bluuebunny/crossref_metadata_2025 huggingface dataset:
Placebo Effect in Randomized Trials of Major Depressive Disorder With Psychotic Features
Authors: Perivolaris Argyrios , Ainsworth Nicholas J. , Alexopoulos George S. , Bingham Kathleen S. , Flint Alastair J. , Marino Patricia , Neufeld Nicholas H. , Rothschild Anthony J. , Voineskos Aristotle N. , Whyte Ellen M. , Mulsant Benoit H. ,   on behalf of the STOP-PD II Study Group
Published: August 2022

Background

In the 1980s, the response rate of major depressive disorder with psychotic features (MDD-Psy) to placebo pills was reported to be close to 0%. To our knowledge, this placebo response rate has not been systematically reassessed. We undertook a systematic review of randomized controlled trials (RCTs) that have used a placebo or sham control group for MDD-Psy.

Methods

We searched MEDLINE and identified 9 relevant publications reporting on 10 studies comparing a placebo or sham interventions versus an active intervention. We extracted reported rates of response or of dropout for all causes associated with placebo versus active intervention(s) and aggregated response and dropout rates across trials.

Results

Two sham-controlled electroconvulsive therapy (ECT) trials did not provide response rates. In the 3 pharmacotherapy studies published in the 1980s, 0 of 12 participants (0%) responded to placebo versus 13 of 38 (34.2%) responding to the active interventions. In contrast, 5 RCTs published in the 2000s, 114 of 339 participants (33.6%) randomized to placebo responded versus 149 of 373 participants (39.9%) randomized to active interventions; dropout rates were 71/236 (30.1%) for placebo versus 84/282 (29.8%) for the active interventions.

Conclusions

As expected, response rates to placebo pills in RCTs for MDD-Psy increased markedly from the 1980s to the 2000s. Methodological issues in the design and conduct of more recent RCTs may have contributed to the high placebo response. However, one needs to consider this placebo response rate when interpreting the result of recent trials of MDD-Psy, which typically have not included a “pure” placebo condition.
Outcomes and Predictors of Sustained Remission After Drug Withdrawal in Pediatric Crohn Disease
Authors: Stein Ronen , Daniel Scott G. , Baldassano Robert N. , Feigenbaum Kara , Kachelries Kelly , Sigall‐Boneh Rotem , Weston Sarah , Levine Arie , Bittinger Kyle
Published: August 2022

Objectives:

The primary aim of this study was to determine the proportion of pediatric Crohn disease (CD) subjects in sustained drug‐free remission 52 weeks after stopping pharmacological therapy. We also aimed to explore the effects of the Crohn Disease Exclusion Diet (CDED) and microbiome composition on remission.

Methods:

We performed a prospective study following 18 CD patients ages 13–21 years in deep clinical remission withdrawing from immunomodulator (n = 7) or anti‐TNFα (n = 11) monotherapy at two tertiary care centers. Stool for calprotectin and microbiome analyses was collected over 52 weeks. Participants followed either the CDED or free diet after drug withdrawal. The primary endpoint was sustained relapse‐free drug‐free remission (calprotectin <250 µg/g) at 52 weeks.

Results:

Seventeen participants were followed through 52 weeks with 11 (64.7%) in sustained remission. There was no improvement in remission among participants following the CDED (5/9; 55.6%), P = 0.63. By 104 weeks, only 8 (47.1 %) participants remained off immunosuppressive therapies. Analysis of shotgun metagenomic sequence data revealed that taxonomic and gene function abundance in the gut microbiome was relatively stable for participants in remission and relapse. However, a predictive model incorporating gut microbial gene pathway abundance for amino sugar/nucleotide sugar metabolism and galactose metabolism from baseline samples predicted relapse at 52 weeks with 80% accuracy.

Conclusions:

After withdrawal of immunomodulator or anti‐TNFα monotherapy among a small cohort of pediatric CD subjects in deep remission, nearly 65% sustained remission at 52 weeks. Baseline microbiome alterations predicted relapse. Large prospective studies are needed to better understand outcomes after treatment de‐escalation.
Artificially long legs directly enhance long sprint running performance
Authors: Weyand Peter G. , Brooks Lance C. , Prajapati Sunil , McClelland Emily L. , Hatcher S. K. , Callier Quinn M. , Bundle Matthew W.
Published: August 2022

This comment addresses the incomplete presentation and incorrect conclusion offered in the recent manuscript of Beck
et al
. (
R. Soc. Open Sci.
9
, 211799 (
doi:10.1098/rsos.211799
)). The manuscript introduces biomechanical and performance data on the fastest-ever, bilateral amputee 400 m runner. Using an advantage standard of not faster than the fastest non-amputee runner ever (i.e. performance superior to that of the intact-limb world record-holder), the Beck
et al
. manuscript concludes that sprint running performance on bilateral, lower-limb prostheses is not unequivocally advantageous compared to the biological limb condition. The manuscript acknowledges the long-standing support of the authors for the numerous eligibility applications of the bilateral-amputee athlete. However, it does not acknowledge that the athlete's anatomically disproportionate prosthetic limb lengths (+15 cm versus the World Para Athletics maximum) are
ineligible
in both Olympic and Paralympic track competition due to their performance-enhancing properties. Also not acknowledged are the slower sprint performances of the bilateral-amputee athlete on limbs of shorter length that directly refute their manuscript's primary conclusion. Our contribution here provides essential background information and data not included in the Beck
et al.
manuscript that make the correct empirical conclusion clear: artificially long legs artificially enhance long sprint running performance.
The thermal performance curve for aerobic metabolism of a flying endotherm
Authors: Glass Jordan R. , Harrison Jon F.
Published: August 2022

