bluuebunny/crossref_metadata_2025 huggingface dataset:
Geographically Biased Composition of NetMHCpan Training Datasets and Evaluation of MHC-Peptide Binding Prediction Accuracy on Novel Alleles
Authors: Atkins Thomas Karl , Solanki Arnav , Vasmatzis George , Cornette James , Riedel Marc
Published: September 2023

Bias in neural network model training datasets has been observed to decrease prediction accuracy for groups underrepresented in training data. Thus, investigating the composition of training datasets used in machine learning models with health-care applications is vital to ensure equity. Two such machine learning models are NetMHCpan-4.1 and NetMHCIIpan-4.0, used to predict antigen binding scores to major histocompatibility complex class I and II molecules, respectively. As antigen presentation is a critical step in mounting the adaptive immune response, previous work has used these or similar predictions models in a broad array of applications, from explaining asymptomatic viral infection to cancer neoantigen prediction. However, these models have also been shown to be biased toward hydrophobic peptides, suggesting the network could also contain other sources of bias. Here, we report the composition of the networks’ training datasets are heavily biased toward European Caucasian individuals and against Asian and Pacific Islander individuals. We test the ability of NetMHCpan-4.1 and NetMHCpan-4.0 to distinguish true binders from randomly generated peptides on alleles not included in the training datasets. Unexpectedly, we fail to find evidence that the disparities in training data lead to a meaningful difference in prediction quality for alleles not present in the training data. We attempt to explain this result by mapping the HLA sequence space to determine the sequence diversity of the training dataset. Furthermore, we link the residues which have the greatest impact on NetMHCpan predictions to structural features for three alleles (HLA-A*34:01, HLA-C*04:03, HLA-DRB1*12:02).
Recurrent circuits encode visual center-surround computations in the mouse superior colliculus
Authors: Cui Peng , Song Kuisong , Mariatos-Metaxas Dimitris , Isla Arturo G. , Femenia Teresa , Lazaridis Iakovos , Meletis Konstantinos , Kumar Arvind , Kardamakis Andreas A.
Published: September 2023

Center-surround interactions are fundamental to visual saliency computation, but debate continues over whether and how subcortical visual circuits actively contribute. To address this, we developed an optogenetic approach to delineate the visual center and surround zones of individual neurons in the superficial layer of the superior colliculus (SCs) using only retinal ganglion cell input. Using whole-cell recordings, we demonstrate that surround network activation suppresses center excitability, indicating that SCs circuitry is self-sufficient in driving center-surround dynamics. Through cell-type-specific trans-synaptic tracing and large-scale modeling, we identified an SCs-based circuit with two key motifs driving surround modulation: recurrent excitation and feedback inhibition. We propose that subcortical visual circuits in the SCs have evolved to perform surround suppression alongside retinal and cortical suppression, facilitating the distribution of parallel saliency computations across different levels.

Significance statement

This study questions the notion that the superior colliculus (SC) merely acts as a passive recipient of saliency information from upstream circuits. We demonstrate that the SC can independently generate center-surround interactions that could contribute to visual saliency through local circuits without top-down input. This ability represents a computation that has been conserved since the dawn of vertebrate evolution. By mapping these interactions, we reveal that the mouse SC actively induces visual surround suppression. These findings suggest that phylogenetically older circuits in the SC may play a more independent role in active vision than previously acknowledged, prompting a reevaluation of visual saliency processing across subcortical brain regions.
MCT4 and CD147 co-localize with MMP14 in invadopodia and autolysosomes and collectively stimulate breast cancer cell invasion by increasing extracellular matrix degradation
Authors: Meng Signe , Sørensen Ester E. , Ponniah Muthulakshmi , Thorlacius-Ussing Jeppe , Crouigneau Roxane , Borre Magnus T. , Willumsen Nicholas , Flinck Mette , Pedersen Stine F.
Published: September 2023

The lactate-proton cotransporter MCT4 and its chaperone CD147 are upregulated in breast cancers, correlating with decreased patient survival. Here, we test the hypothesis that MCT4 and CD147 favor breast cancer invasion through interdependent effects on extracellular matrix (ECM) degradation. MCT4 and CD147 expression and membrane localization were strongly reciprocally interdependent in MDA-MB-231 invasive breast cancer cells. Knockdown (KD) and overexpression (OE) of MCT4 and/or CD174 in- and decreased, respectively, migration, invasion, and fluorescent gelatin degradation. OE of both proteins increased gelatin degradation and appearance of the matrix metalloprotease (MMP)-generated collagen-I cleavage product reC1M more than each protein alone, suggesting a concerted role in ECM degradation. MCT4 and CD147 co-localized strongly with invadopodia markers at the plasma membrane and with MMP14, the lysosomal marker LAMP-1, and in some cases the autophagosome marker LC3, in F-actin-decorated, large intracellular vesicles.

