostatic interactions between residues 337 and 352. The transactivation assay performed in yeast by tuning the expression of wild-type and mutant p53 proteins revealed that p53 tetramerization mutations could decrease transactivation potential and alter transactivation specificity, in particular, by better tolerating the negative features in weak DNA binding sites. These results establish the effect of naturally occurring variations at positions 337 and 352 on p53 conformational stability and function.
Melanocyte-secreted Fibromodulin constrains skin inflammation in mice injected with lupus serum
Authors: Halasi Marianna , Nyska Abraham , Rubin Limor , Tal Yuval , Tsokos George C. , Adini Irit
Published: May 2022

Skin pigmentation has been linked to the development, prevalence, and severity of several immune-mediated diseases such as SLE. Here, we asked whether fibromodulin (FMOD), which is highly expressed in skin with light complexion, can explain the known differences in the magnitude of inflammation. C57 mice with different levels of pigmentation and FMOD were injected with human lupus serum to induce skin inflammation. Histopathologic studies revealed that black C57 FMOD+/+ that produce low levels of FMOD and white C57 FMOD -/- mice develop more severe inflammation compared with white FMOD +/+ mice. This study also revealed that dark pigmentation and FMOD deletion correlates with the increased numbers of Langerhans cells. Altogether, we identify low pigmentation and FMOD are linked to low severity of inflammation and approaches to promote FMOD expression should offer clinical benefit.
Synonymous codon usage regulates translation initiation
Authors: Barrington Chloe L. , Koch Amanda L. , Galindo Gabriel , Larkin-Gero Emma , Morrison Evan J. , Tisa Samantha , Stasevich Timothy J. , Rissland Olivia S.
Published: May 2022

Synonymous codon usage regulates gene expression such that transcripts rich in optimal codons produce significantly more protein than their nonoptimal counterparts. A major unresolved issue has been understanding the mechanisms by which synonymous codons regulate gene expression. We and others have previously shown that nonoptimal codons slow translation elongation speeds and thereby trigger mRNA degradation. However, differences in transcript abundance are not always sufficient to explain differences in protein levels, suggesting there are additional mechanisms by which codon usage regulates gene expression. Using reporter assays in human and Drosophila cells, we found that transcript levels account for less than half of the variation in protein abundance. We demonstrate that the differences at the protein level are not attributable to either protein folding or stability. Instead, we find that mRNAs with nonoptimal codons are bound by fewer ribosomes and that nonoptimal codon usage represses translation initiation. Nonoptimal transcripts are also less bound by the key translation initiation factors eIF4E and eIF4G, providing a mechanistic explanation for their reduced initiation rates. Our results reveal a new mechanism of regulation by codon usage, where nonoptimal codons repress further rounds of translation.
Conformational fluctuations in molten globule state ofα-lactalbumin
Authors: Ghosh Moulick Abhik , Chakrabarti J.
Published: May 2022

Molten globule (MG) state is an intermediate state of protein observed during folding into native structure. MG state of protein is induced by various denaturing agent (like Urea), extreme pH, pressure and heat. Experiments suggest that MG state of some protein is functionally relevant even if there is no well-defined tertiary structure. Earlier experimental and theoretical studies suggest that MG state of the protein is dynamic in nature, where conformational states are interconverted in nanosecond time scales. These observations lead us to study and compare conformational fluctuations of MG state to those of intrinsic disordered protein (IDP). We considerα-Lactalbumin(aLA) protein, which shows MG state at low pH upon removal of calcium (Ca2+) ion. We use constant pH molecular dynamics simulation (CpHMD) to maintain low pH during simulation. We use the dihedral principal component analysis, the density based clustering method and the machine learning technique to identify the conformational fluctuations. We observe metastable states in the MG state. The residues containing the essential coordinates responsible for metastability belong to stable helix in crystal structure, but most of them prefer unstructured or bend conformation in MG state. These residues control the exposure of the putative binding residues for fatty acids. Thus, the MG state of protein behaves as intrinsic disorder protein, although the disorder here is induced by external conditions.
Nlrc4 inflammasome is critical for host protection against flagellated Salmonella
Authors: López-Yglesias Américo H. , Lu Chun-Chi , Lai Marvin A. , Quarles Ellen K. , Zhao Xiaodan , Hajjar Adeline M. , Smith Kelly D.
Published: May 2022

