Miracle-dz/UniFAR-FTUs huggingface dataset:
Gene flow in phylogenomics: Sequence capture resolves species limits and biogeography of Afromontane forest endemic frogs from the Cameroon Highlands

Puddle frogs of the Phrynobatrachus steindachneri species complex are a useful group for investigating speciation and phylogeography in Afromontane forests of the Cameroon Highlands (Cameroon Volcanic Line) in western Central Africa. The species complex is represented by six morphologically relatively cryptic mitochondrial DNA lineages, with only two of them distinguished at the species level – southern P. jimzimkusi and Lake Oku endemic P. njiomock, leaving the remaining four lineages with a pooled identification as ‘P. steindachneri’. In this study, the six mtDNA lineages are subjected to genomic sequence capture analyses to delimit species (together with morphology) and to study biogeography. Nuclear DNA data (387 loci; 571,936 aligned base pairs) distinguished all six mtDNA lineages, but the splitting pattern and depths of divergences supported only four main clades—besides P. jimzimkusi and P. njiomock, only two from the four ‘P. steindachneri’ mtDNA lineages. One is here described as a new species, P. sp. nov. Reticulate evolution (hybridization) was detected within the species complex with morphologically intermediate hybrid individuals placed between the parental species in phylogenomic analyses, forming a phylogenetic artefact – a ladder-like tree pattern. The presence of hybrids is undesirable in standard phylogenetic analyses, but is essential and beneficial in the network multispecies coalescent. This latter approach allowed us an insight into the reticulate evolutionary history of these endemic frogs. Introgressions likely occurred during the Middle and Late Pleistocene climatic oscillations, due to the cyclic connections (likely dominating during cold glacials) and separations (warm interglacials) of montane forests. The genomic phylogeographic pattern supports the earliest division between southern (Mt. Manengouba to Mt. Oku) and northern mountains at the onset of the Pleistocene. Further subdivisions occurred in the Early Pleistocene separating populations from the northernmost (Tchabal Mbabo, Gotel Mts.) and middle mountains (Mt. Mbam, Mt. Oku, Mambilla Plateau), as well as the microendemic lineage restricted to Lake Oku (Mt. Oku). Mount Oku harboring three species is of particular conservation importance. This unique model system is highly threatened as all the species within the complex have exhibited severe population declines in the past decade, placing them on the brink of extinction. We therefore urge for conservation actions in the Cameroon Highlands to preserve their diversity before it is too late.
Neutralizing antibodies from early cases of SARS-CoV-2 infection offer cross-protection against the SARS-CoV-2 D614G variant

The emergence of a SARS-CoV-2 variant with a point mutation in the spike (S) protein, D614G, has taken precedence over the original Wuhan isolate by May 2020. With an increased infection and transmission rate, it is imperative to determine whether antibodies induced against the D614 isolate may cross-neutralize against the G614 variant. In this report, profiling of the anti-SARS-CoV-2 humoral immunity reveals similar neutralization profiles against both S protein variants, albeit waning neutralizing antibody capacity at the later phase of infection. These findings provide further insights towards the validity of current immune-based interventions. IMPORTANCE Random mutations in the viral genome is a naturally occurring event that may lead to enhanced viral fitness and immunological resistance, while heavily impacting the validity of licensed therapeutics. A single point mutation from aspartic acid (D) to glycine (G) at position 614 of the SARS-CoV-2 spike (S) protein, termed D614G, has garnered global attention due to the observed increase in transmissibility and infection rate. Given that a majority of the developing antibody-mediated therapies and serological assays are based on the S antigen of the original Wuhan reference sequence, it is crucial to determine if humoral immunity acquired from the original SARS-CoV-2 isolate is able to induce cross-detection and cross-protection against the novel prevailing D614G variant.
RBMX enables productive RNA processing of ultra-long exons important for genome stability