We conclude that MCT4 and CD147 reciprocally regulate each other and support migration and invasiveness of MDA-MB-231 breast cancer cells in an interdependent manner. Mechanistically, this involves the MCT4-CD147-dependent stimulation of ECM degradation and specifically of MMP-mediated collagen-I degradation. We suggest that the MCT4-CD147 complex is co-delivered to invadopodia with MMP14.
Multistable mechanosensitive behavior of cell adhesion driven by actomyosin contractility and elastic properties of force-transmitting linkages
Authors: Liu Ping , Wang Qiuyu , Yao Mingxi , Efremov Artem K.
Published: September 2023

The ability of cells to sense the mechanical properties of their microenvironment is essential to many physiological processes. The molecular clutch theory has played an important role in explaining many mechanosensitive cell behaviors. However, its current implementations have limited ability to understand how molecular heterogeneity, such as adhesion molecules with different elasticities, regulates the mechanical response of cell adhesion. In this study, we developed a model incorporating the experimentally measured elastic properties of such proteins to investigate their influence on cell adhesion. It was found that the model not only could accurately fit previous experimental measurements of cell traction force and retrograde actin flow, but also predicted multistablility of cell adhesion as well as a feedback loop between the densities of the extracellular matrix proteins and contractile myosin II motors in living cells. The existence of such a feedback loop was successfully confirmed in experiments. Taken together, our study provides a theoretical framework for understanding how the mechanical properties of adaptor proteins, local substrate deformations and myosin II contractility affect cell adhesion across different cell types and physiological conditions.
Mettl1-dependent m7G tRNA modification is essential for maintaining spermatogenesis and fertility inDrosophila melanogaster
Authors: Kaneko Shunya , Miyoshi Keita , Tomuro Kotaro , Terauchi Makoto , Kondo Shu , Tani Naoki , Ishiguro Kei-Ichiro , Toyoda Atsushi , Noguchi Hideki , Iwasaki Shintaro , Saito Kuniaki
Published: September 2023

N7-methylguanosine (m7G) in the variable loop region of tRNA is catalyzed by METTL1/WDR4 heterodimer and stabilizes target tRNA. Here, we reveal essential functions of Mettl1 inDrosophilafertility. Knockout of Mettl1 (Mettl1-KO) lost the elongated spermatids and mature sperm, which was fully rescued by a Mettl1-transgene expression, but not a catalytic-dead Mettl1 transgene. This demonstrates that Mettl1-dependent m7G is required for spermatogenesis. Mettl1-KO resulted in a loss of m7G modification on a subset of tRNAs and a decreased level of tRNA expression. Strikingly, overexpression of the translational elongation factor, EF1α1, which can compete with the rapid tRNA decay (RTD) pathway inS. cerevisiae, significantly counteracted the sterility of Mettl1-KO males, supporting a critical role of m7G modification of tRNAs in spermatogenesis. Ribosome profiling showed that Mettl1-KO led to the ribosome stalling at codons decoded by tRNAs that were reduced in expression. Mettl1-KO also significantly reduced the translation efficiency of genes involved in elongated spermatid formation and sperm stability. These findings reveal a developmental role for m7G tRNA modifications and indicate that m7G modification-dependent tRNA stability differs among tissues.
Twisted plywood-like tissue formationin vitro. Does curvature do the twist?
Authors: Schamberger Barbara , Ehrig Sebastian , Dechat Thomas , Spitzer Silvia , Bidan Cécile M. , Fratzl Peter , Dunlop John W. C. , Roschger Andreas
Published: September 2023

Little is known about the contribution of 3D surface geometry on the development of multi-layered tissues containing fibrous extracellular matrix components such as those found in bone. Here we elucidate the role of curvature in the formation of chiral, twisted plywood-like structures. Tissues consisting of murine pre-osteoblast cells (MC3T3-E1) were grown on 3D scaffolds with constant mean curvature and negative Gaussian curvature for up to 32 days. Using 3D fluorescence microscopy, the influence of surface curvature on actin stress-fiber alignment and chirality was investigated. To gain mechanistic insights, also MC3T3-E1 cells deficient in nuclear A-type lamins or treated with drugs targeting cytoskeleton proteins were used in our study. We find that wild type cells grow multilayered tissue with fibers predominantly aligned along directions of negative curvature, but where subsequent layers twist in orientation with respect to older tissues with time. Fiber orientation is conserved below the tissue surface thus creating a twisted plywood like material. We further show that this directional organization strongly depends on structural components of the cells (A-type lamins, actin and myosin). Our data indicate the importance of substrate curvature in the formation of 3D tissues and provides new insights into the emergence of chirality.

Significance Statement

Biological tissues (like compact bone) often consist of multiple fibrous layers which are staggered with a twisting angle relative to each other, thereby improving mechanical performance. The underlying principles of how such tissues are formed and what determines the fiber direction are still debated. Here we report the formation of a twisted plywood-like tissue grownin vitroon constant mean and negative Gaussian curvature substrates and present evidence that for tissue consisting of pre-osteoblast like cells, surface curvature is a main determinant for fiber orientation.
Neuronal FOS reports synchronized activity of presynaptic neurons
Authors: Anisimova Margarita , Lamothe-Molina Paul J. , Franzelin Andreas , Aberra Aman S. , Hoppa Michael B. , Gee Christine E. , Oertner Thomas G.
Published: September 2023