Salmonella enterica serovar Typhimurium is a leading cause of gastroenteritis worldwide and a deadly pathogen in children, immunocompromised patients, and the elderly. Salmonella induces innate immune responses through the Nlrc4 inflammasome, which has been demonstrated to have distinct roles during systemic and mucosal detection of flagellin and non-flagellin molecules. We hypothesized that Nlrc4 recognition of Salmonella flagellin is the dominant protective pathway during infection. To test this hypothesis, we used wild-type, flagellin-deficient, and flagellin-overproducing Salmonella to establish the role of flagellin in mediating Nlrc4-dependent host resistance during systemic and mucosal infection. We observed that during the systemic phase of infection, Salmonella efficiently evades Nlrc4-mediated innate immunity. However, during mucosal Salmonella infection, flagellin recognition by the Nlrc4 inflammasome pathway is the dominant mediator of protective innate immunity. These data establish that recognition of Salmonella’s flagellin by the Nlrc4 inflammasome during mucosal infection is the dominant innate protective pathway for host resistance against the enteric pathogen.
NMR as a readout to monitor and restore the integrity of complex chemoenzymatic reactions
Authors: Marincin Kenneth A. , Hwang Yousang , Kengmana Everett S. , Meyers David J. , Frueh Dominique P.
Published: May 2022

The non-invasive nature of NMR offers a means to monitor biochemical reactions in situ at the atomic-level. We harness this advantage to monitor a complex chemoenzymatic reaction that sequentially modifies reagents and loads the product on a nonribosomal peptide synthetase carrier protein. We present a protocol including a novel pulse sequence that permits to assess both the integrity of reagents and the completion of each step in the reaction, thus alleviating otherwise time-consuming and costly approaches to debug and repeat inefficient reactions. This study highlights the importance of NMR as a tool to establish reliable and reproducible experimental conditions in biochemical studies.

Graphical Abstract
First report of classical knockdown resistance (kdr) mutation, L1014F, in human head louse Pediculus humanus capitis (Phthiraptera: Anoplura)
Authors: Mallick Prashant K. , Sindhania Ankita , Gupta Toshi , Singh Dhirendra P , Saini Seema , Singh Om P.
Published: May 2022

There are at least three known knockdown resistance (kdr) mutations reported globally in the human head louse Pediculus humanus capitis (Phthiraptera: Anoplura) that are associated with reduced sensitivity to pyrethroids. However, prevalence of kdr mutation is not known in the Indian subcontinent. To identify kdr mutations in the Indian population, the genomic region of the voltage-gated sodium channel gene encompassing IIS1-2 linker to IIS6 segments was PCR-amplified and sequenced from P. humanus capitis samples collected from different geographic localities of India. DNA sequencing revealed the presence of four kdr mutations, i.e., M827I, T929I, L932F and L1014F. The presence of a classical kdr mutation, L1014F, a most widely reported mutation across insect-taxa associated with kdr-trait, is being reported for the first time in P. humanus capitis.
Unique gut microbiome signatures among adult patients with moderate to severe atopic dermatitis in southern Chinese
Authors: Wang Yiwei , Hou Jinpao , Tsui Joseph Chi-Ching , Wang Lin , Zhou Junwei , Chan Un Kei , Lo Claudia Jun Yi , Siu Pui Ling Kella , Loo Steven King Fan , Tsui Stephen Kwok Wing
Published: May 2022