Previously we showed that the germline-specific RNA binding protein RBMXL2 is essential for male meiosis where it represses cryptic splicing patterns (1). Here we find that its ubiquitously expressed paralog RBMX helps underpin human genome stability by preventing non-productive splicing. In particular, RBMX blocks selection of aberrant splice and polyadenylation sites within some ultra-long exons that would interfere with genes needed for normal replication fork activity. Target exons include within the ETAA1 (Ewings Tumour Associated 1) gene, where RBMX collaborates with its interaction partner Tra2β to enable full-length exon inclusion by blocking selection of an aberrant 3’ splice site. Our data reveal a novel group of RNA processing targets potently repressed by RBMX, and help explain why RBMX is associated with gene expression networks in cancer, replication and sensitivity to genotoxic drugs.
Atypical Molecular Basis for Drug Resistance to Mitochondrial Function Inhibitors in Plasmodium falciparum

The continued emergence of drug-resistant Plasmodium falciparum parasites hinders global attempts to eradicate malaria, emphasizing the need to identify new antimalarial drugs. Attractive targets for chemotherapeutic intervention are the cytochrome (cyt) bc1 complex, which is an essential component of the mitochondrial electron transport chain (mtETC) required for ubiquinone recycling and mitochondrially localized dihydroorotate dehydrogenase (DHODH) critical for de novo pyrimidine synthesis. ABSTRACT The continued emergence of drug-resistant Plasmodium falciparum parasites hinders global attempts to eradicate malaria, emphasizing the need to identify new antimalarial drugs. Attractive targets for chemotherapeutic intervention are the cytochrome (cyt) bc1 complex, which is an essential component of the mitochondrial electron transport chain (mtETC) required for ubiquinone recycling and mitochondrially localized dihydroorotate dehydrogenase (DHODH) critical for de novo pyrimidine synthesis. Despite the essentiality of this complex, resistance to a novel acridone class of compounds targeting cyt bc1 was readily attained, resulting in a parasite strain (SB1-A6) that was panresistant to both mtETC and DHODH inhibitors. Here, we describe the molecular mechanism behind the resistance of the SB1-A6 parasite line, which lacks the common cyt bc1 point mutations characteristic of resistance to mtETC inhibitors. Using Illumina whole-genome sequencing, we have identified both a copy number variation (∼2×) and a single-nucleotide polymorphism (C276F) associated with pfdhodh in SB1-A6. We have characterized the role of both genetic lesions by mimicking the copy number variation via episomal expression of pfdhodh and introducing the identified single nucleotide polymorphism (SNP) using CRISPR-Cas9 and assessed their contributions to drug resistance. Although both of these genetic polymorphisms have been previously identified as contributing to both DSM-1 and atovaquone resistance, SB1-A6 represents a unique genotype in which both alterations are present in a single line, suggesting that the combination contributes to the panresistant phenotype. This novel mechanism of resistance to mtETC inhibition has critical implications for the development of future drugs targeting the bc1 complex or de novo pyrimidine synthesis that could help guide future antimalarial combination therapies and reduce the rapid development of drug resistance in the field.
Do We Belittle Essential Tremor by Calling It a Syndrome Rather Than a Disease? Yes

Essential tremor (ET) is among the most prevalent neurological diseases. Appreciation in recent years of a richer tremor phenomenology, additional motor and non-motor features, variability in the natural course of tremor, associations with a host of other neurological conditions, and etiological and pathophysiological heterogeneity have resulted in general awareness of the clinical richness of ET. Along with this evolving view of ET have surfaced several conundrums regarding nomenclature. One of these is whether ET should be labeled a “syndrome” or “disease. ” Here, we revisit the classical definitions of “syndrome” and “disease” and discuss ET in this context. Considering the characteristics of “disease” and “syndrome” and evaluating the characteristics of ET, it seems to fit more into the “disease” construct. There are several reasons: There is considerable knowledge of the underlying etiologies and pathophysiology of ET, in numerous studies ET has been linked with other neurological conditions, the condition is progressive and deteriorative, and therapeutic approaches are grounded in an understanding of disease mechanisms and its associated neuroanatomy. Moreover, the etiological–pathological–clinical heterogeneity suggests that ET should be regarded as a “family of diseases” more appropriately termed “the essential tremors. ” This nomenclatural issue is not a mere matter of words; public health implications are numerous. A condition with the label “syndrome” may not be recognized as a serious problem, may be plagued by diminished public awareness, and may not garner funds for research that a condition with the label “disease” or “diseases” would. ET should be regarded as a family of diseases.
Learning when effort matters: Neural dynamics underlying updating and adaptation to changes in performance efficacy