Performance benefits of stable, warm muscles are believed to be important for the evolution of endothermy in mammals, birds and flying insects. However, thermal performance curves have never been measured for a free-flying endotherm, as it is challenging to vary body temperatures of these animals, and maximal flight performance is difficult to elicit. We varied air temperatures and gas densities to manipulate thoracic temperatures of flying honeybees from 29°C to 44°C, with low air densities used to increase flight metabolic rates to maximal values. Honeybees showed a clear thermal performance curve with an optimal temperature of 39°C. Maximal flight metabolic rates increased by approximately 2% per 1°C increase in thoracic temperature at suboptimal thoracic temperatures, but decreased approximately 5% per 1°C increase as the bees continued to heat up. This study provides the first quantification of the maximal metabolic performance benefit of thermoregulation in an endotherm. These data directly support aerobic capacity models for benefits of thermoregulation in honeybees, and suggest that improved aerobic capacity probably contributes to the multiple origins of endothermic heterothermy in bees and other insects.
Gut microbiota individuality is contingent on temporal scale and age in wild meerkats
Authors: Risely Alice , Schmid Dominik W. , Müller-Klein Nadine , Wilhelm Kerstin , Clutton-Brock Tim H. , Manser Marta B. , Sommer Simone
Published: August 2022

Inter-individual differences in gut microbiota composition are hypothesized to generate variation in host fitness—a premise for the evolution of host–gut microbe symbioses. However, recent evidence suggests that gut microbial communities are highly dynamic, challenging the notion that individuals harbour unique gut microbial phenotypes. Leveraging a long-term dataset of wild meerkats, we reconcile these concepts by demonstrating that the relative importance of identity for shaping gut microbiota phenotypes depends on the temporal scale. Across meerkat lifespan, year-to-year variation overshadowed the effects of identity and social group in predicting gut microbiota composition, with identity explaining on average less than 2% of variation. However, identity was the strongest predictor of microbial phenotypes over short sampling intervals (less than two months), predicting on average 20% of variation. The effect of identity was also dependent on meerkat age, with the gut microbiota becoming more individualized and stable as meerkats aged. Nevertheless, while the predictive power of identity was negligible after two months, gut microbiota composition remained weakly individualized compared to that of other meerkats for up to 1 year. These findings illuminate the degree to which individualized gut microbial signatures can be expected, with important implications for the time frames over which gut microbial phenotypes may mediate host physiology, behaviour and fitness in natural populations.
Pigmentation biosynthesis influences the microbiome in sea urchins
Authors: Wessel Gary M. , Kiyomoto Masato , Reitzel Adam M. , Carrier Tyler J.
Published: August 2022

Organisms living on the seafloor are subject to encrustations by a wide variety of animals, plants and microbes. Sea urchins, however, thwart this covering. Despite having a sophisticated immune system, there is no clear molecular mechanism that allows sea urchins to remain free of epibiotic microorganisms. Here, we test the hypothesis that pigmentation biosynthesis in sea urchin spines influences their interactions with microbesin vivousing CRISPR/Cas9. We report three primary findings. First, the microbiome of sea urchin spines is species-specific and much of this community is lost in captivity. Second, different colour morphs associate with bacterial communities that are similar in taxonomic composition, diversity and evenness. Lastly, loss of the pigmentation biosynthesis genes polyketide synthase and flavin-dependent monooxygenase induces a shift in which bacterial taxa colonize sea urchin spines. Therefore, our results are consistent with the hypothesis that host pigmentation biosynthesis can, but may not always, influence the microbiome in sea urchin spines.
Biodiversity cradles and museums segregating within hotspots of endemism
Authors: Sonne Jesper , Dalsgaard Bo , Borregaard Michael K. , Kennedy Jonathan , Fjeldså Jon , Rahbek Carsten
Published: August 2022

The immense concentrations of vertebrate species in tropical mountains remain a prominent but unexplained pattern in biogeography. A long-standing hypothesis suggests that montane biodiversity hotspots result from endemic species aggregating within ecologically stable localities. Here, the persistence of ancient lineages coincides with frequent speciation events, making such areas both ‘cradles’ (where new species arise) and ‘museums’ (where old species survive). Although this hypothesis refers to processes operating at the scale of valleys, it remains supported primarily by patterns generated from coarse-scale distribution data. Using high-resolution occurrence and phylogenetic data on Andean hummingbirds, we find that old and young endemic species are not spatially aggregated. The young endemic species tend to have non-overlapping distributions scattered along the Andean treeline, a long and narrow habitat where populations easily become fragmented. By contrast, the old endemic species have more aggregated distributions, but mainly within pockets of cloud forests at lower elevations than the young endemic species. These findings contradict the premise that biogeographical cradles and museums should overlap in valley systems where pockets of stable climate persist through periods of climate change. Instead, Andean biodiversity hotspots may derive from large-scale fluctuating climate complexity in conjunction with local-scale variability in available area and habitat connectivity.
Long-term changes in avian biomass and functional diversity within disturbed and undisturbed Amazonian rainforest
Authors: Luther David A. , Cooper W. Justin , Jirinec Vitek , Wolfe Jared D. , Rutt Cameron L. , Bierregaard Jr Richard O. , Lovejoy Thomas E. , Stouffer Philip C
Published: August 2022

