Miracle-dz/UniFAR-FTUs huggingface dataset:
KMD clustering: robust general-purpose clustering of biological data

KMD clustering, a new clustering method with few and interpretable hyperparameters, shows high performance in multiple challenging biological domains including noisy, high-dimensional and large scale datasets. The noisy and high-dimensional nature of biological data has spawned advanced clustering algorithms that are tailored for specific biological datatypes. However, the performance of such methods varies greatly between datasets and they require post hoc tuning of cryptic hyperparameters. We present k minimal distance (KMD) clustering, a general-purpose method based on a generalization of single and average linkage hierarchical clustering. We introduce a generalized silhouette-like function to eliminate the cryptic hyperparameter k, and use sampling to enable application to million-object datasets. Rigorous comparisons to general and specialized clustering methods on simulated, mass cytometry and scRNA-seq datasets show consistent high performance of KMD clustering across all datasets.
ATF6 is essential for human cone photoreceptor development

Significance Inactivating genetic variants in the Unfolded Protein Response (UPR) regulator Activating Transcription Factor 6 (ATF6) result in loss of color vision, which is linked to dysfunctional cone photoreceptors and the development of achromatopsia. The pathomechanims involving the lack of functional ATF6 remain unknown; retinal organoids from patient induced pluripotent stem cells and ATF6 null hESCs were generated to elucidate this question. Data from this study identified an unexpected UPR-independent role for ATF6 signaling during cone photoreceptor differentiation in human retinal development, identifying a pathogenic mechanism underlying ATF6-associated achromatopsia. It is believed that pharmacologic targeting of ATF6 may present a viable treatment option for color blinding diseases at early stages of retinal development. Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR regulator Activating Transcription Factor 6 (ATF6) cause severe congenital vision loss diseases such as achromatopsia by unclear pathomechanisms. To investigate this, we generated retinal organoids from achromatopsia patient induced pluripotent stem cells carrying ATF6 disease variants and from gene-edited ATF6 null hESCs. We found that achromatopsia patient and ATF6 null retinal organoids failed to form cone structures concomitant with loss of cone phototransduction gene expression, while rod photoreceptors developed normally. Adaptive optics retinal imaging of achromatopsia patients carrying ATF6 variants also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the defect in cone formation observed in our retinal organoids. These results establish that ATF6 is essential for human cone development. Interestingly, we find that a selective small molecule ATF6 signaling agonist restores the transcriptional activity of some ATF6 disease-causing variants and stimulates cone growth and gene expression in patient retinal organoids carrying these variants. These findings support that pharmacologic targeting of the ATF6 pathway can promote human cone development and should be further explored for blinding retinal diseases.
How motivational signals disrupt metacognitive signals in the human VMPFC

A growing body of evidence suggests that, during decision-making, BOLD signal in the VMPFC correlates both with motivational variables – such as incentives and expected values – and metacognitive variables – such as confidence judgments, which reflect the subjective probability of being correct. At the behavioral level, we recently demonstrated that the value of monetary stakes bias confidence judgments, with gain (respectively loss) prospects increasing (respectively decreasing) confidence judgments, even for similar levels of difficulty and performance. If and how this value-confidence interaction is also reflected in VMPFC signals remains unknown. Here, we used an incentivized perceptual decision-making task that dissociates key decision-making variables, thereby allowing to test several hypotheses about the role of the VMPFC in the incentive-confidence interaction. While initial analyses seemingly indicate that VMPFC combines incentives and confidence to form an expected value signal, we falsified this conclusion with a meticulous dissection of qualitative activation patterns. Rather, our results show that strong VMPFC confidence signals observed in trials with gain prospects are disrupted in trials with no – or negative (loss) monetary prospects. Deciphering how decision variables are represented and interact at finer scales (population codes, individual neurons) seems necessary to better understand biased (meta)cognition.
MetaGraph: Indexing and Analysing Nucleotide Archives at Petabase-scale