To determine how much cognitive control to invest in a task, people need to consider whether exerting control matters for obtaining rewards. In particular, they need to account for the efficacy of their performance – the degree to which rewards are determined by performance or by independent factors. Yet it remains unclear how people learn about their performance efficacy in an environment. Here we combined computational modeling with measures of task performance and EEG, to provide a mechanistic account of how people (a) learn and update efficacy expectations in a changing environment, and (b) proactively adjust control allocation based on current efficacy expectations. Across two studies subjects performed an incentivized cognitive control task while their performance efficacy (the likelihood that rewards are performance- contingent or random) varied over time. We show that people update their efficacy beliefs based on prediction errors – leveraging similar neural and computational substrates as those that underpin reward learning – and adjust how much control they allocate according to these beliefs. Using computational modeling, we show that these control adjustments reflect changes in information processing, rather than the speed-accuracy tradeoff. These findings demonstrate the neurocomputational mechanism through which people learn how worthwhile their cognitive control is.
Function expansion of antitumor transcriptional activator NFE2L1 by the original discovery of its non-transcription factor activity

Antitumor transcription activator NFE2L1, with the functions to regulate redox homeostasis, protein turnover, and material metabolism, plays an important role in embryonic development and specialization of tissue and organ functions. Deficiency of NFE2L1 gene in different regions yields distinct phenotypes, suggesting that NFE2L1 may have a transcription factor-independent function. Here we originally discovered the non-transcription factor activity of NFE2L1 by constructing a truncated protein-NFE2L1ΔC without 152 aa at the C-terminus which lost the transcription factor activity. The regulation of NFE2L1 on redox homeostasis, proteasome function, and immune response mainly depends on its transcription activator function in nucleus, while the regulation on metabolism, ribosome function, and canceration is germanely to its non-transcription factor activity in cytoplasm. Surprisingly, the results indicated the tumor suppressive effect of NFE2L1 by repression of Wnt/β-catenin signaling in a non-transcription factor manner, indicating the potential value of NFE2L1 as a therapeutic target in clinical cancer treatment independent of its transcription factor activity. Our observations reveal the non-transcription factor activity of NFE2L1 for the first time, and lay foundation for the basic and applied research of NFE2L1.
Genomic heritability of song and condition in wild singing mice

Courtship displays are dramatic examples of complex behaviors that vary within and among species. Evolutionary explanations for this diversity rely upon genetic variation, yet the heritability of complex phenotypes is seldom investigated in the field. Here, we estimate genomic heritability of advertisement song and body condition in a wild population of singing mice. The heritability of song exhibits a systematic pattern, with high heritability for spectral characteristics linked to vocal morphology, intermediate heritability for rhythmic patterns, and lower but significant heritability for measures of motivation, like song length and rate. Physiological measures of condition, like hormonal markers of adiposity, exhibited intermediate heritability. Among singing mice, song rate and body condition have a strong phenotypic correlation; our estimate suggests a comparable genetic correlation that merits further study. Our results illustrate how advances in genomics and quantitative genetics can be integrated in free-living species to address longstanding challenges in behavior and evolution.
A Comprehensive Toolkit for Quick and Easy Visualization of Marker Proteins, Protein–Protein Interactions and Cell Morphology in Marchantia polymorpha