The immediate early gene FOS is frequently used as a marker for highly active neurons. Implicit in this use is the assumption that there is a correlation between neuronal spiking and FOS expression. Here we use optogenetic stimulation of hippocampal neurons to investigate the relation between spike frequency and FOS expression, and report several surprising observations. First, FOS expression is cell-type specific, spiking CA2 pyramidal neurons rarely express FOS. Second, FOS has a U-shaped dependence on frequency: Spiking at 0.1 Hz is more effective than high frequency spiking (50 Hz) while intermediate frequencies do not induce FOS. Third, the pathway from spiking to FOS is not cell-autonomous. Instead, transmitter release and metabotropic glutamate receptor (mGluR) activation are required and, at 0.1 Hz, FOS is induced independently of CREB/calcineurin/MEK pathways. We propose that FOS does not primarily encode a neuron’s own spike frequency but indicates repeated participation in highly synchronized activity, e.g. sharp wave ripples.
Serial colonization shapes genetic variation and defines conservation units in Asian elephants
Authors: Khan Anubhab , Sil Maitreya , Thekaekara Tarsh , Garg Kritika M. , Sinha Ishani , Khurana Rupsy , Sukumar Raman , Ramakrishnan Uma
Published: September 2023

Asian elephants (Elephas maximus) are the largest extant terrestrial megaherbivores native to Asia, with 60% of their wild population found in India. Despite ecological and cultural importance, their population genetic structure and diversity, demographic history, and ensuing implications for management/conservation remain understudied. We analysed 34 whole genomes (between 11X - 32X) from most known elephant landscapes in India and identified five management/conservation units corresponding to elephants in Northern (Northwestern/Northeastern) India, Central India and three in Southern India. Our genetic data reveal signatures of serial colonisation, and a dilution of genetic diversity from north to south of India. The Northern populations diverged from other populations more than 70,000 years ago, have higher genetic diversity, and low inbreeding/high effective size (Pi = 0.0016±0.0001; FROH>1MB= 0.09±0.03). Two of three populations in Southern India (South of Palghat Gap: SPG, and South of Shencottah Gap:SSG) have low diversity and are inbred, with very low effective population sizes compared to current census sizes (Pi = 0.0014±0.00009 and 0.0015±0.0001; FROH>1MB= 0.25±0.09 and 0.17±0.02). Analyses of genetic load reveals purging of potentially high-effect insertion/deletion (indel) deleterious alleles in the Southern populations and potential dilution of all deleterious alleles from north to south in India. However, despite dilution and purging for the damaging mutation load in Southern India, the load that remains is homozygous. High homozygosity of deleterious alleles, coupled with low neutral genetic diversity make these populations (SPG and SSG) high priority for conservation attention. Most surprisingly, our study suggests that patterns of genetic diversity and genetic load can correspond to geographic signatures of serial founding events, even in large, highly mobile, endangered mammals.
Linking serotonergic median raphe input to dorsal CA1 with mnemonic functions
Authors: Gerdey Jill , Masseck Olivia Andrea
Published: September 2023

The role of serotonergic signaling within the hippocampus and its role in mnemonic function is still not well understood. We used optogenetics to specifically alter median raphe serotonin input to the dorsal CA1 subfield to investigate its role in hippocampus-dependent behavior. Unexpectedly, neither activation nor inhibition of serotonin release at dCA1 fiber terminals significantly modulated object recognition, spatial memory, or anxiety behavior. Nevertehless, we observed opposite effects of increased and decreased serotonergic input on spatial learning, and a marked reduction in the use of a direct search strategy in spatial navigation following activation of serotonergic terminals in dCA1, i.e. release of serotonin.Furthermore, since the 5-HT1Areceptor is one of the most abundant serotonergic receptors in CA1, we also optogenetically activated 5-HT1Apathways specifically in pyrdamidal neurons of dCA1. Activation of 5-HT1Asignaling significantly improved spatial memory without affecting object recognition or avoidance behavior. In conclusion, our data reveal modulatory effects of serotonin specifically on the acquisition of spatial memory.
Experimental nerve block study on painful withdrawal reflex responses in humans
Authors: Thorell Oumie , Mahns David A. , Otto Jan , Liljencrantz Jaquette , Svantesson Mats , Olausson Håkan , Nagi Saad S.
Published: September 2023

The nociceptive withdrawal reflex (NWR) is a protective limb withdrawal response triggered by painful stimuli, used to assess spinal nociceptive excitability. Conventionally, the NWR is understood as having two reflex responses: a short-latency Aβ-mediated response, considered tactile, and a longer-latency Aδ-mediated response, considered nociceptive. However, nociceptors with conduction velocities similar to Aβ tactile afferents have been identified in human skin. In this study, we investigated the effect of a preferential conduction block of Aβ fibers on pain perception and NWR signaling evoked by intradermal electrical stimulation in healthy participants. We recorded a total of 198 NWR responses in the intact condition, and no dual reflex responses occurred within our latency bandwidth (50-150 ms). The current intensity required to evoke the NWR was magnitude higher than the perceptual pain threshold, indicating that NWR did not occur before pain was felt. In the block condition, when the Aβ-mediated tuning fork sensation was lost while Aδ-mediated nonpainful cooling was still detectable (albeit reduced), we observed that the reflex was abolished. Further, short-latency electrical pain intensity at pre-block thresholds was greatly reduced, with any residual pain sensation having a longer latency. Although electrical pain was unaffected at suprathreshold current intensities, the reflex could not be evoked despite a two-fold increase in the pre-block current intensity and a five-fold increase in the pre-block pulse duration. These observations lend support to the possible involvement of Aβ-fiber inputs in pain and reflex signaling.
Reliability of the TMS-evoked potential in dorsolateral prefrontal cortex
Authors: Gogulski Juha , Cline Christopher C. , Ross Jessica M. , Parmigiani Sara , Keller Corey J.
Published: September 2023

Background

We currently lack a robust and reliable method to probe cortical excitability noninvasively from the human dorsolateral prefrontal cortex (dlPFC), a region heavily implicated in psychiatric disorders. We recently found that the strength ofearlyandlocaldlPFC single pulse transcranial magnetic stimulation (TMS)-evoked potentials (EL-TEPs) varied widely depending on the anatomical subregion probed, with more medial regions eliciting stronger responses than anterolateral sites. Despite these differences inamplitudeof response, thereliabilityat each target is not known.