The amount of biological sequencing data available in public repositories is growing exponentially, forming an invaluable biomedical research resource. Yet, making all this sequencing data searchable and easily accessible to life science and data science researchers is an unsolved problem. We present MetaGraph, a versatile framework for the scalable analysis of extensive sequence repositories. MetaGraph efficiently indexes vast collections of sequences to enable fast search and comprehensive analysis. A wide range of underlying data structures offer different practically relevant trade-offs between the space taken by the index and its query performance. MetaGraph provides a flexible methodological framework allowing for index construction to be scaled from consumer laptops to distribution onto a cloud compute cluster for processing terabases to petabases of input data. Achieving compression ratios of up to 1,000-fold over the already compressed raw input data, MetaGraph can represent the content of large sequencing archives in the working memory of a single compute server. We demonstrate our framework’s scalability by indexing over 1.4 million whole genome sequencing (WGS) records from NCBI’s Sequence Read Archive, representing a total input of more than three petabases. Besides demonstrating the utility of MetaGraph indexes on key applications, such as experiment discovery, sequence alignment, error correction, and differential assembly, we make a wide range of indexes available as a community resource, including those over 450,000 microbial WGS records, more than 110,000 fungi WGS records, and more than 20,000 whole metagenome sequencing records. A subset of these indexes is made available online for interactive queries. All indexes created from public data comprising in total more than 1 million records are available for download or usage in the cloud. As an example of our indexes’ integrative analysis capabilities, we introduce the concept of differential assembly, which allows for the extraction of sequences present in a foreground set of samples but absent in a given background set. We apply this technique to differentially assemble contigs to identify pathogenic agents transfected via human kidney transplants. In a second example, we indexed more than 20,000 human RNA-Seq records from the TCGA and GTEx cohorts and use them to extract transcriptome features that are hard to characterize using a classical linear reference. We discovered over 200 trans-splicing events in GTEx and found broad evidence for tissue-specific non-A-to-I RNA-editing in GTEx and TCGA.
Estimating the viability of vesicular-arbuscular mycorrhizae fungal spores using tetrazolium salts as vital stains.

The tetrazolium salts 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide and 2-(p-iodophenyl)-3-(p-nitrophenyl)-5-phenyl-2H-tetrazolium chloride were evaluated as vital stains for est.
Development of a three-compartment in vitro simulator of the Atlantic Salmon GI tract and associated microbial communities: SalmoSim

Atlantic salmon are a species of major economic importance. Intense innovation is underway to improve salmon feeds and feed additives to enhance fish performance, welfare, and the environmental sustainability of the industry. Several gut models targeted at monogastric vertebrates are now in operation. Here we report progress in the development of an Atlantic salmon in vitro gut model, SalmoSim, to simulate three gut compartments (stomach, pyloric caecum and mid gut) and associated microbial communities. The artificial gut model was established in a series of linked bioreactors seeded with biological material derived for adult marine phase salmon. In biological triplicate, the response of the in vitro system to two distinct dietary formulations (fish meal and fish meal free) was compared to a parallel in vivo trial over forty days. 16S rDNA sequencing, qPCR, ammoniacal nitrogen and volatile fatty acid measurements were undertaken to survey microbial community dynamics and function. SalmoSim communities were indistinguishable (p=0.230) from their founding inocula at 20 days and most abundant genera (e.g. Psycrobacter, Staphylococcus, Pseudomonas) proliferated the in vitro system. Real salmon and SalmoSim responded similarly to the introduction of the novel feed, with most taxa (96% Salmon, 97% SalmoSim) unaffected, while a subset of taxa was affected non-identically across both systems. Consistent with a low impact of the novel feed on microbial community function, VFA profiles were not significantly different in SalmoSim pre and post the switch feed. This study represents an important first-step in the development of an in vitro gut system as a tool for the improvement of salmon nutrition.
The transcription factor BCL11A defines a distinctive subset of dopamine neurons in the developing and adult midbrain