Even though stable genomic transformation of sporelings and thalli of Marchantia polymorpha is comparatively straightforward and efficient, numerous problems can arise during critical phases of the process such as efficient spore production, poor selection capacity of antibiotics or low transformation efficiency. It is therefore also desirable to establish quick methods not relying on stable transgenics to analyze the localization, interactions and functions of proteins of interest. The introduction of foreign DNA into living cells via biolistic mechanisms has been first reported roughly 30 years ago and has been commonly exploited in established plant model species such as Arabidopsis thaliana or Nicotiana benthamiana. Here we report the fast and reliable transient biolistic transformation of Marchantia thallus epidermal cells using fluorescent protein fusions. We present a catalogue of fluorescent markers which can be readily used for tagging of a variety of subcellular compartments. Moreover, we report the functionality of the bimolecular fluorescence complementation (BiFC) in M. polymorpha with the example of the p-body markers MpDCP1/2. Finally, we provide standard staining procedures for live cell imaging in M. polymorpha, applicable to visualize cell boundaries or cellular structures, to complement or support protein localizations and to understand how results gained by transient transformations can be embedded in cell architecture and dynamics. Taken together, we offer a set of easy and quick tools for experiments that aim at understanding subcellular localization, protein-protein interactions and thus functions of proteins of interest in the emerging early diverging land plant model M. polymorpha.
Environmental DNA Metabarcoding Reveals Winners and Losers of Global Change in Coastal Waters

Studies of the ecological effects of global change often focus on one or few species at a time. Consequently, we know relatively little about the changes underway at real-world scales of biological communities, which typically have hundreds or thousands of interacting species. Here, we use monthly samples of environmental DNA to survey 222 planktonic taxa along a gradient of temperature, salinity, dissolved oxygen, and carbonate chemistry in nearshore marine habitat. The result is a high-resolution picture of changes in ecological communities using a technique replicable across a wide variety of ecosystems. We estimate community-level differences associated with time, space and environmental variables, and use these results to forecast near-term community changes due to warming and ocean acidification. We find distinct communities in warmer and more acidified conditions, with overall reduced richness in diatom assemblages and increased richness in dinoflagellates. Individual taxa finding greater suitable habitat in near-future waters are more taxonomically varied and include the ubiquitous coccolithophore Emiliania huxleyi and the harmful dinoflagellate Alexandrium sp. These results suggest foundational changes for nearshore food webs under near-future conditions.
Integration of prophages into CRISPR loci remodels viral immunity in Streptococcus pyogenes

CRISPR loci are composed of short DNA repeats separated by sequences that match the genomes of phages and plasmids, known as spacers. Spacers are transcribed and processed to generate RNA guides used by CRISPR-associated nucleases to recognize and destroy the complementary nucleic acids of invaders. To counteract this defense, phages can produce small proteins that inhibit these nucleases. Here we demonstrate that the ΦAP1. 1 temperate phage utilizes an alternate approach to antagonize the type II-A CRISPR response in Streptococcus pyogenes. Immediately after infection this phage expresses a canonical anti-CRISPR, AcrIIA23 that prevents Cas9 function, allowing ΦAP1. 1 to integrate into the direct repeats of the CRISPR locus and neutralizing immunity. However, acrIIA23 is not transcribed during lysogeny and phage integration/excision cycles can result in the deletion and/or transfer of spacers, enabling a complex modulation of the type II-A CRISPR immune response.
Unravelling the evolutionary relationships of hepaciviruses within and across rodent hosts

Hepatitis C virus (HCV; genus Hepacivirus) represents a major public health problem, infecting about 3 % of the human population (± 185,000,000 people). Because no plausible animal reservoir carrying closely related hepaciviruses has been identified, the zoonotic origins of HCV still remain elusive. Motivated by recent findings of divergent hepaciviruses in rodents and a plausible African origin of HCV genotypes, we have screened a comprehensive collection of small mammals samples from seven sub-Saharan African countries. Out of 4,303 samples screened, 80 were found positive for the presence of hepaciviruses in 29 different host species. We here report 56 novel genomes that considerably increase the diversity of three divergent rodent hepacivirus lineages, which previously were almost exclusively represented by New World and European hepaciviruses. Further-more, we provide undisputable evidence for hepacivirus co-infections in rodents, which remarkably, we exclusively but repeatedly found in four sampled species of brush-furred mice. We also point at hepacivirus co-infections indirectly in different animal hosts by demonstrating evidence for recombination within specific host lineages. Our study considerably expands the available hepacivirus genomic data and elucidates the relatively deep evolutionary history that these pathogens have in rodents compared to other mammalian hosts. Overall, our results emphasize the importance of rodents as a potential hepacivirus reservoir and as models for investigating HCV infection dynamics.
Attack behaviour in naïve Gyrfalcons is modelled by the same guidance law as in Peregrines, but at a lower guidance gain