Imbalance of the immune system caused by alterations of gut microbiome is considered to be a critical factor in the pathogenesis of infant eczema but the exact role of the gut microbiome in adult atopic dermatitis (AD) patients remains to be clarified. To investigate the differences of the gut microbiome between adult AD patients and healthy individuals, stool samples of 234 adults, containing 104 AD patients and 130 healthy subjects were collected for amplicon sequencing. Altered structure and metabolic dysfunctions of the gut microbiome were identified in adult AD patients. Our results illustrated that the adult AD patients were more likely to have allergies, particularly non-food allergies. And the gut microbiome composition of the AD and normal groups were considerably different. Besides, Romboutsia and Clostridium_sensu_stricto_1 was enriched in the normal group, whereas Blautia, Butyricicoccus, Lachnoclostridium, Eubacterium_hallii_group, Erysipelatoclostridium, Megasphaera, Oscillibacter, Flavonifractor were dominated in the AD group. Moreover, purine nucleotide degradation pathways were significantly enriched in the AD group and the enrichment of proteinogenic amino acid biosynthesis pathways was found in the normal group. This study provides insights into new therapeutic strategies targeting the gut microbiome for AD and evidence for the involvement of gut-skin axis in AD patients.
Prevalence of Lung Cancer in Colombia and a New Diagnostic Algorithm Using Health Administrative Databases: A Real-World Evidence Study
Authors: Amaya-Nieto Javier , Torres Gabriel F. , Buitrago Giancarlo
Published: May 2022

Reliable, timely and detailed information on lung cancer prevalence, mortality and costs from middle-income countries is essential to policy design. Thus, we aimed to develop an electronic algorithm to identify lung cancer prevalent patients in Colombia by using administrative claims databases, as well as to estimate prevalence rates by age, sex and geographic region. We performed a cross-sectional study based on national claim databases in Colombia (Base de datos de suficiencia de la Unidad de Pago por Capitación and Base de Datos Única de Afiliados) to identify lung cancer prevalent patients in 2017. Several algorithms based on the presence or absence of oncological procedures (chemotherapy, radiotherapy and surgery) and a minimum number of months that each individual had lung cancer ICD-10 codes were developed. After testing 16 algorithms, those with the closest prevalence rates to those rates reported by aggregated official sources (Global Cancer Observatory and Cuenta de Alto Costo) were selected. We estimated prevalence rates by age, sex and geographic region. Two algorithms were selected: i) one algorithm that was defined as the presence of ICD-10 codes for 4 months or more (the sensitive algorithm); and ii) one algorithm that was defined by adding the presence of at least one oncological procedure (the specific algorithm). The estimated prevalence rates per 100,000 inhabitants were 15.3 and 9.7 for the sensitive and specific algorithms, respectively. These rates were higher in men (9.9 per 100,000), over 65-years-old (37.1 per 100,000) who lived in Central and Bogota regions (14.7 and 10.9 per 100,000, respectively). Selected algorithms showed similar aggregated prevalence estimations to those rates reported by official sources and allowed us to estimate prevalence rates in specific aging, regional and gender groups for Colombia by using national claims databases. These findings could be useful to identify clinical and economical outcomes related to lung cancer patients by using national individual-level databases.
Topology Adaptive Graph Convolution Network With Heterogeneous Entities For Predicting Adverse Events from Drug-Drug-Interactions
Authors: Bagchi Srijani , Sarkar Anasua , Maulik Ujjwal
Published: May 2022

In times like this, it is imperative to be cautious about the effects of drugs or vaccination doses on patients who are already suffering from other serious diseases. It’s not only the virus which can affect the body metabolisms, drugs to encounter the virus may also end up having unwanted negative effects. Therapeutic activities of drugs are often influenced by co-administration of drugs that may cause inevitable drug-drug interactions and inadvertent side effects. Therefore, prediction and identification of DDIs are extremely vital for patient safety and treatment modalities. In this context, we intend to develop a computational method based on functional similarity of drugs. Our objective has been enhanced by the usage of knowledge graphs which allows capturing underlying information embeddings in a biological network with heterogenous entities. On providing this knowledge graph as the input to a Topology Adaptive Graph Convolution Network which performs topologically-aware flexible convolutions, we achieve improvements on priorly proposed GCN models that has been shown as comparison.
Bacterial sterol methylation confounds eukaryotic biomarker interpretations
Authors: Brown Malory O. , Olagunju Babatunde O. , Giner José-Luis , Welander Paula V.
Published: May 2022