Midbrain dopaminergic (mDA) neurons are diverse in their projection targets, impact on behavior and susceptibility to neurodegeneration. Little is known about the molecular mechanisms that establish this diversity in mDA neurons during development. We find that the transcription factor Bcl11a defines a subset of mDA neurons in the developing and adult murine brain. By combining intersectional labeling and viral-mediated tracing we show that Bcl11a-expressing mDA neurons form a highly specific subcircuit within the dopaminergic system. We demonstrate that Bcl11a-expressing mDA neurons in the substantia nigra (SN) are particularly vulnerable to neurodegeneration in an α-synuclein overexpression model of Parkinson’s disease. Inactivation of Bcl11a in developing mDA neurons results in anatomical changes, deficits in motor learning and a dramatic increase in the susceptibility to α-synuclein-induced degeneration in SN-mDA neurons. In summary, we identify an mDA subpopulation with highly distinctive characteristics defined by the expression of the transcription factor Bcl11a already during development.
Optimization of acidic labneh whey lactose hydrolysis with immobilized beta-galactosidase enzyme from Kluyveromyces lactis.

Hydrolysis of lactose with β-galactosidase is one of the most promising biotechnological applications in the food industry because of it is use in the production of low lactose dairy products. Acid whey samples were collected from the dairy pilot plant at the University of Jordan, Faculty of Agriculture. β-Galactosidase enzyme from Kluyveromyces lactis with initial activity of 3000 LAU/ml was immobilized in a sodium alginate and used for acid whey hydrolysis in fluidized bed reactor. Optimization parameters of lactose hydrolysis were (12 and 24% v/v enzyme concentration), (10 and 20 ml/mint flow rate). The process reaction was done at a temperature of 37 C o and 6.5 pH. Lactose hydrolysis of 81% and 85% were obtained during 6 h of incubation for 12 and 24% v/v enzyme concentration at flow rate of 10 ml/min.
Refugees, displacement and territorial stability

ABSTRACT What is special about refugees? In this paper, I argue that the two main accounts of who should count as a refugee have major shortcomings. The first, based on protection from persecution, is too narrow, as it excludes many people who have to flee their homes for other reasons than persecution. The second, based on the protection of human rights, overcomes this problem, but at the expense of a narrow view of refugee protection, which only amounts to the protection of fundamental human rights. By developing a territorial account of refugeehood, which builds on the human rights account, I propose that what is special about refugees is the harm of displacement. The conceptual implication is a grounding of states’ duties towards refugees in the legitimacy of their territorial rights. The practical implication is a strong critique of temporary forms of protection. To redress the harm of displacement, a territorial account holds, refugee protection must offer territorial stability, ultimately through a pathway to citizenship. I thus show how it is possible to marry the human rights account of refugees with a notion of refugee protection as membership in a new state.
Comparative Genomics Platform and Phylogenetic Analysis of Fungal Laccases and Multi-Copper Oxidases

Abstract Laccases (EC 1.10.3.2), a group of multi-copper oxidases (MCOs), play multiple biological functions and widely exist in many species. Fungal laccases have been extensively studied for their industrial applications, however, there was no database specially focused on fungal laccases. To provide a comparative genomics platform for fungal laccases, we have developed a comparative genomics platform for laccases and MCOs (http://laccase.riceblast.snu.ac.kr/). Based on protein domain profiles of characterized sequences, 3,571 laccases were predicted from 690 genomes including 253 fungi. The number of putative laccases and their properties exhibited dynamic distribution across the taxonomy. A total of 505 laccases from 68 genomes were selected and subjected to phylogenetic analysis. As a result, four clades comprised of nine subclades were phylogenetically grouped by their putative functions and analyzed at the sequence level. Our work would provide a workbench for putative laccases mainly focused on the fungal kingdom as well as a new perspective in the identification and classification of putative laccases and MCOs.
Comparison of Soil Higher Fungal Communities between Dead and Living Abies koreana in Mt. Halla, the Republic of Korea

