Miracle-dz/UniFAR-FTUs huggingface dataset:
Topological Augmentation of Latent Information Streams in Feed-Forward Neural Networks

The algorithmic rules that define deep neural networks are clearly defined, however the principles that define their performance remain poorly understood. Here, we use systems neuroscience and information theoretic approaches to analyse a feedforward neural network as it is trained to classify handwritten digits. By tracking the topology of the network as it learns, we identify three distinct phases of topological reconfiguration. Each phase brings the connections of the neural network into alignment with patterns of information contained in the input dataset, as well as the preceding layers. Performing dimensionality reduction on the data reveals a process of low-dimensional category separation as a function of learning. Our results enable a systems-level understanding of how deep neural networks function, and provide evidence of how neural networks reorganize edge weights and activity patterns so as to most effectively exploit the information theoretic content of input data during edge-weight training. Summary Trained neural networks are capable of remarkable performance on complex categorization tasks, however the precise rules according to which the network reconfigures during training remain poorly understood. We used a combination of systems neuroscience and information theoretic analyses to interrogate the network topology of a simple, feed-forward network as it was trained on a digitclassification task. Over the course of training, the hidden layers of the network reconfigured in characteristic ways that were reminiscent of key results in network neuroscience studies of human brain imaging. In addition, we observed a strong correspondence between the topological changes at different learning phases and information theoretic signatures of the data that were entered into the network. In this way, we show how neural networks learn.
Distinctive alteration of presynaptic proteins in the outer molecular layer of the dentate gyrus in Alzheimer’s disease

Synaptic degeneration has been reported as one of the best pathological correlate of cognitive deficit in Alzheimer’s Disease (AD). However, the location of these synaptic alterations within hippocampal sub-regions, the vulnerability of the presynaptic versus postsynaptic compartments, and the biological mechanisms for these impairments remain unknown. Here, we performed immunofluorescence labeling of different synaptic proteins in fixed and paraffin embedded human hippocampal sections and report reduced levels of several presynaptic proteins of the neurotransmitter release machinery (complexin-1, syntaxin-1A, synaptotagmin-1 and synaptogyrin-1) in AD cases. The deficit was restricted to the outer molecular layer (OML) of the dentate gyrus whereas other hippocampal sub-fields were preserved. Interestingly, standard markers of postsynaptic densities (SHANK2) and dendrites (MAP2) were unaltered, as well as the relative number of granule cells in the dentate gyrus, indicating that the deficit is preferentially presynaptic. Notably, staining for the axonal components, myelin basic protein, SMI-312 and Tau, was unaffected, suggesting that the local presynaptic impairment does not result from axonal loss or alterations of structural proteins of axons. There was no correlation between the reduction in presynaptic proteins in OML and the extent of the amyloid load or of the dystrophic neurites expressing phosphorylated forms of Tau. Altogether, this study highlights the distinctive vulnerability of the OML of dentate gyrus and supports the notion of presynaptic failure in AD.
A critical residue in the α1M2-M3 linker regulating GABAA receptor pore gating by diazepam

Benzodiazepines (BZDs) are a class of widely prescribed psychotropic drugs. Their anxiolytic and sedative effects are conferred by modulating the activity of GABAA receptors (GABAARs), which are the primary inhibitory neurotransmitter receptors throughout the central nervous system. However, the physical mechanism by which BZDs exert their effects on the receptor is poorly understood. In particular, BZDs require coapplication with an agonist to effectively open the channel pore, making it difficult to dissect whether the drug has altered either agonist binding or channel gating as these two processes are intimately coupled. To isolate effects on gating we used a spontaneously active gain of function mutant (α1L9’Tβ2γ2L) that is directly gated by BZDs alone in the absence of agonist. In the α1L9’T background we explored effects of alanine substitutions throughout the α1M2-M3 linker on modulation of the channel pore by the BZD positive modulator diazepam (DZ). The M2-M3 linker is known to be an important element for channel activation. Linker mutations generally impaired unliganded pore opening, indicating that side chain interactions are important for channel gating in the absence of bound agonist. All but one mutation had no effect on the transduction of chemical energy from DZ binding to pore gating. Strikingly, α1V279A doubles DZ’s energetic contribution to gating, whereas larger side chains at this site do not. In a wild-type background α1V279A enhances DZ-potentiation of currents evoked by saturating GABA, consistent with a direct effect on the pore closed/open equilibrium. Our observations identify an important residue regulating coupling between the BZD site and the pore gate, thereby shedding new light on the molecular mechanism of a frequently prescribed class of psychotropic drugs.
Phages weaponize their bacteria with biosynthetic gene clusters