Recent long-term studies in protected areas have revealed the loss of biodiversity, yet the ramifications for ecosystem health and resilience remain unknown. Here, we investigate how the loss of understory birds, in the lowest stratum of the forest, affects avian biomass and functional diversity in the Amazon rainforest. Across approximately 30 years in the Biological Dynamics of Forest Fragments Project, we used a historical baseline of avian communities to contrast the avian communities in today's primary forest with those in modern disturbed habitat. We found that in primary rainforest, the reduced abundance of insectivorous species led to reduced functional diversity, but no reduction of biomass, indicating that species with similar functional traits are less likely to coexist in modern primary forests. Because today's forests contain fewer functionally redundant species—those with similar traits—we argue that avian communities in modern primary Amazonian rainforests are less resilient, which may ultimately disrupt the ecosystem in dynamic and unforeseen ways.
The effects of ants on pest control: a meta-analysis
Authors: Anjos Diego V. , Tena Alejandro , Viana-Junior Arleu Barbosa , Carvalho Raquel L. , Torezan-Silingardi Helena , Del-Claro Kleber , Perfecto Ivette
Published: August 2022

Environmental impacts of conventional agriculture have generated interest in sustainable agriculture. Biological pest control is a fundamental tool, and ants are key players providing ecological services, as well as some disservices. We have used a meta-analytical approach to investigate the contribution of ants to biological control, considering their effects on pest and natural enemy abundance, plant damage and crop yield. We also evaluated whether the effects of ants are modulated by traits of ants, pests and other natural enemies, as well as by field size, crop system and experiment duration. Overall (considering all meta-analyses), from 52 studies on 17 different crops, we found that ants decrease the abundance of non-honeydew-producing pests, decrease plant damage and increase crop yield (services). In addition, ants decrease the abundance of natural enemies, mainly the generalist ones, and increase honeydew-producing pest abundance (disservices). We show that the pest control and plant protection provided by ants are boosted in shaded crops compared to monocultures. Furthermore, ants increase crop yield in shaded crops, and this effect increases with time. Finally, we bring new insights such as the importance of shaded crops to ant services, providing a good tool for farmers and stakeholders considering sustainable farming practices.
Scalable Bayesian functional GWAS method accounting for multivariate quantitative functional annotations with applications to studying Alzheimer’s disease
Authors: Chen Junyu , Wang Lei , De Jager Philip L. , Bennett David A. , Buchman Aron S. , Yang Jingjing
Published: August 2022

Existing methods for integrating functional annotations in GWAS to fine-map and prioritize potential causal variants are either limited to using non-overlapped categorical annotations, or limited by the computation burden of modeling genome-wide variants. To overcome these limitations, we propose a scalable Bayesian functional GWAS method to account for multivariate quantitative functional annotations (BFGWAS_QUANT), accompanied by a scalable computation algorithm enabling joint modeling of genome-wide variants. Simulation studies validated the performance of BFGWAS_QUANT for accurately quantifying annotation enrichment and improving GWAS power. Applying BFGWAS_QUANT to study five Alzheimer’s disease (AD) related phenotypes using individual-level GWAS data (n=∼1K), we found that histone modification annotations have higher enrichment than eQTL annotations for all considered phenotypes, with the highest enrichment in H3K27me3 (polycomb regression). We also found that cis-eQTL in microglia had higher enrichment than eQTL of bulk brain frontal cortex tissue for all considered phenotypes. A similar enrichment pattern was also identified using the IGAP summary-level GWAS data of AD (n=∼54K). The strongest known APOE E4 risk allele was identified for all five phenotypes and the APOE locus was validated using the IGAP data. BFGWAS_QUANT fine-mapped 32 significant variants from 1073 genome-wide significant variants in the IGAP data. We further demonstrated that the polygenic risk scores (PRS) using effect size estimates by BFGWAS_QUANT had similar prediction accuracy as other methods assuming a sparse causal model. Overall, BFGWAS_QUANT provides a useful GWAS tool for quantifying annotation enrichment and prioritizing potential causal variants.
Comparative Analysis of Reported Deaths Cases Associated with the New Coronavirus COVID-19 Pandemic in the South Caucasus Countries (Armenia, Azerbaijan, Georgia) from March 2020 to May 2022
Authors: Amiranashvili Avtandil G. , Khazaradze Ketevan R. , Japaridze Nino D.
Published: August 2022

The results of a statistical analysis of daily, total by days of the week and monthly data on officially reported deaths cases from the new coronavirus COVID-19 in the countries of the South Caucasus (Armenia, Azerbaijan, Georgia) from March 12, 2020 to May 31, 2022 are presented. All data are normalized per 1 million populations (mortality rate, hereinafter, this normalization is assumed everywhere). In particular, the following results were obtained.

The daily mortality rate in Armenia averaged 3.591 (range: 0-23.622), in Azerbaijan - 1.184 (range: 0-10.969), in Georgia - 5.596 (range: 0-23.189). The total monthly mortality rate in Armenia averaged 107.9 (variability range: 1.01-415.4), in Azerbaijan - 35.6 (variability range: 0.39-122.9), in Georgia - 168.1 (variability range: 0-547.4).