Sterol lipids are required by most eukaryotes and are readily preserved as sterane molecular fossils. These geologic steranes are broadly interpreted as biomarkers for ancient eukaryotes1,2although diverse bacteria also produce sterols3. Steranes with side-chain methylations can act as more specific biomarkers4if their sterol precursors are limited to particular extant eukaryotes and are absent in bacteria. An abundance of one such sterane, 24-isopropylcholestane, in late Neoproterozoic rocks has been attributed to marine demosponges and potentially represents the earliest evidence for animals on Earth5. However, debates over this interpretation6–14continue given the potential for alternative sources of 24-isopropylcholestane and the lack of experimental evidence demonstrating the function of enzymes that methylate sterols to give the 24-isopropyl side-chain. Here we show that sterol methyltransferases from both sponges and bacteria are functional and identify three bacterial methyltransferases each capable of sequential methylations resulting in the 24-isopropyl sterol side-chain. We identified two of these propylating enzymes in a demosponge metagenome suggesting bacterial symbionts contribute to 24-isopropyl sterol biosynthesis in demosponges. Our results demonstrate yet-uncultured bacteria have the genomic capacity to synthesize side-chain alkylated sterols and should therefore be considered when interpreting side-chain alkylated sterane biomarkers in the rock record.
Sexual selection and pseudogenization in primate fertilization
Authors: Carlisle Jolie A. , Bickell Andrew L. , Hart Michael W.
Published: May 2022

The mouse sperm protein ZP3R interacts with proteins in the egg coat and mediates sperm–egg adhesion in a species-specific manner. Understanding the function and evolution of such genes has important implications for studies of speciation, reproductive success, and infertility. A recent analysis showed that (1) the human pseudogeneC4BPAP1is the ortholog ofZp3r, (2)ZP3Rpseudogenization evolved independently in parallel among several primate lineages, and (3) functionalZP3Rgenes evolve under positive selection among other primate species. The causes of this pseudogenization ofZP3Rare unknown. To explore one plausible cause (changes in sexual selection on males), we searched forZP3Rpseudogenes in recently published genomes, then compared sexually selected male traits among lineages with and without a functionalZP3R. We found that traits associated with more intense sexual selection on males (large male body size, larger male canines, larger testes) were associated with functionalZP3Rexpression, and suggest that a relaxation of sexual selection may be associated with selection forZP3Rpseudogenization. This proposed causal relationship implies an evolutionary cost to maintaining redundancy in the suite of primate fertilization genes.

Lay summary

In sexual interactions more is often assumed to be better. But the evolution of animal genomes suggests that sometimes less is more: the adaptive loss of genes that function in sex may be favored by selection. How could this happen? One surprising answer comes from analyzing humans and some other primate species that have turned off a key gene calledZP3Rthat helps sperm bind to eggs. The loss of that gene function in some primates is associated with male traits (smaller bodies, smaller canines, smaller testes) that often indicate less vigorous selection on males to compete for matings with females. That correlation implies that the same selection acting on male morphological traits may also act on sperm molecular traits. The correlation also implies that it’s expensive to keep some genes turned on, and that when they’re no longer helpful it’s adaptive to turn them off or allow them to become fallow. This economy of gene expression in sex is an under-explored area of research.
On the interplay between lipids and asymmetric dynamics of an NBS degenerate ABC transporter
Authors: Tóth Ágota , Janaszkiewicz Angelika , Crespi Veronica , Di Meo Florent
Published: May 2022