Bacteria produce many different specialized metabolites, which are encoded by biosynthetic gene clusters (BGCs). Despite high industrial relevance owing to broad bioactive potential of these metabolites, their ecological roles remain largely unexplored. We analyze all available genomes for BGCs of phage origin. The BGCs predominantly reside within temperate phages infecting certain commensal and pathogenic bacteria. Nearly all phage BGCs encode bacteriocins, which appear to serve as a strong proxy for phage specificity. Using the gut-associated bacterium Bacillus subtilis, we demonstrate how a temperate phage equips its host with a functional BGC, providing it with a competitive fitness advantage over close relatives. Therefore, certain temperate phages use BGCs to weaponize their bacteria against close relatives, leading to evolutionary benefits from lysogeny to the infected host, and hence, to the phage itself. Our study is a large step towards understanding the natural role of specialized metabolites, as well as mutualistic phage-host relationships.
Studies on the fertilization of mouse eggs in vitro

ICR-JCL系成熟雄マウスの精巣上体尾部から採取した精子をKrebs-Ringer-Bicarbonate液を基本とする 培養液内に懸濁させ,5%CO2,95%空気,温度37°Cの条件で3~120分の種々の時間培養した後,体外受精に供した。 卵子としてはHCG注射後16~17時間の過排卵卵子を用いた。 その結果,体外に培養された精子は雄から採取直後の精子よりも早く卵子に侵入することが明らかとなり,in vitroにおいてマウス精子の受精能獲得が起こることが示唆された。 追記: 本報の投稿後に知ったIwAMATSU&CHANGの最近の報告(J.exp.Zool.175,271,1970)によると,1)精巣上体精子は牛の卵胞液の存在下に授精後約1時間から卵子への侵入を開始し侵入率は授精後5時間まで漸増する。 2)牛の卵胞液とともに3~4時間体外培養された精子は新鮮精子よりも早く卵子へ侵入する,ことが報じられている。 前報の成績17)に比し侵入時期が早くなっているのは技術的な改良によると推察している。 ただし,牛の卵胞液を用いずに精子を前処理する試みはなされていない。
Providers Versus Platforms: Marketing Communications in the Sharing Economy

Peer-to-peer (P2P) business models have become increasingly prevalent in the marketplace. However, little is known about what factors influence consumer perceptions of purchases from firms using these models. The authors propose that features inherent to the P2P model lead consumers to perceive high provider–firm independence, where providers are viewed as relatively independent from the platform on which they offer goods/services. Across a series of studies, the authors show that when P2P brands use provider-focused (vs. platform-focused) marketing communications, consumers perceive a purchase as helping an individual provider to a greater extent, which increases consumers’ willingness to pay and their likelihood of both making a purchase and downloading the brand’s app. This is because provider-focused marketing communications in this context lead consumers to think about their purchase from the provider’s perspective, thus adopting an “empathy lens. ” The authors further show that this effect does not extend to other business models. This work thus identifies provider- (vs. platform-) focused marketing communications as a way for marketing managers of P2P brands to drive important purchase-related outcomes.
Studying Large Plainchant Corpora Using chant21