A direct linear correlation was observed between the indicated countries in cases of daily and total monthly mortality.

An analysis of the intraweek course of mortality showed that in Armenia, on weekdays, the average daily mortality is 4.319, and on weekends - 3.477 (an increase compared to weekends by about 24%); in Azerbaijan, on weekdays and weekends, the average daily mortality is 1.368 and 1.421, respectively (the difference is insignificant); in Georgia on weekdays, the average daily mortality is 7.558, and on weekends - 6.855 (an increase of about 10% compared to weekends).
Development and implementation of a clinical decision support system tool for the evaluation of suspected monkeypox infection
Authors: Albin John S. , Lazarus Jacob E , Hysell Kristen M. , Rubins David M. , Germaine Lindsay , Dugdale Caitlin M. , Heller Howard M. , Hohmann Elizabeth L. , Baugh Joshua J. , Shenoy Erica S.
Published: August 2022

Monkeypox virus was historically rare outside of West and Central Africa until the current 2022 global outbreak, which has required clinicians to be alert to identify individuals with possible monkeypox, institute isolation, and take appropriate next steps in evaluation and management. Clinical decision support systems (CDSS), which have been shown to improve adherence to clinical guidelines, can support frontline clinicians in applying the most current evaluation and management guidance in the setting of an emerging infectious diseases outbreak when those guidelines are evolving over time. Here we describe the rapid development and implementation of a CDSS tool embedded in the electronic health record to guide frontline clinicians in the diagnostic evaluation of monkeypox infection and triage patients with potential monkeypox infection to individualized infectious diseases physician review. We also present data on the initial performance of this tool in a large integrated healthcare system.
Mitochondrial DNA haplogroup variation in hydrocephalus
Authors: Munch Tina N , Hedley Paula L , Hagen Christian M , Elson Joanna , Bækvad-Hansen Marie , Geller Frank , Bybjerg-Grauholm Jonas , Nordentoft Merete , Børglum Anders , Mortensen Preben B , Werge Thomas M , Melbye Mads , Hougaard David M , Christiansen Michael
Published: August 2022

Hydrocephalus is a genetically and phenotypically heterogenous condition with complex etiology. Ciliary dysfunction has been shown to play a role, either through interference with signaling functions in primary cilia, cerebrospinal fluid flow by motile cilia, or both. Ciliary function is highly energy-dependent, consequently, variation in mitochondrial OXPHOS function might be a susceptibility factor for hydrocephalus. Furthermore, familial hydrocephalus exhibits preferential maternal inheritance. Mitochondrial DNA (mtDNA) haplogroups, have been associated with different characteristics of OXPHOS function as well as susceptibility to autism spectrum disorders, a frequent co-morbidity of hydrocephalus. This nested case-cohort study, a substudy of the iPSYCH study, used mtDNA data from 191 hydrocephalus cases and 24,831 population controls and found no association between hydrocephalus and any mtDNA haplogroup. Likewise, the distribution of European macro-haplogroups, HV, JT, and UK, did not differ between 172 hydrocephalus cases and 21,850 population controls. Thus, mtDNA haplogroups are not susceptibility factors for hydrocephalus.
Increased GDF11 expression associated with increased survival of Grade 3 Gliomas
Authors: Lehrer Steven , Rheinstein Peter H.
Published: August 2022

Background

Infusing young mouse blood into old mice makes the old mice biologically younger. When an old mouse and a young mouse share a circulatory system, the old mouse’s muscle function is improved, and the production of olfactory neurons is increased. GDF11 seems to be a crucial element of the young blood in both instances.

Methods

Because of GDF11’s potential neuroprotective actions, we used The Cancer Genome Atlas (TCGA) to assess the effect of GDF11 expression in malignant gliomas. We analyzed the GDC TCGA lower grade glioma data set. To access TCGA data we used the Xena platform and cBioportal. Statistical analysis was done with SPSS v26.

Results

increased GDF11 expression in IDH1 mutant subjects was significant. There was significantly increased survival (p = 0.00065, log rank test) with high GDF11 expression in grade 3 gliomas. The survival effect was less prominent in grade 2 gliomas. GDF11 gene expression was highest in anaplastic oligodendrogliomas and mixed gliomas with 1p 19q co-deletions and few or no TP53 or ATRX mutations. GDF11 gene expression was lowest in anaplastic astrocytomas with no 1p 19q co-deletions and many TP53 and ATRX mutations.