Multidrug resistance-associated proteins are ABC C-family exporters. They are crucial in pharmacology as they transport various substrates across membranes. However, the role of the degenerate nucleotide-binding site (NBS) remains unclear likewise the interplay with the surrounding lipid environment. Here, we propose a dynamic and structural overview of MRP1 fromca. 110 µs molecular dynamics simulations. ATP binding to NBS1 is likely maintained along several transport cycles. Asymmetric NBD behaviour is ensured by lower signal transduction from NBD1 to the rest of the protein owing to the absence of ball-and-socket conformation between NBD1 and coupling helices. Even though surrounding lipids play an active role in the allosteric communication between the substrate-binding pocket and NBDs, our results suggest that lipid composition has a limited impact, mostly by affecting transport kinetics. We believe that our work can be extended to other degenerate NBS ABC proteins and provide hints for deciphering mechanistic differences among ABC transporters.
The genomic and bioclimatic characterization of Ethiopian barley (Hordeum vulgare L.) unveils challenges and opportunities to adapt to a changing climate
Authors: Lakew Basazen F. , Caproni Leonardo , Kassaw Seyoum A. , Miculan Mara , Ahmed Jemal Seid , Grazioli Simona , Kidane Yosef Gebrehawaryat , Fadda Carlo , Pè Mario Enrico , Dell’Acqua Matteo
Published: May 2022

The climate crisis is impacting agroecosystems of the global South, threatening the food security of millions of smallholder farmers. Understanding the effect of current and future climates on crop agrobiodiversity may guide breeding efforts and adaptation strategies to sustain the livelihoods of farmers cropping in challenging conditions. Here, we combine a genomic and climatic characterization of a large collection of traditional barley varieties from Ethiopia, key to food security in local smallholder farming systems. We employ data-driven approaches to characterize their local adaptation to current and future climates and identify barley genomic regions with potential for breeding for local adaptation. We used a sequencing approach to genotype at high- density 436 barley varieties, finding that their genetic diversity can be traced back to geography and environmental diversity in Ethiopia. We integrate this information in a genome-wide association study targeting phenology traits measured in common garden experiments as well as climatic features at sampling points of traditional varieties, describing 106 genomic loci associated with local adaptation. We then employ a machine learning approach to link barley genomic diversity with climate variation, estimating barley genomic offset in future climate scenarios. Our data show that the genomic characterization of traditional agrobiodiversity coupled with climate modelling may contribute to the mitigation of the climate crisis effects on smallholder farming systems.
Phage resistance profiling identifies new genes required for biogenesis and modification of the corynebacterial cell envelope
Authors: McKitterick Amelia C. , Bernhardt Thomas G.
Published: May 2022

Bacteria of the order Corynebacteriales including pathogens such as Mycobacterium tuberculosis and Corynebacterium diphtheriae are characterized by their complex, multi-layered envelope. In addition to a peptidoglycan layer, these organisms possess an additional polysaccharide layer made of arabinogalactan and an outer membrane layer composed predominantly of long-chain fatty acids called mycolic acids. This so-called mycolata envelope structure is both a potent barrier against antibiotic entry into cells and a target of several antibacterial therapeutics. A better understanding of the mechanisms underlying mycolata envelope assembly therefore promises to reveal new ways of disrupting this unique structure for the development of antibiotics and antibiotic potentiators. Because they engage with receptors on the cell surface during infection, bacteriophages have long been used as tools to uncover important aspects of host envelope assembly. However, surprisingly little is known about the interactions between Corynebacteriales phages and their hosts. We therefore made use of the phages Cog and CL31 that infect Corynebacterium glutamicum (Cglu), a model member of the Corynebacteriales, to discover host factors important for phage infection. A high-density transposon library of Cglu was challenged with these phages followed by transposon sequencing to identify resistance loci. The analysis identified an important role for mycomembrane porins in phage infection as well as components of the arabinogalactan and mycolic acid synthesis pathways. Importantly, the approach also implicated a new gene (cgp_0396) in the process of arabinogalactan modification and identified a conserved new factor (AhfA, Cpg_0475) required for mycolic acid synthesis in Cglu.
Clonally selected lines after CRISPR/Cas editing are not isogenic
Authors: Panda Arijit , Suvakov Milovan , Mariani Jessica , Drucker Kristen L. , Park Yohan , Jang Yeongjun , Kollmeyer Thomas M. , Sarkar Gobinda , Bae Taejeong , Kim Jean J. , Yoon Wan Hee , Jenkins Robert B. , Vaccarino Flora , Abyzov Alexej
Published: May 2022