Objective

To evaluate the reliability of EL-TEPs across the dlPFC.

Methods

In 15 healthy subjects, we quantified within-session reliability of dlPFC EL-TEPs after single pulse TMS to six dlPFC subregions. We evaluated the concordance correlation coefficient (CCC) across targets and analytical parameters including time window, quantification method, region of interest, sensor-vs. source-space, and number of trials.

Results

At least one target in the anterior and posterior dlPFC produced reliable EL-TEPs (CCC>0.7). The medial target was most reliable (CCC = 0.78) and the most anterior target was least reliable (CCC = 0.24). ROI size and type (sensor vs. source space) did not affect reliability. Longer (20-60 ms, CCC = 0.62) and later (30-60 ms, CCC = 0.61) time windows resulted in higher reliability compared to earlier and shorter (20-40 ms, CCC 0.43; 20-50 ms, CCC = 0.55) time windows. Peak-to-peak quantification resulted in higher reliability than the mean of the absolute amplitude. Reliable EL-TEPs (CCC up to 0.86) were observed using only 25 TMS trials for a medial dlPFC target.

Conclusions

Medial TMS location, wider time window (20-60ms), and peak-to-peak quantification improved reliability. Highly reliable EL-TEPs can be extracted from dlPFC after only a small number of trials.

Highlights

Medial dlPFC target improved EL-TEP reliability compared to anterior targets.

After optimizing analytical parameters, at least one anterior and one posterior target was reliable (CCC>0.7).

Longer (20-60 ms) and later (30-60 ms) time windows were more reliable than earlier and shorter (20-40 ms or 20-50 ms) latencies.

Peak-to-peak quantification resulted in higher reliability compared to the mean of the absolute amplitude.

As low as 25 trials can yield reliable EL-TEPs from the dlPFC.
Microbially-conjugated Bile Salts Found in Human Bile Activate the Bile Salt Receptors TGR5 and FXR
Authors: Ay Ümran , Leníček Martin , Haider Raphael S. , Classen Arno , van Eijk Hans , Koelfat Kiran V.K. , van der Kroft Gregory , Neumann Ulf. P. , Hoffmann Carsten , Bolm Carsten , Olde Damink Steven W.M. , Schaap Frank G.
Published: September 2023

Background & Aims

Bile salts of hepatic and microbial origin mediate inter-organ crosstalk in the gut-liver axis. Here, we assessed whether the newly discovered class of microbial bile salt conjugates (MBSCs), activate the main host bile salt receptors (TGR5 and FXR) and enter the human systemic and enterohepatic circulation.

Approach & Results

N-amidates of (chenodeoxy)cholic acid and leucine, tyrosine and phenylalanine were synthesized. Receptor activation was studied in cell-free and cell-based assays. MBSCs were quantified in mesenteric and portal blood and bile of patients undergoing pancreatic surgery. MBSCs were activating ligands of TGR5 as evidenced by recruitment of Gsαprotein, activation of a cAMP-driven reporter, and diminution of LPS-induced cytokine release from macrophages. Intestine- and liver-enriched FXR isoforms were both activated by MBSCs, provided that a bile salt importer was present. Affinity of MBSCs for TGR5 and FXR was not superior to host-derived bile salt conjugates. Individual MBSCs were generally not detected (i.e. <2.5 nmol/L) in human mesenteric or portal blood, but Leu- and Phe-variants were readily measurable in bile, where MBSCs comprised up to 213 ppm of biliary bile salts.

Conclusions

MBSCs activate the cell surface receptor TGR5 and the transcription factor FXR, and are substrates for intestinal (ASBT) and hepatic (NTCP) transporters. Their entry into the human circulation is, however, non-substantial. Given low systemic levels and surplus of other equipotent bile salt species, the studied MBSCs are unlikely to have an impact on enterohepatic TGR5/FXR signaling in humans. Origin and function of biliary MBSCs remain to be determined.

Graphical Abstract

Created withBioRender.com
Ring Array Illumination Microscopy: Combination of Super-Resolution with Large Field of View Imaging and long Working Distances
Authors: von Hase Johann , Birk Udo , Humbel Bruno M. , Liu Xiaomin , Failla Antonio V. , Cremer Christoph
Published: September 2023