Conclusion

GDF11 or an analogue might be therapeutic in grade 3 glioma. GDF11 does not cross the blood brain barrier but affects the brain by acting on brain endothelial cells. GDF11 might be delivered to a brain tumor intranasally.
Genome-Wide Association Study Finds Multiple Loci Associated with Intraocular Pressure in HS Rats
Authors: Fowler Samuel , Wang Tengfei , Munro Daniel , Kumar Aman , Chitre Apurva S. , Hollingsworth TJ , Martinez Angel Garcia , St. Pierre Celine L. , Bimschleger Hannah , Gao Jianjun , Cheng Riyan , Mohammadi Pejman , Chen Hao , Palmer Abraham A. , Polesskaya Oksana , Jablonski Monica M.
Published: August 2022

Elevated intraocular pressure (IOP) is influenced by environmental and genetic factors. Increased IOP is a major risk factor for most types of glaucoma, including primary open angle glaucoma (POAG). Investigating the genetic basis of IOP may lead to a better understanding of the molecular mechanisms of POAG. The goal of this study was to identify genetic loci involved in regulating IOP using outbred heterogeneous stock (HS) rats. HS rats are a multigenerational outbred population derived from eight inbred strains that have been fully sequenced. This population is ideal for genome-wide association studies (GWASs) owing to the accumulated recombinations among well-defined haplotypes, the relatively high allele frequencies, the accessibility to a large collection of tissue samples, and the large allelic effect size compared to human studies. Both male and female HS rats (N=1,812) were used in the study. Genotyping-by-sequencing was used to obtain ~3.5 million single nucleotide polymorphisms (SNP) from each individual. SNP heritability for IOP in HS rats was 0.32, which agrees with other studies. We performed a GWAS for the IOP phenotype using a linear mixed model and used permutation to determine a genome-wide significance threshold. We identified three genome-wide significant loci for IOP on chromosomes 1, 5, and 16. Next, we sequenced the mRNA of 51 whole eye samples to find cis-eQTLs to aid in identification of candidate genes. We report 5 candidate genes within those loci:Tyr,Ctsc,Plekhf2,Ndufaf6 and Angpt2.Tyr,Ndufaf6andAngpt2genes have been previously implicated by human GWAS of IOP-related conditions.CtscandPlekhf2genes represent novel findings that may provide new insight into the molecular basis of IOP. This study highlights the efficacy of HS rats for investigating the genetics of elevated IOP and identifying potential candidate genes for future functional testing.

Contribution to the field statement

Glaucoma is the leading cause of irreversible blindness worldwide. Intraocular pressure (IOP) is the only known modifiable risk factor. This study describes results of the genome-wide association study (GWAS) performed in outbred rats that identifies known and novel genes involved in IOP regulation. To our knowledge, this is the first GWAS performed for IOP in a rat model. Identifying novel candidate genes in the rat model provides insight into the risk factors for glaucoma in humans and potential pharmacological targets for regulating IOP. The rat model is advantageous for studying natural variations in IOP, controlling environmental exposures, and providing easier access to tissue that can be used in phenotyping and gene expression in future studies.
Genomic health is dependent on long-term population demographic history
Authors: Wootton Eric , Robert Claude , Taillon Joëlle , Côté Steeve , Shafer Aaron B.A.
Published: August 2022

Current genetic methods of population assessment in conservation biology have been challenged by genome-scale analyses due to their quantitatively novel insights. These analyses include assessments of runs-of-homozygosity (ROH), genomic evolutionary rate profiling (GERP), and mutational load. Here, we aim to elucidate the relationships between these measures using three divergent ungulates: the white-tailed deer, caribou, and mountain goat. The white-tailed deer is currently expanding, while caribou are in the midst of a significant decline. Mountain goats remain stable, having suffered a large historical bottleneck. We assessed genome-wide signatures of inbreeding using the inbreeding coefficientFand %ROH (FROH) and identified evolutionarily constrained regions with GERP. Mutational load was estimated by identifying mutations in highly constrained elements (CEs) and sorting intolerant from tolerant (SIFT) mutations. Our results show thatFandFROHare higher in mountain goats than in caribou and white-tailed deer. Given the extended bottleneck and lowNeof the mountain goat, this supports the idea that the genome-wide effects of demographic change take time to accrue. Similarly, we found that mountain goats possess more highly constrained CEs and the lowest dN/dS values, both of which are indicative of greater purifying selection; this is also reflected by fewer mutations in CEs and deleterious mutations identified by SIFT. In contrast, white-tailed deer presented the highest mutational load with both metrics, in addition to dN/dS, while caribou were intermediate. Our results demonstrate that extended bottlenecks may lead to reduced diversity and increasedFROHin ungulates, but not necessarily the accumulation of deleterious alleles, likely due to the purging of deleterious alleles in small populations.
FSTest: an efficient tool for cross-population fixation index estimation on variant call format files
Authors: Vahedi Seyed Milad , Salek Ardestani Siavash
Published: August 2022

Fixation index (Fst) statistics provide critical insights into the evolutionary processes affecting the structure of genetic variation within and among populations. The Fst statistics have been widely applied in population and evolutionary genetics to identify genomic regions targeted by selection pressures. The FSTest 1.3 software was developed to estimate four Fst statistics of Hudson, Weir and Cockerham, Nei, and Wright using high-throughput genotyping or sequencing data. Here, we introduced FSTest 1.3 and compared its performance with two widely used software of VCFtools 0.1.16 and PLINK 2.0. Chromosome 1 of 1000 Genomes Phase III variant data belonging to South Asian (N = 211) and African (N = 274) populations were included as an example case in this study. Different Fst estimates were calculated for each single nucleotide polymorphism (SNP) in a pairwise comparison of South Asian against African populations, and the results of FSTest 1.3 were confirmed by VCFtools 0.1.16 and PLINK 2.0. Two different sliding window approaches, one based on a fixed number of SNPs and another based on a fixed number of base pair (bp) were conducted using FSTest 1.3 and VCFtools 0.1.16. Our results showed that regions with low coverage genotypic data could lead to an overestimation of Fst in sliding window analysis using a fixed number of bp. FSTest 1.3 could mitigate this challenge by estimating the average of consecutive SNPs along the chromosome. FSTest 1.3 allows direct analysis of VCF files with a small amount of code and can calculate Fst estimates on a desktop computer for more than a million SNPs in a few minutes. FSTest 1.3 is freely available athttps://github.com/similab/FSTest.
Analysis of the complete genome sequence forHalococcus dombrowskiiATCC BAA-364T
Authors: Lim Sung W. , Maurais Elizabeth G. , Farwell Ashlyn C. , Barber Nicolette , Olsen Abbey J. , Shalygina Kristina F. , Omeragic Medina , Fedorov Eugenia A. , MacLea Kyle S.
Published: August 2022