Abstract To improve our understanding of the relationship between soil higher fungi (belonging to Ascomycota and Basidiomycota) and Abies koreana, we surveyed A. koreana soil fungal communities in a forest in Mt. Halla, Jeju Island, Korea by next-generation sequencing (Illumina Miseq). To confirm the soil higher fungal communities, we collected two types of soils from a defined plot: soils with dead (AKDTs) and living A. koreana (AKLTs), respectively. Soil fungi were classified into 2 phyla, 19 classes, 64 orders, 133 families, 195 genera, and 229 OTUs (895,705 sequence reads). Nonmetric multidimensional scaling (NMDS) showed significantly different soil higher fungal communities between AKDTs and AKLTs (p < .05). In addition, the saprophyte composition was significantly affected by A. koreana status (p < .05). The proportion of the mycorrhizal Clavulina spp. was different between soils with AKDTs and AKLTs, suggesting that Clavulina spp. may be a crucial soil fungal species influencing A. koreana. This study will lead to a better understanding of the ecological status of A. koreana in Mt. Halla. In addition, this study could be useful for the conservation and management of A. koreana habitats.
Anti-Oxidant Activity and Anti-Inflammatory Effects of Spiraea fritschiana Schneid Extract

Background : We studied the anti-oxidant activity and anti-inflammatory effects of Spiraea fritschiana Schneid extract (SFSE). Methods and Results : The SFSE was prepared using methanol and was evaluated for its total phenol and flavonoid content, DPPH (1,1-diphenyl-2-picrylhydrazyl) free-radical scavenging activity, reducing power, and effect on nitric oxide (NO) production, and cell viability by using real-time polymerase chain reaction (PCR). The total phenol content was c acid equivalent (GAE)/mg and the total flavonoid content was equivalent (QE)/mg. The extract showed antioxidant activity (DPPH free-radical scavenging activity) with value of . The reducing power of the extract was Abs 0.58 at . Cell viability was determined using the MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. To evaluate anti-inflammatory activity, we examined the inhibitory effects on lipopolysaccharide-(LPS)-induced NO production in RAW 264.7 cells. The NO inhibition rate was 90% at SFSE. At the same concentration, the expression of pro-inflammatory genes such as inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 also decreased. Conclusions : Our results suggest that SFSE is a novel resource for the development of foods and drugs that possess anti-oxidant and anti-inflammatory activity.
A hybrid mesh and voxel based Monte Carlo algorithm for accurate and efficient photon transport modeling in complex bio-tissues

Over the past decade, an increasing body of evidence has suggested that threedimensional (3-D) Monte Carlo (MC) light transport simulations are affected by the inherent limitations and errors of voxel-based domain boundaries. In this work, we specifically address this challenge using a hybrid MC algorithm, namely split-voxel MC or SVMC, that combines both mesh and voxel domain information to greatly improve MC simulation accuracy while remaining highly flexible and efficient in parallel hardware, such as graphics processing units (GPU). We achieve this by applying a marching-cubes algorithm to a pre-segmented domain to extract and encode sub-voxel information of curved surfaces, which is then used to inform ray-tracing computation within boundary voxels. This preservation of curved boundaries in a voxel data structure demonstrates significantly improved accuracy in several benchmarks, including a human brain atlas. The accuracy of the SVMC algorithm is comparable to that of mesh-based MC (MMC), but runs 2x-6x faster and requires only a lightweight preprocessing step. The proposed algorithm has been implemented in our open-source software and is freely available at http://mcx.space.
Heat Stress Interferes with Formation of Double-Strand Breaks and Homology Synapsis in Arabidopsis thaliana