Here we present a novel fluorescence microscopy concept which enables a direct integration of Super-Resolution Microscopy (SRM) approaches (SIM/Nanosizing, STED, SMLM, MINFLUX, SIMFLUX) into microscopy systems with working distances (WD) up to the multicentimeter range while still allowing nanometer scale resolution at selected sites. This becomes possible by a “synthetic aperture” illumination mode with multiple, constructively interfering excitation beams positioned in a “Ring-Array” arrangement around a beam free interior zone containing instrumentation involved in complementary imaging modes. The feasibility of such a direct correlative microscopy method is validated by extensive numerical simulations; on the basis of these calculations, experimental implementation options are discussed. Such “Ring Array” illumination modes may be useful for various correlative microscopy methods, such as a direct combination of correlative light and electron microscopy in the same device (dCLEM); or a direct combination of low NA/large field-of-view widefield microscopy and super-resolution of selected sites in the same device (direct Correlative Opical Microscopy/dCOLM). Ring-Array supported correlative microscopy modes will open novel imaging perspectives in a variety of disciplines, from material sciences to biomedical applications.
BiœmuS: A new tool for neurological disorders studies through real-time emulation and hybridization using biomimetic Spiking Neural Network
Authors: Beaubois Romain , Cheslet Jérémy , Duenki Tomoya , Khoyratee Farad , Branchereau Pascal , Ikeuchi Yoshiho , Lévi Timothée
Published: September 2023

Characterization and modeling of biological neural networks has emerged as a field driving significant advancements in our understanding of brain function and related pathologies. As of today, pharmacological treatments for neurological disorders remain limited, pushing the exploration of promising alternative approaches such as electroceutics. Recent research in bioelectronics and neuromorphic engineering have led to the design of the new generation of neuroprostheses for brain repair.

However, its complete development requires deeper understanding and expertise in biohybrid interaction. Here, we show a novel real-time, biomimetic, cost-effective and user-friendly neural network for bio-hybrid experiments and real-time emulation. Our system allows investigation and reproduction of biophysically detailed neural network dynamics while promoting cost-efficiency, flexibility and ease of use. We showcase the feasibility of conducting biohybrid experiments using standard biophysical interfaces and various biological cells as well as real-time emulation of complex models. We anticipate our system to be a step towards developing neuromorphicbased neuroprostheses for bioelectrical therapeutics by enabling communication with biological networks on a similar time scale, facilitated by an easy-to-use and accessible embedded real-time system. Our real-time device further enhances its potential for practical applications in biohybrid experiments.
Competitive integration of time and reward explains value-sensitive foraging decisions and frontal cortex ramping dynamics
Authors: Bukwich Michael , Campbell Malcolm G , Zoltowski David , Kingsbury Lyle , Tomov Momchil S , Stern Joshua , Kim HyungGoo R , Drugowitsch Jan , Linderman Scott W , Uchida Naoshige
Published: September 2023

Patch foraging presents a ubiquitous decision-making process in which animals decide when to abandon a resource patch of diminishing value to pursue an alternative. We developed a virtual foraging task in which mouse behavior varied systematically with patch value. Mouse behavior could be explained by a model integrating time and rewards antagonistically, scaled by a latent patience state. The model accounted for deviations from predictions of optimal foraging theory. Neural recordings throughout frontal areas revealed encoding of decision variables from the integrator model, most robustly in frontal cortex. Regression modeling followed by unsupervised clustering identified a subset of ramping neurons. These neurons' firing rates ramped up gradually (up to tens of seconds), were inhibited by rewards, and were better described as a continuous ramp than a discrete stepping process. Together, these results identify integration via frontal cortex ramping dynamics as a candidate mechanism for solving patch foraging problems.
A transcription factor module mediating C2photosynthesis
Authors: Dickinson Patrick J. , Triesch Sebastian , Schlüter Urte , Weber Andreas P.M. , Hibberd Julian M.
Published: September 2023

C4photosynthesis has arisen from the ancestral C3state in over sixty lineages of angio-sperms. It is widely accepted that an early step in C4evolution is restriction of glycine decarboxylase activity to bundle sheath cells to generate the so-called C2pathway. In C2Moricandiaspecies, changes to thecis-regulatory region controlling expression of the P-subunit ofGLYCINE DECARBOXYLASE(GLDP) in mesophyll cells enables this trait, but the mechanism underpinningGLDPexpression in the bundle sheath is not known. We identify a MYC-MYB transcription factor module previously associated with the control of glucosinolate bio-synthesis as the basis ofGLDPexpression in bundle sheath cells. In C3Arabidopsis thalianathis module drivesGLDPexpression in bundle sheath cells along with as yet unidentified factors driving expression in mesophyll cells. In the C2speciesMoricandia arvensis, GLDPexpression is lost from mesophyll cells and the MYC-MYB dependent expression in the bundle sheath is revealed. Evolution of C2photosynthesis is thus associated with a MYC-MYB based transcriptional network already present in the C3state. This work identifies a molecular genetic mechanism underlying the bundle sheath accumulation of glycine decarboxylase required for C2photosynthesis and thus a foundational step in the evolution of C4photosynthesis.
Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies
Authors: Olešová Dominika , Dobešová Dana , Majerová Petra , Brumarová Radana , Kvasnička Aleš , Kouřil Štěpán , Stevens Eva , Hanes Jozef , Fialová Ľubica , Michalicová Alena , Piešťanský Juraj , Friedecký David , Kováč Andrej
Published: September 2023

Background

Abnormal aggregation of tau protein that leads to brain inclusions is a common feature of neurodegenerative disorders called tauopathies. Recent evidence suggests the involvement of lipid metabolic deregulations in the pathogenesis of tauopathies. However, the role of tau protein in the regulation of lipid metabolism is much less characterized and not well understood.