We describe sequencing and assembly of completeHalococcus dombrowskiiH4T(=ATCC BAA-364T) genome using short- and long-read sequencing technologies. The first closed genome within its genus is composed of a 2,767,537 bp chromosome and five additional plasmids totalling 3,965,466 bp, with GC content of 62.18%. The genome contains 4,029 genes, 3,963 coding sequences and two CRISPR arrays. Unusually, this Euryarchaeote carries multiple rRNA operons with divergent ITS identities across both its chromosome and plasmids.
Centripetal integration of past events by hippocampal astrocytes and its regulation by the locus coeruleus
Authors: Rupprecht Peter , Duss Sian N , Becker Denise , Lewis Christopher M , Bohacek Johannes , Helmchen Fritjof
Published: August 2022

An essential feature of neurons is their ability to centrally integrate information from their dendrites. The activity of astrocytes, in contrast, has been described as mostly uncoordinated across cellular compartments without clear central integration. Here, we describe conditional centripetal integration as a principle of how astrocytes integrate calcium signals from their distal processes to induce somatic activation. We found in mouse hippocampus that global astrocytic activity, as recorded with population calcium imaging, is well explained as a leaky integration of past neuronal and behavioral events on a timescale of seconds. Salient past events, indicated by pupil dilations, facilitated propagation of calcium signals from distal processes to the soma on this slow timescale. Centripetal propagation was reproduced by optogenetic activation of the locus coeruleus, a key regulator of arousal, and reduced by pharmacological inhibition of α1-adrenergic receptors. Together, our results establish astrocytes as computational units of the brain that slowly and conditionally integrate calcium signals to activate their somata upon behaviorally relevant events.
Adverse effects of hunting with hounds on participating animals and human bystanders
Authors: Treves Adrian , Menefee Laura
Published: August 2022

Hunting mammals with hounds is little studied. We present two datasets consisting of quantitative and qualitative data from self-selected respondents. The first came from hound handlers’ reports of hound injuries with post hoc verifications by government agents. The second came from by-standers reporting eyewitness encounters with hounds or handlers. Self-selected samples cannot be used to extrapolate rates in space or time but do provide nuances of human-animal and human-human interactions. From In the state of Wisconsin, USA, we describe government data on 176 hounds reported to have suffered injury during encounters with wolves. The government did not collect data on wolves or other non-target animals that may have been injured during these encounters. We investigate two wolf-centered hypotheses for wolf-hound interactions, find little support for either, and propose new hound-centered hypotheses. We also describe 105 human bystanders’ reports of experiences with hounds, handlers, and law enforcement agents.
UFCG: database of universal fungal core genes and pipeline for genome-wide phylogenetic analysis of fungi
Authors: Kim Dongwook , Gilchrist Cameron L.M. , Chun Jongsik , Steinegger Martin
Published: August 2022

In phylogenomics the evolutionary relationship of organisms is studied by their genomic information. A common approach to phylogenomics is to extract related genes from each organism, build a multiple sequence alignment and then reconstruct evolution relations through a phylogenetic tree. Often a set of highly conserved genes occurring in single-copy, called core genes, are used for this analysis, as they allow efficient automation within a taxonomic clade. Here we introduce the Universal Fungal Core Genes (UFCG) database and pipeline for genome-wide phylogenetic analysis of fungi. The UFCG database consists of 61 curated fungal marker genes, including a novel set of 41 computationally derived core genes and 20 canonical genes derived from literature, as well as marker gene sequences extracted from publicly available fungal genomes. Furthermore, we provide an easy-to-use, fully automated and open-source pipeline for marker gene extraction, training and phylogenetic tree reconstruction. The UFCG pipeline can identify marker genes from genomic, proteomic and transcriptomic data, while producing phylogenies consistent with those previously reported, and is publicly available together with the UFCG database athttps://ufcg.steineggerlab.com.
Extraction and selection of high-molecular-weight DNA for long-read sequencing from Chlamydomonas reinhardtii
Authors: Chaux-Jukic Frédéric , Agier Nicolas , Eberhard Stephan , Xu Zhou
Published: August 2022