Meiotic recombination (MR) drives reciprocal exchange of genetic information which allows novel combination of alleles and contributes to genomic diversity of eukaryotes. In this study, we report that heat stress (36-38°C) over fertile threshold fully abolishes crossover occurrence by lowering the formation of SPO11-dependent double-strand breaks (DSBs) in Arabidopsis. The high temperature partially suppresses chromosome fragmentation in the rad51 and syn1 mutants by reducing DSB formation. In addition, we found that although the SYN1-mediated formation of chromosome axis is not influenced by the high temperature, ASY1-associated axial element of synaptonemal complex (SC) is partially compromised, and the ZYP1-dependent central element of axis is severely disrupted, indicating that homology synapsis is another prominent target of high temperature. Besides, we observed that the loading of recombinase DMC1 on chromatin is significantly reduced by high temperatures, suggesting that heat stress interferes with DMC1-dependent MR. Moreover, we found that the numbers of DSB and DMC1 keep stable within a limited range of temperature increase, while decrease when the DSB-processing system reaches threshold to heat. Furthermore, transcriptome study revealed a universal variation of the expression of meiotic genes under low (4°C) and high (32°C) temperatures, suggesting that temperature may influence MR by modulating the transcription of MR-related factors. We also found that the landscape of 5-methylcytosine (5mC) was altered under high temperatures, suggesting that environmental temperature may influence the distribution of MR via reshaped DNA methylation status of chromatin. Taken together, our findings provide evidence shedding light on how environment temperatures influence MR in Arabidopsis.
Airway bacterial and fungal microbiome in chronic obstructive pulmonary disease

Background Little is known about airway mycobiome, and its relationship with bacterial microbiome in chronic obstructive pulmonary disease (COPD). Methods Here we report the first simultaneous characterization of sputum bacterial and fungal microbiome in 84 stable COPD and 29 healthy subjects, using 16S ribosomal DNA and fungal internal transcribed spacer DNA sequencing. Results Ascomycota predominated over Basidiomycota in fungal microbiome both in COPD patients and healthy controls. Meyerozyma, Candida, Aspergillus and Schizophyllum were most abundant at the genus level. There was a significant inverse correlation between bacterial and fungal microbial diversity, both of which altered in opposite directions in COPD patients versus controls, and in frequent versus non-frequent exacerbators. An enhanced bacterial-fungal ecological interaction was observed in COPD patients, which was characterized by higher proportion of co-occurrence intrakingdom interactions and co-exclusive interkingdom interactions. In COPD, four mutually co-occurring fungal operational taxonomic units (OTUs) in Candida palmioleophila, Aspergillus and Sordariomycetes exhibited co-exclusive relationships with other fungal OTUs, which was specifically present in frequent exacerbators but not in non-frequent exacerbators. Conversely, the mutual co-occurrence interactions between bacterial OTUs in Rothia mucilaginosa, Streptococcus, Veillonella and Prevotella, showed up in non-frequent exacerbators but not in frequent exacerbators. The perturbed bacterial-fungal interactions in COPD were associated with increased airway inflammatory mediators such as IL-6 and IL-8. Interpretation The disruption of airway bacterial-fungal community balance, characterized by the loss of commensal bacterial taxa and enriched pathogenic fungal taxa, is implicated in COPD. The airway mycobiome is an important cofactor mediating COPD pathogenic infection and host inflammation. Clinical Trial Registration www.clinicaltrials. gov (NCT 03240315).
Torsin ATPases influence chromatin interaction of the Torsin regulator LAP1

The inner nuclear membrane is functionalized by diverse transmembrane proteins that associate with nuclear lamins and/or chromatin. When cells enter mitosis, membrane-chromatin contacts must be broken to allow for proper chromosome segregation; yet how this occurs remains ill-understood. Unexpectedly, we observed that an imbalance in the levels of the lamina-associated polypeptide 1 (LAP1), an activator of ER-resident Torsin AAA+-ATPases, causes a failure in membrane removal from mitotic chromatin, accompanied by chromosome segregation errors and changes in post-mitotic nuclear morphology. These defects are dependent on a hitherto unknown chromatin-binding region of LAP1 that we have delineated. LAP1-induced NE abnormalities are efficiently suppressed by expression of wild-type but not ATPase-deficient Torsins. Furthermore, a dominant-negative Torsin induces chromosome segregation defects in a LAP1-dependent manner. These results indicate that association of LAP1 with chromatin in the nucleus can be modulated by Torsins in the perinuclear space, shedding new light on the LAP1-Torsin interplay.