Methods

We used a transgenic rat model for tauopathy to reveal metabolic alterations induced by neurofibrillary pathology. Transgenic rats express a tau fragment truncated at the N-and C-terminals. For phenotypic profiling, we performed targeted metabolomic and lipidomic analysis of brain tissue, CSF, and plasma, based on the LC-MS platform. To monitor disease progression, we employed samples from transgenic and control rats aged 4, 6, 8, 10, 12, and 14 months. To study neuron-glia interplay in lipidome changes induced by pathological tau we used well well-established multicomponent cell model system. Univariate and multivariate statistical approaches were used for data evaluation.

Results

We showed that tau has an important role in the deregulation of lipid metabolism. In the lipidomic study, pathological tau was associated with higher production of lipids participating in protein fibrillization, membrane reorganization, and inflammation. Interestingly, significant changes have been found in the early stages of tauopathy before the formation of high-molecular-weight tau aggregates and neurofibrillary pathology. Increased secretion of pathological tau proteinin vivoandin vitroinduced upregulated production of phospholipids and sphingolipids and accumulation of lipid droplets in microglia. During the later stages of tauopathy, we found a connection between the transition of tau into an insoluble fraction and changes in brain metabolism. The results showed that dysregulation of lipid composition by pathological tau leads to disruption of the microenvironment and further propagation of pathology.

Conclusion

Our results revealed that lipid metabolism is significantly affected during different stages of tau pathology and provide new evidence that supports the contribution of pathological tau proteins in individual lipid pathways. Our data suggests that biologically active membrane lipids such as phospholipids and sphingolipids could represent new potential next-generation therapeutic targets in tauopathies.
Deep unsupervised learning methods for the identification and characterization of TCR specificity to Sars-Cov-2
Authors: Miraoui Yanis
Published: September 2023

The T-cell receptor (TCR) is one of the key players in the immune response to the Sars-Cov-2 virus. In this study, we used deep unsu-pervised learning methods to identify and characterize TCR speci-ficity. Our research focused on developing and applying state-of-the-art modelling techniques, including AutoEncoders, Variational Au-to Encoders and transfer learning with Transformers, to analyze TCR data. Through our experiments and analyses, we have achieved promis-ing results in identifying TCR patterns and understanding TCR speci-ficity for Sars-Cov-2. The insights gained from our research provide valuable tools and knowledge for interpreting the immunological re-sponse to the virus, ultimately contributing to the development of effective vaccines and treatments against the viral infection.
Single-Molecule Reaction-Diffusion
Authors: Xu Lance W.Q. , Jazani Sina , Kilic Zeliha , Pressé Steve
Published: September 2023

We propose to capture reaction-diffusion on a molecule-by-molecule basis from the fastest acquirable timescale, namely individual photon arrivals. We illustrate our method on intrinsically disordered human proteins, the linker histone H1.0 as well as its chaperone prothymosinα, as these diffuse through an illuminated confocal spot and interact forming larger ternary complexes on millisecond timescales. Most importantly, single-molecule reaction-diffusion, smRD, reveals single molecule properties without trapping or otherwise confining molecules to surfaces. We achieve smRD within a Bayesian paradigm and term our method Bayes-smRD. Bayes-smRD is further free of the average, bulk, results inherent to the analysis of long photon arrival traces by fluorescence correlation spectroscopy. In learning from thousands of photon arrivals continuous spatial positions and discrete conformational and photophysical state changes, Bayes-smRD estimates kinetic parameters on a molecule-by-molecule basis with two to three orders of magnitude less data than tools such as fluorescence correlation spectroscopy thereby also dramatically reducing sample photodamage.
Spatial distribution and functional integration of displaced ipRGCs
Authors: Duda Sabrina , Block Christoph T. , Pradhan Dipti R. , Arzhangnia Yousef , Greschner Martin , Puller Christian
Published: September 2023

The mammalian retina contains many distinct types of ganglion cells, which form mosaics to evenly tile the retina with cells of each type at each position of the visual field. It is well known that displaced retinal ganglion cells (dRGCs) exist with cell bodies in the inner nuclear layer, along with regularly placed RGCs with cell bodies in the ganglion cell layer. A prominent example of dRGCs are M1-type intrinsically photosensitive ganglion cells (ipRGCs) which exist in various species including humans and non-human primates. Little is known, however, about their spatial relationship with regularly placed ipRGCs.

Here, we identified mouse ipRGC types M1, M2, and M4/sONɑ by immunohistochemistry and light microscopy to anatomically investigate the distribution of displaced and regularly placed cells. Reconstruction of immunolabeled dendritic mosaics from M1 and sONɑ RGCs indicated that dRGCs tiled the retina evenly with their regularly placed RGC partners. Multi-electrode array recordings revealed conventional receptive fields of displaced sONɑ RGCs which fit into the functional mosaic of their regularly placed counterparts. We further analyzed the RGC distributions across complete retinas. The analysis of regularly placed M1 ipRGCs and ɑRGCs revealed distinct density gradients where ∼16% and ∼8% occurred as dRGCs, respectively. The density distributions of dRGCs showed type-specific patterns which followed neither the global density distribution of all ganglion cells nor the local densities of corresponding cell types.

Our study shows that the displacement of ganglion cell bodies into the inner nuclear layer occurs in a type-dependent manner, where dRGCs are positioned to form complete mosaics with their regularly placed RGC partners. Our data suggest that dRGCs and regularly placed RGCs serve the same functional role within their corresponding population of ganglion cells.