We present chant21, a Python package to support the plainchant formats gabc and Volpiano in music21, and two large corpora of plainchant. The CantusCorpus contains over 60,000 medieval melodies collected from the Cantus database, encoded in the Volpiano typeface. The GregoBaseCorpus contains over 9,000 transcriptions from more recent chant books in the gabc format. Chant21 converts both formats to music21, while retaining the textual structure of the chant: its division in sections, words, syllables and neumes. We present two case studies. First, we report evidence for the melodic arch hypothesis from the GregoBaseCorpus. Second, we analyze connections between differentiæ and antiphon openings in the CantusCorpus, and show that the systematicity of the connection can be quantified using an entropy-based measure.
Nudging the N170 forward with prior stimulation – Bridging the gap between N170 and recognition potential

Some neural responses are classified by the stimulus conditions leading up to that response while other neural responses are also classified by the morphology of the responses themselves. However, morphology-based classification may not be appropriate if one can nudge a neural response into looking like another neural response. Morphology-based classification occurs with the N170 and RP (Recognition Potential), ERP components that are studied in separate literatures and yet share much in common in terms of functionality. In this study, we demonstrate a gradual transformation in the morphology of the N170 to the RP using a simple parametric manipulation of forward masks that is unlikely to cause a change in the underlying processing. Both the N170 and RP are N1 components, meaning that they are the first negative deflection of the evoked response. However, the RP is often measured with a forward mask that ends at stimulus onset whereas the N170 is often measured with no masking at all. This study investigates how ISI may delay and distort the N170 into an RP by manipulating the temporal gap (ISI) between forward mask and target. The results revealed reverse relationships between the ISI on the one hand, and the N170 latency, single-trial N1 jitter (an approximation of N1 width) and reaction time on the other hand. Importantly, we find that scalp topographies have a unique signature at the N1 peak across all conditions, from the longest gap (N170) to the shortest (RP). These findings prove that the mask-delayed N1 is still the same N170, even under conditions that are normally associated with a different component like the RP. In general, our results suggest that greater caution should be taken to interpret the time course of a measured effect when forward masks are employed.
Multicenter Clinicopathologic Correlation of Kidney Biopsies Performed in COVID-19 Patients Presenting With Acute Kidney Injury or Proteinuria

Rationale and Objective Kidney biopsy data inform us about pathologic processes associated with SARS CoV-2 infection. We conducted a multi-center evaluation of kidney biopsy findings in living patients to identify various kidney disease pathology in patients with COVID-19 and their association with SARS-CoV-2 infection. Study Design Case series. Setting and Participants We identified 14 native and 3 transplant kidney biopsies performed for-cause in patients with documented recent or concurrent COVID-19 infection treated at 7 large hospital systems in the United States. Observations Males and females were equally represented in our study cohort, with a higher proportion of Black (n=8) and Hispanic (n=5) patients. All 17 patients had RT-PCR confirmed COVID-19 infection, but only 3 presented with severe COVID-19 symptoms. Acute kidney injury (AKI; n=15) and proteinuria (n=11) were the most common indications for biopsy and these symptoms developed concurrently or within 1 week of COVID-19 symptoms in all patients. Acute tubular injury (n=14), collapsing glomerulopathy (n=7) and endothelial injury/thrombotic microangiopathy (n=6) were the most common histologic findings. Two of the three transplant patients developed active antibody-mediated rejection weeks after COVID-19 infection. Eight patients required dialysis, but others improved with conservative management. Limitations Small study size and short clinical follow up. Conclusions Cases of even symptomatically mild COVID-19 infection were accompanied by AKI and/or heavy proteinuria that prompted a diagnostic kidney biopsy. While acute tubular injury was seen among the majority of them, uncommon pathology such as collapsing glomerulopathy and acute endothelial injury were detected, and most of these patients progressed to irreversible kidney injury and dialysis.
Notes on the Morphology and Distribution of the Himalayan Genus Pseudothilmanus, Including the First Record of the Genus from Nepal (Coleoptera: Rhagophthalmidae)

ABSTRACT Pseudothilmanus Pic, 1918 is a genus of beetles currently placed in Rhagophthalmidae. The species P. alatus Pic, 1918 and P. marginatus Pic, 1918 were described based on single holotypes from India with little descriptive information. Later, in a revision of the genus, a new specimen of P. alatus was examined, but also without specific locality. This paper provides the description of the wing venation and new distributional records for this genus, including the first record in Nepal.
Assessing in vivo mutation frequencies and creating a high-resolution genome-wide map of fitness costs of Hepatitis C virus