The aerial hunting behaviours of birds are strongly influenced by their flight morphology and ecology, but little is known of how this variation relates to the behavioural algorithms guiding flight. Here we use onboard GPS loggers to record the attack trajectories of captive-bred Gyrfalcons (Falco rusticolus) during their maiden flights against robotic aerial targets, which we compare to existing flight data from Peregrines (Falco peregrinus) The attack trajectories of both species are modelled most economically by a proportional navigation guidance law, which commands turning in proportion to the angular rate of the line-of-sight to target, at a guidance gain N. However, Gyrfalcons operate at significantly lower values of N than Peregrines, producing slower turning and a longer path to intercept. Gyrfalcons are less agile and less manoeuvrable than Peregrines, but this physical constraint is insufficient to explain their lower guidance gain. On the other hand, lower values of N promote the tail-chasing behaviour that is typical of wild Gyrfalcons, and which apparently serves to tire their prey in a prolonged high-speed pursuit. Moreover, during close pursuit of fast evasive prey such as Ptarmigan (Lagopus spp.), proportional navigation will be less prone to being thrown off by erratic target manoeuvres if N is low. The fact that low-gain proportional navigation successfully models the maiden attack flights of Gyrfalcons suggests that this behavioural algorithm is embedded in a hardwired guidance loop, which we hypothesise is ancestral to the clade containing Gyrfalcons and Peregrines. SUMMARY STATEMENT Naïve Gyrfalcons attacking aerial targets are modelled by the same proportional navigation guidance law as Peregrines, but with a lower navigation constant that promotes tail-chasing rather than efficient interception.
Multiplane Mesoscope reveals distinct cortical interactions following expectation violations

Cortical columns interact through dynamic routing of neuronal activity. Monitoring these interactions in animals performing a behavioral task as close as possible to real time will advance our understanding of cortical computation. We developed the Multiplane Mesoscope which combines three established concepts in microscopy: spatio-temporal multiplexing, remote focusing, and random-access mesoscopy. With the Multiplane Mesoscope, we recorded excitatory and inhibitory neuronal subpopulations simultaneously across two cortical areas and multiple cortical layers in behaving mice. In the context of a visual detection of change task, we used this novel platform to study cortical areas interactions and quantified the cell-type specific distribution of neuronal correlations across a set of visual areas and layers. We found that distinct cortical subnetworks represent expected and unexpected visual events. Our findings demonstrate that expectation violations modify signal routing across cortical columns and establish the Allen Brain Observatory Multiplane Mesoscope as a unique platform to study signal routing across connected pairs of cortical areas.
Synergistic effect of deoxynucleosides and AAV gene therapy for thymidine kinase 2 deficiency

Autosomal recessive thymidine kinase 2 (TK2) mutations causes TK2 deficiency, which typically manifests as a progressive and fatal mitochondrial myopathy in infants and children. Treatment with deoxycytidine and thymidine ameliorates mitochondrial defects and extends lifespan of Tk2 knock-in mouse (TK2−/−); however, efficacy is limited by age- and tissue-dependent expression of the cytosolic enzymes Tk1 and Dck. Thus, therapies aimed at systemic restoration of TK2 activity are needed. Here, we demonstrate that delivery of human TK2 cDNA to Tk2−/− mice using AAV9 efficiently rescued Tk2 activity in all the tissues tested except kidney, delayed disease onset, and increased lifespan. Sequential treatment of Tk2−/− mice with AAV9 first followed by AAV2 at different ages allowed us to reduce the viral dose while further prolonging the lifespan. Furthermore, addition of deoxycytidine and deoxythymidine supplementation to AAV9 + AAV2 treated Tk2−/− mice dramatically improved mtDNA copy numbers in liver and kidney, animal growth, and lifespan. These data indicate that combined pharmacological and gene therapies may be highly efficacious for human TK2 deficiency.