Significance statement

We applied large-scale anatomical and electrophysiological experiments in mice to show that displaced intrinsically photosensitive retinal ganglion cells (ipRGCs) complete the mosaics of their regularly placed counterparts with their dendritic trees and receptive fields. Therefore, displaced ipRGCs likely serve the same functional role as corresponding regularly placed cells. The density distributions of displaced ipRGCs showed distinct, type-specific patterns. Interestingly, they followed neither the global density distribution of all ganglion cells nor the local densities of corresponding cell types.
Phenotypic and genomic characterization ofBacillus sensu latofor their biofertilization effect and plant growth promotion features in soybean plants
Authors: Torres P. , Altier N. , Beyhaut E. , Martin N. , Fresia P. , Garaycochea S. , Abreo E.
Published: September 2023

Bacillus sensu latowere screened for their capacity to mineralize organic phosphorus (P) and promote plant growth, improving nitrogen (N) and phosphorus nutrition of soybean plants. Isolates were first identified based on their genomic sequences through TYGS and ANII. ILBB95, ILBB510 and ILBB592 were identified asPriestia megaterium, ILBB139 asBacillus wiedmannii, ILBB44 as a member of a sister clade ofB. pumilus(together with a human pathogenic strain), ILBB15 asPeribacillus butanolivoransand ILBB64 asLysinibacillussp. These strains were evaluated for their capacity to mineralize organic P as sodium phytate and solubilize inorganic P forms in liquid medium. Thesein vitroassays allowed the strains to be ranked according to their P mobilization potential, with ILBB15 and ILBB64 showing the highest orthophosphate production from phytate, ILBB592 the lowest and ILBB510 nil. In addition, features related to their rhizocompetence and plant growth promotion were evaluatedin vitroandin silico.Finally, plant bioassays were deployed to assess the effect of the co-inoculation ofBacillus s.l.strains and rhizobial inoculant on nodulation, plant growth and nutrition.In plantabioassays showed thatB. pumilusILBB44 andP. megateriumILBB95 increased P absorbed in plants grown on a poor substrate of sand and vermiculite and also on the richer mix of sand, vermiculite and peat.Priestia megateriumILBB592 increased rhizobial nodulation and N content in plants grown on sand, vermiculite and peat mixture only. ILBB15 reduced plant growth and nutrition on both substrates. Genomes of ILBB95 and ILBB592 were characterized by genes related with plant growth and biofertilization whereas ILBB15 was differentiated by genes related to bioremediation.Priestia megateriumILBB592 can be described as nodule-enhancing rhizobacteria (NER) and together with ILBB95, can be envisaged as prospective PGPR with the capacity to exert a positive effect on N and P nutrition of soybean plants.
Screening of the Pandemic Response Box identifies anti-microsporidia compounds
Authors: Huang Qingyuan , Chen Jie , Pan Guoqing , Reinke Aaron W.
Published: September 2023

Microsporidia are fungi obligate intracellular pathogens, which infect most animals and cause microsporidiosis. Despite the serious threat that microsporidia pose to humans and agricultural animals, few drugs are available for the treatment and control of microsporidia. To identify novel inhibitors, we took advantage of the model organismCaenorhabditis elegansinfected with its natural microsporidianNematocida parisii. We used this system to screen the Pandemic Response Box, a collection of 400 diverse compounds with known antimicrobial activity. After testing these compounds in a 96-well format at high (100 μM) and low (40 μM) concentrations, we identified four inhibitors that restored the ability ofC. elegansto produce progeny in the presence ofN. parisii. All four compounds reduced the pathogen load of bothN. parisiiandPancytospora epiphaga, aC. elegans-infecting microsporidia related to human-infecting species. One of these compounds, a known inhibitor of a viral protease, MMV1006203, inhibited invasion and prevented the firing of spores. A bis-indole derivative, MMV1593539, decreased spore viability. An albendazole analog, MMV1782387, inhibited proliferation ofN. parisii. We tested albendazole as well as 5 other analogs and observed that MMV1782387 was amongst the strongest inhibitors ofN. parisiiand displayed the least host toxicity. Our study further demonstrates the effectiveness of theC. elegans-N. parisiisystem for discovering microsporidia inhibitors and the compounds we identified provide potential scaffolds for anti-microsporidia drug development.
KLF7 is a general inducer of human pluripotency
Authors: Arboit Mattia , Zorzan Irene , Pellegrini Marco , Martini Paolo , Carbognin Elena , Martello Graziano
Published: September 2023

Pluripotency is the capacity to give rise to all differentiated cells of the body and the germ line and is governed by a self-reinforcing network of transcription factors. The forced expression of only some of these factors enables the reprogramming of somatic cells to pluripotency. In murine cells, several kruppel-like factors (KLFs) have been identified as stabilisers and inducers of pluripotency. Human somatic cells are routinely reprogrammed by expression of KLF4 in combination with OCT4, SOX2 and cMYC (OSKM). An extensive transcriptome analysis revealed, however, that KLF4 is barely expressed in conventional human pluripotent stem cells (PSCs). Here we show that KLF7 is robustly expressed in conventional human PSCs and it allows transcription factor-mediated somatic reprogramming. Moreover, we find that KLF7 is highly expressed in naive PSCs and its forced expression in conventional hPSCs induces upregulation of naive markers and boosts efficiency of chemical resetting to naive PSCs, overall suggesting that KLF7 is a general human pluripotency factor and an inducer of pluripotency.
Methylosome and SMN complexes are dispensable for snRNP assembly in Arabidopsis
Authors: Goretti Daniela , Collani Silvio , Nardeli Sarah Muniz , Schmid Markus
Published: September 2023