Like many viruses, Hepatitis C Virus (HCV) has a high mutation rate, which helps the virus adapt quickly, but mutations come with fitness costs. Fitness costs can be studied by different approaches, such as experimental or frequency-based approaches. The frequency-based approach is particularly useful to estimate in vivo fitness costs, but this approach works best with deep sequencing data from many hosts are. In this study, we applied the frequency-based approach to a large dataset of 195 patients and estimated the fitness costs of mutations at 7957 sites along the HCV genome. We used beta regression and random forest models to better understand how different factors influenced fitness costs. Our results revealed that costs of nonsynonymous mutations were three times higher than those of synonymous mutations, and mutations at nucleotides A or T had higher costs than those at C or G. Genome location had a modest effect, with lower costs for mutations in HVR1 and higher costs for mutations in Core and NS5B. Resistance mutations were, on average, costlier than other mutations. Our results show that in vivo fitness costs of mutations can be site and virus specific, reinforcing the utility of constructing in vivo fitness cost maps of viral genomes.
Mucins-2 and Cathepsin D Expressions in Colorectal Cancer

Objective To investigate the roles of the expressions of mucinst-2 (MUC-2) and cathepsin-D (Cath-D) in carcinogensis and progression of colorectal cancer (CRC). Methods MUC-2 and Cath-D expression were studied immuneohistochemistrically in 60 specimens of CRC. Results The expression rate of MUC-2 was 70. 00% in CRC. The significant relationship was observed between low MUC-2 expression and Dukes stage,cellular dedifferentiation and metastasis of distant organs,no correction to sex, age, growth style and metastasis of lymph node. The expression rate of Cath-D was 66. 67% in CRC. The important relationship was observed between high Cath-D expression and metastasis of distant organs and lymph node,no correction to sex, age, growth style,Dukes stage and cellular dedifferentiation. Conclusion The detection of expression a-bout MUC-2 and Cath-D may be helpful to judge the malignant behavier and metastasis with colorectal carcinoma.
Antibody-drug conjugates targeting CD45 plus Janus kinase inhibitors effectively condition for allogeneic hematopoietic stem cell transplantation

Despite the curative potential of hematopoietic stem cell transplantation (HSCT), transplant conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADC) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely involved syngeneic HSCT; however, for treatment of acute leukemias or tolerance induction for solid organ transplantation, strategies for allogeneic HSCT (allo-HSCT) are needed. Using murine allo-HSCT models, we show that combining CD45-targeted ADCs with the Janus kinase inhibitor baricitinib enables multilineage alloengraftment with >80-90% donor chimerism. Mechanistically, baricitinib impaired T and NK cell survival, proliferation and effector function, with NK cells being particularly susceptible due to inhibited IL-15 signaling. Unlike irradiated mice, CD45-ADC-conditioned mice did not manifest graft-versus-host alloreactivity when challenged with mismatched T cells. Our studies demonstrate novel allo-HSCT conditioning strategies that exemplify the promise of immunotherapy to improve the safe application of HSCT for treating hematologic diseases.
Decolonizing Psocopteran Systematics: Holarctic Lineages Cannot Inform Diversity and Evolution in Tropics

Despite tropical psocids comprise ~60% of species diversity within the Psocidae (Insecta, Psocodea), previous studies on the Psocidae phylogeny have poorly sampled tropical species (<40% species in trees). Here we discuss the evolution and systematics of the Psocidae based on the most comprehensive species-level sampling of the Psocidae. We sequenced and inferred the phylogenetic position of 43 previously unsampled Neotropical species from COI, H3, WNT, 18S, 16S, and 12S. Based on our phylogenies we found that Neotropical psocids are generally not closely related to morphologically similar taxa in the Holarctic region. Consequently, the monophyletic status for the major groups within Psocidae (subfamilies and tribes) is recovered only when Holarctic groups are sampled (7–10 of 11 higher-level groups are monophyletic) but violated when Neotropical species are included in the dataset (1 of 11 higher-level groups are monophyletic). Leveraging the largest phylogeny of the Psocidae, our study pinpoints the downfalls of simply extending taxonomic knowledge from lineages of a certain area to inform diversity and evolution of lineages in other regions. Highlights Tropical psocids comprise >60% of the extant family richness Previous phylogenies have undersampled Tropical psocids Holarctic and Neotropical species are classified under the same morphological groups Holarctic and Neotropical generally correspond to evolutionarily distinct lineages Phylogenies based on Holarctic psocids poorly inform evolution in the Neotropics
Single Cell Analysis Reveals Multi-faceted miR-375 Regulation of the Intestinal Crypt