Recent advances in long-read sequencing technologies have enabled the complete assembly of eukaryotic genomes from telomere to telomere by allowing repeated regions to be fully sequenced and assembled, thus filling the gaps left by previous short-read sequencing methods. Furthermore, long-read sequencing can also help characterizing structural variants, with applications in the fields of genome evolution or cancer genomics. For many organisms, the main bottleneck to sequence long reads remains the lack of robust methods to obtain high-molecular-weight (HMW) DNA. For this purpose, we developed an optimized protocol to extract DNA suitable for long-read sequencing from the unicellular green alga Chlamydomonas reinhardtii, based on CTAB/phenol extraction followed by a size selection step for long DNA molecules. We provide validation results for the extraction protocol, as well as statistics obtained with Oxford Nanopore Technologies sequencing.
Characterization of an Eye Field-like State during Optic Vesicle Organoid Development
Authors: Owen Liusaidh J. , Rainger Jacqueline , Bengani Hemant , Kilanowski Fiona , FitzPatrick David R. , Papanastasiou Andrew S.
Published: August 2022

Specification of the eye field (EF) within the neural plate marks the earliest detectable stage of eye development. Experimental evidence, primarily from non-mammalian model systems, indicates that the stable formation of this group of cells requires the activation of a set of key transcription factors (TFs). This critical event is challenging to probe in mammals and, quantitatively, little is known regarding the regulation of the transition of cells to this ocular fate. Using optic vesicle organoids to model the onset of the EF, we generate timecourse transcriptomic data allowing us to identify dynamic gene-expression programs that characterise this cellular-state transition. Integrating this with chromatin accessibility data suggests a direct role of canonical EFTFs in regulating these gene-expression changes, and high-lights candidate cis-regulatory elements through which these TFs act. Finally, we begin to test a subset of these candidate enhancer elements, within the organoid system, by perturbing the underlying DNA sequence and measuring transcriptomic changes during EF activation.
Separate and shared low-dimensional neural architectures for error-based and reinforcement motor learning
Authors: Areshenkoff Corson N. , de Brouwer Anouk , Gale Daniel J. , Nashed Joseph Y. , Gallivan Jason P.
Published: August 2022

Abstract

Motor learning is supported by multiple systems adapted to processing different forms of sensory information (e.g., reward versus error feedback), and by higher-order systems supporting strategic processes. Yet, the extent to which these systems recruit shared versus separate neural pathways is poorly understood. To elucidate these pathways, we separately studied error-based (EL) and reinforcement-based (RL) motor learning in two functional MRI experiments in the same human subjects. We find that EL and RL occupy opposite ends of neural axis broadly separating cerebellar and striatal connectivity, respectively, with somatomotor cortex, and that alignment of this axis to each task is related to performance. Further, we identify a separate neural axis that is associated with strategy use during EL, and show that the expression of this same axis during RL predicts better performance. Together, these results offer a macroscale view of the common versus distinct neural architectures supporting different learning systems.
Nudibranch predation boosts sponge silicon cycling
Authors: López-Acosta María , Potel Clémence , Gallinari Morgane , Pérez Fiz F. , Leynaert Aude
Published: August 2022

Sponges are singular players in the marine silicon cycle. They accumulate vast stocks of biogenic silica within their bodies and in the sediments beneath them over long periods. These silica stocks are recycled at slow rates, much slower than that of other silicon users such as diatoms. The observation of an abrupt change in sponge biomass in a temperate coastal ecosystem led us to study the effect of nudibranch (Doris verrucosa) predation on the silicon budget of a sponge (Hymeniacidon perlevis) population on an annual scale. Predation rates and the associated sponge silicon fluxes were determined. After 5 months of predation, the abundance of sponge individuals did not change but their biomass decreased by 95%, of which 48% can be explained by nudibranch predation. About 97% of sponge spicules ingested by nudibranchs while feeding was excreted, most of them unbroken, implying a high rate of sponge silica deposition in the surrounding sediments. After predation, sponges partially recovered their biomass stocks within 7 months. This involved a rapid growth rate and large consumption of dissolved silicon, with the highest rates ever recorded unexpectedly occurring when the dissolved silicon concentration was minimal in seawater (< 1.5 μM). These findings reveal that the annual sponge predation-recovery cycle triggers unprecedented intra-annual changes in sponge silicon stocks and boosts nutrient cycling. They also highlight the need for intra-annual data collection to understand the dynamics and resilience of sponge ecosystem functioning.
Automatic and accurate ligand structure determination guided by cryo-electron microscopy maps
Authors: Muenks Andrew , Zepeda Samantha , Zhou Guangfeng , Veesler David , DiMaio Frank
Published: August 2022

Advances in cryo-electron microscopy (cryoEM) and deep-learning guided protein structure prediction have expedited structural studies of protein complexes. However, methods for accurately determining ligand conformations are lacking. In this manuscript, we develop a tool for automatically determining ligand structures guided by medium-resolution cryoEM density. We show this method is robust at predicting ligands in maps as low as 6Å resolution, and is able to correct receptor sidechain errors. Combining this with a measure of placement confidence, and running on all protein/ligand structures in EMDB, we show that 58% of ligands replicate the deposited model, 16% confidently find alternate conformations, 22% have ambiguous density where multiple conformations might be present, and 4% are incorrectly placed. For five cases where our approach finds an alternate conformation with high confidence, high-resolution crystal structures validate our placement. This tool and the resulting analysis should prove critical in using cryoEM to investigate protein-ligand complexes.
An image is worth a thousand species: mapping plant biodiversity with citizen science, remote sensing, and deep learning
Authors: Gillespie Lauren , Ruffley Megan , Expósito-Alonso Moisés
Published: August 2022