The role of RNA splicing as modulator of the molecular responses to stress is well described. In contrast, its importance in the acclimation of plants to changes in ambient temperatures started to emerge only recently. Here, we analyzed the role of temperature in spliceosome assembly, a key step often neglected in studies focusing on splicing. Taking advantage of mutants showing temperature-dependent phenotypes we conducted a comprehensive study of the role that the methylosome and SMN complexes have in plant snRNP assembly. Genetic analyses, as well asin vivoandin vitroevidence suggest a mechanism for snRNP assembly in plants that differs remarkably from vertebrate animals. The SMN complex in plants is apparently reduced to a single protein, GEMIN2, that is not essential for plant development. Similarly, the methylosome has a less crucial role in spliceosome assembly than previously thought. Our results highlight how an evolutionary conserved molecular process like RNA splicing has nevertheless evolved plant specific characteristics.
Putting a finger on histidine methylation
Authors: Boutz Paul L.
Published: September 2023

Specialized enzymes add methyl groups to the nitrogens of the amino acid histidine, altering the chemical properties of its imidazole ring and, in turn, the function of the modified (poly)peptide. In this issue ofGenes & Development, Shimazu and colleagues (pp. 724–742) make the remarkable discovery that CARNMT1 acts as a dual-specificity histidine methyltransferase, modifying both the small-molecule dipeptide carnosine and a set of proteins, predominantly within RNA-binding C3H zinc finger (C3H ZF) motifs. As a result, CARNMT1 modulates the activity of its protein targets to affect RNA processing and metabolism, ultimately contributing an essential function during mammalian development.
Buyer–seller interactions and customer satisfaction – the moderating role of COVID-19 protocols: a study of small apparel fashion enterprises in the regional shopping malls in Ghana
Authors: Yeboah Solomon Tawiah , Haider Yasmeen , Amoako George
Published: September 2023

Purpose

The study explored the relationship between buyer–seller interactions and customer satisfaction in the small apparel fashion enterprises in the emerging markets. The moderating role of COVID-19 protocols implementations on buyer–seller interactions and customer satisfaction was further examined.

Design/methodology/approach

Buyer–seller interactions affecting customer satisfaction were divided into three constructs, namely, interactions relating to the overall customers shopping experience, smooth payment process and in-store interactions, and the COVID-19 protocols implementations were used as a moderator. A convenient sampling strategy was adopted to survey 450 customers of apparel fashion enterprises within the four regions in Ghana, of which 397 were validly used for the analysis. Existing questionnaires were adapted to collect data from the respondents. The data collected was therefore analysed using SPSS and SmartPLS programme to ascertain the nature of the relationships among the variables.

Findings

The study found that, in-store interactions, shopping experience and smooth payment processes directly influence customer satisfaction. However, the implementation of COVID-19 protocols failed to moderate the relationship between buyer–seller interactions and customer satisfaction.

Research limitations/implications

The limitations of the study involve its context-specific, focusing on the small apparel and fashion market. Also, future researchers can re-examine the model in other geographical jurisdictions, focusing on small apparel owners’ competencies and other variables that position buyer–seller interactions as precursors of customer satisfaction in the small apparel fashion industry. The theoretical and managerial relevance of the findings are also discussed.

Originality/value

The paper extends the domain of buyer–seller interactions and customer satisfaction phenomena within the apparel fashion industry. Its examination of the impact of COVID-19 protocols’ implementation on customer satisfaction provides an insight into managers regarding how the applications can affect customers in a typical shopping environment.
An impetus for the research paradigm of corporate citizenship and customer loyalty: imprints from scale construction
Authors: Gulati Twinkle , Shankar Siddharatha
Published: September 2023

Purpose

The purpose of this research is to construct a logical, consistent and validated instrument to appraise the effect of corporate citizenship on customer loyalty, all-inclusive of possible factors.

Design/methodology/approach

To attain this intent, a literature review is organized at the onset and then statements are created, improved and confirmed. In total, 384 customer-filled forms have been analyzed in parts, initially with exploratory factor analysis (EFA) and thereafter with confirmatory factor analysis (CFA).

Findings

EFA outcomes obtain 26 items and three dimensions: corporate citizenship and customer acquisition, corporate citizenship and customer inclination, and corporate citizenship and customer patronization. The comprehensiveness, solidness, and judiciousness of the same have been tested by CFA.

Research limitations/implications

This investigation would function as an impetus that can further evolve the empirical paradigm of corporate citizenship and customer loyalty by significantly impacting theory and practice.

Practical implications

It presents the pragmatic perspectives of customers about modern-age citizenship endeavors for marketers, thus attuning their socially responsible marketing movements with upright citizenship actions.

Originality/value

Since the discipline of corporate citizenship has received inadequate empirical understanding from the marketing outlook, possibly because of the lack of a confirmed and consistent instrument from the customers' angle, this developed scale can fill up that space.