The role of individual miRNAs in small intestinal (SI) epithelial homeostasis is under-explored. In this study, we discovered that miR-375 is among the most enriched miRNAs in intestinal crypts and stem cells (ISCs), especially facultative ISCs. We then showed by multiple manipulations, including CRISPR/Cas9 editing, that miR-375 is strongly suppressed by Wnt-signaling. Single-cell RNA-seq analysis of SI crypt-enriched cells from miR-375 knockout (375-KO) mice revealed elevated numbers of tuft cells and increased expression of pro-proliferative genes in ISCs. Accordingly, the genetic loss of miR-375 promoted resistance to helminth infection and enhanced the regenerative response to irradiation. The conserved effects of miR-375 were confirmed by gain-of-function studies in Drosophila midgut stem cells in vivo. Moreover, functional experiments in enteroids uncovered a regulatory relationship between miR-375 and Yap1 that controls cell survival. Finally, analysis of mouse model and clinical data revealed an inverse association between miR-375 levels and intestinal tumor development. Highlights miR-375 is one of the most enriched miRNAs in ISCs, especially facultative ISCs. miR-375 modifies tuft cell abundance and pro-proliferative gene expression in ISCs. Loss of miR-375 in mice enhances the host response to helminth infection and crypt regeneration. Mouse and human intestinal cancer are associated with reduced miR-375 expression. eTOC Blurb Sethupathy and colleagues show that miR-375 is a Wnt-responsive, ISC-enriched miRNA that serves as a break on intestinal crypt proliferation. They also show that miR-375 modulates tuft cell abundance and pro-proliferative gene expression in ISCs, that miR-375 loss enhances the host response to helminth infection as well as crypt regeneration post-irradiation, and its reduced expression is associated with intestinal cancer.
Higher Order AMMI (HO-AMMI) analysis: A novel stability model to study genotype-location interactions

Additive main effects and multiplicative interaction (AMMI) model is most widely used to analyse genotype*environment interactions (GEI) wherein interaction effects of location is masked by year effect. Hence, presently available models are not able to estimate interaction effects of genotype*location (GLI) and genotype*year (GYI) separately. Moreover, genotype ranking differs as number of years of evaluation vary making selection of genotype for target location difficult. In the present study we propose a novel stability model i.e Higher-order-AMMI (HO-AMMI) analysis which is capable of calculating GLI without the confounding effect of GYI and GLYI. GEI of AMMI model and all 2-way interactions of HO-AMMI model follow χ2 distribution, whereas 3-way interaction (GLYI) of HO-AMMI follow noncentral χ2 distribution. With increase in number of years of evaluation contribution of GLI towards total variation increased whereas in AMMI model contribution of GEI towards total variation decreased. Variation explained by multiplicative components is higher in HO-AMMI compared to AMMI model. Genotypes were ranked using GL, GY and GL+GY+GLY interactions of HO-AMMI and GEI of AMMI for stability and yield and compared their ranks with field ranking. Correlation and linear regression analysis have indicated high association of GLI (HO-AMMI) with field ranking with high R2 values. Further, HO-AMMI model was able to remove the confounding effect of GYI and GLYI on GLI for accurate identification of genotype for target location irrespective of number of years of evaluation. Hence, HO-AMMI model can be used under multi-environment trials (MET) for selecting genotypes efficiently. Availability and Information Source code implemented in R is available from corresponding author.