Anthropogenic habitat destruction and climate change are altering the composition of plant communities worldwide1,2. However, traditional species distribution models cannot detect rapid, local plant species changes due to their low spatial and temporal resolution3,4, and remote sensing models can only identify changes in coarse vegetation categories5,6. Here we combine open-access remote sensing imagery, citizen science observations, and deep learning to create a multi-species prediction model at high spatial and temporal resolution. We train a novel deep convolutional neural network using ∼half a million observations within California to simultaneously predict the presence of over 2,000 plant species at meter-level resolution. This model—deepbiosphere—accurately performs many key biodiversity monitoring tasks, from fine-mapping geographic distributions of individual species and communities, to detecting rapid plant community changes in space and time.Deepbiosphereshifts the paradigm for species distribution modeling, providing a roadmap for inexpensive, automatic, and scalable detection of anthropogenic impacts on species worldwide.
Examining Reproducibility of EEG Schizophrenia Biomarkers Across Explainable Machine Learning Models
Authors: Ellis Charles A. , Sattiraju Abhinav , Miller Robyn , Calhoun Vince
Published: August 2022

Schizophrenia (SZ) is a neuropsychiatric disorder that adversely effects millions of individuals globally. Current diagnostic efforts are symptom based and hampered due to the variability in symptom presentation across individuals and overlap of symptoms with other neuropsychiatric disorders. This spawns the need for (1) biomarkers to aid with empirical SZ diagnosis and (2) the development of automated diagnostic approaches that will eventually serve in a clinical decision support role. In this study, we train random forest (RF) and support vector machine (SVM) models to differentiate between individuals with schizophrenia and healthy controls using spectral features extracted from resting state EEG data. We then perform two explainability analyses to gain insight into key frequency bands and channels. In our explainability analyses, we examine the reproducibility of SZ biomarkers across models with the goal of identifying those that have potential clinical implications. Our model performance results are well above chance level indicating the broader utility of spectral information for SZ diagnosis. Additionally, we find that the RF prioritizes the upper γ-band and is robust to loss of information from individual electrodes, while the SVM prioritizes the α and θ-bands and P4 and T8 electrodes. It is our hope that our findings will inform future efforts towards the empirical diagnosis of SZ and towards the development of clinical decision support systems for SZ diagnosis.
Mitochondrial-encoded complex I impairment induces a targetable dependency on aerobic fermentation in Hürthle cell carcinoma of the thyroid
Authors: Frank Anderson R , Li Vicky , Shelton Spencer D , Kim Jiwoong , Stott Gordon M , Neckers Leonard , Xie Yang , Williams Noelle S , Mishra Prashant , McFadden David G
Published: August 2022

A metabolic hallmark of cancer identified by Warburg is the increased consumption of glucose and secretion of lactate, even in the presence of oxygen. Although many tumors exhibit increased glycolytic activity, most forms of cancer rely on mitochondrial respiration for tumor growth. We report here that Hürthle cell carcinoma of the thyroid (HTC) models harboring mitochondrial DNA-encoded defects in complex I of the mitochondrial electron transport chain exhibit impaired respiration and alterations in glucose metabolism. CRISPR/Cas9 pooled screening identified glycolytic enzymes as selectively essential in complex I-mutant HTC cells. We demonstrate in cultured cells and a PDX model that small molecule inhibitors of lactate dehydrogenase selectively induce an ATP crisis and cell death in HTC. This work demonstrates that complex I loss exposes fermentation as a therapeutic target in HTC and has implications for other tumors bearing mutations that irreversibly damage mitochondrial respiration.
Host Age Structure Defines Interactions with Pathogens: Grandparent Effect under Collaboration and Virulent Mutualism under Competition
Authors: Portner Carsten O.S. , Rong Edward G. , Ramirez Jared A. , Wolf Yuri I , Bosse Angelique P. , Koonin Eugene V. , Rochman Nash D.
Published: August 2022

Background

Symbiotic relationships are ubiquitous in the biosphere. Inter-species symbiosis is impacted by intra-specific distinctions, in particular, those defined by the age structure of a population. Older individuals compete with younger individuals for resources despite being less likely to reproduce, diminishing the fitness of the population. Conversely, however, older individuals can support the reproduction of younger individuals, increasing the population fitness. Parasitic relationships are commonly age structured, typically, more adversely affecting older hosts.

Results

We employ mathematical modeling to explore the differential effects of collaborative or competitive host age structures on host-parasite relationships. A classical epidemiological compartment model is constructed with three disease states: susceptible, infected, and recovered. Each of these three states is partitioned into two compartments representing young, potentially reproductive, and old, post-reproductive, hosts, yielding 6 compartments in total. In order to describe competition and collaboration between old and young compartments, we model the reproductive success to depend on the fraction of young individuals in the population. Collaborative populations with relatively greater numbers of post-reproductive hosts enjoy greater reproductive success whereas in purely competitive populations, increase of the post-reproductive subpopulation reduces reproductive success. However, in competitive populations, virulent pathogens preferentially targeting old individuals can increase the population fitness.

Conclusions

We demonstrate that, in collaborative host populations, pathogens strictly impacting older, post-reproductive individuals can reduce population fitness even more than pathogens that directly impact younger, potentially reproductive individuals. In purely competitive populations, the reverse is observed, and we demonstrate that endemic, virulent pathogens can oxymoronically form a mutualistic relationship with the host, increasing the fitness of the host population. Applications to endangered species conservation and invasive species containment are discussed.