The CRISPR-Cas9 system has enabled researchers to precisely modify/edit the sequence of a genome. A typical editing experiment consists of two steps: (i) editing cultured cells; (ii) cell cloning and selection of clones with and without intended edit, presumed to be isogenic. The application of CRISPR-Cas9 system may result in off-target edits, while cloning will reveal culture-acquired mutations. We analyzed the extent of the former and the latter by whole genome sequencing in three experiments involving separate genomic loci and conducted by three independent laboratories. In all experiments we hardly found any off-target edits, while detecting hundreds to thousands of single nucleotide mutations unique to each clone after relatively short culture of 10-20 passages. Notably, clones also differed in copy number alterations that were several kb to several mb in size and represented the largest source of genomic divergence among clones. We suggest that screening of clones for mutations and copy number alterations acquired in culture is a necessary step to allow correct interpretation of DNA editing experiments. Furthermore, since culture associated mutations are inevitable, we propose that experiments involving derivation of clonal lines should compare a mix of multiple unedited lines and a mix of multiple edited lines.
Emergent low-frequency activity in cortico-cerebellar networks with motor skill learning
Authors: Fleischer Pierson J. , Abbasi Aamir , Fealy Andrew W. , Danielsen Nathan P. , Sandhu Ramneet , Raj Philip R. , Gulati Tanuj
Published: May 2022

The motor cortex controls skilled arm movement by recruiting a variety of targets in the nervous system, and it is important to understand the emergent activity in these regions as refinement of a motor skill occurs. One fundamental projection of the motor cortex is to the cerebellum. However, the emergent activity in the motor cortex and the cerebellum that appears as a dexterous motor skill is consolidated is incompletely understood. Here, we report on low-frequency oscillatory (LFO) activity that emerges in cortico-cerebellar networks with learning the reach-to-grasp motor skill. We chronically recorded the motor and the cerebellar cortices in rats which revealed the emergence of coordinated movement-related activity in the local-field potentials (LFPs) as the reaching skill consolidated. We found that the local and cross-area spiking activity was coordinated with LFOs. Finally, we also found that these neural dynamics were more prominently expressed during accurate behavior. This work furthers our understanding on emergent dynamics in the cortico-cerebellar loop that underlie learning and execution of precise skilled movement.
The archaeological potential of the northern Luangwa Valley, Zambia: the Luwumbu basin
Authors: Burke A. , Bisson M. , Schilt F. , Tolan S. , Drapeau M. , Aleman J. , Peros M.
Published: May 2022

The Luangwa Basin, Zambia, which forms part of the Zambezi drainage, is strategically located between the Central African plateau and the East African Rift system. The Luangwa River and major tributaries, such as the Luwumbu River, are perennial water sources supporting essential resources that sustain human communities and a rich and diverse fauna and flora. The archaeological record of Luangwa is relatively unknown, despite early archaeological exploration hinting at its potential. Recent research in the southern Luangwa valley, however, suggests that it preserves a long record of hominin occupation spanning the Early to Late Stone Age. The research described here details fieldwork carried out in northeastern Luangwa, in the Luwumbu Basin, that confirms that a relatively deep package of Quaternary deposits, containing evidence of the Stone Age occupation of the region persists in the upper piedmont zone.