bluuebunny/crossref_metadata_2025 huggingface dataset:
IDH and 1p19q Diagnosis in Diffuse Glioma from Preoperative MRI Using Artificial Intelligence
Authors: McHugh Hugh , Safaei Soroush , Maso Talou Gonzalo D. , Gock Stephen L. , Yeun Kim Joo , Wang Alan
Published: April 2023

Background

Isocitrate dehydrogenase (IDH) mutation and 1p19q codeletion are important beneficial prognosticators in glioma. IDH and 1p19q diagnosis requires tissue sampling and there are likely benefits of presurgical diagnosis. Research supports the potential of MRI-based IDH and 1p19q diagnosis, however there is a paucity of external validation outside the widely used The Cancer Imaging Archive (TCIA) dataset. We present a combined IDH and 1p19q classification algorithm and assess performance on a local retrospective cohort (NZ) and the Erasmus Glioma Database (EGD).

Methods

2D convolutional neural networks are trained to provide IDH and 1p19q classification. Inputs are T1 post-contrast, T2, and FLAIR sequences. Training data consists of preoperative imaging from the TCIA dataset (n=184) and a locally obtained NZ dataset (n=349). Evaluation data consists of the most recent cases from the NZ dataset (n=205) and the EGD (n=420).

Results

IDH classification accuracy was 93.3% and 91.5% on the NZ and EDG, with AUC values of 95.4% and 95.8%, respectively. 1p19q accuracy was 94.5% and 87.5% with AUC values of 92.5% and 85.4% on the NZ and EGD datasets. Combined IDH and 1p19q accuracy was 90.4% and 84.3% on the NZ and EGD, with AUC values of 92.4% and 91.2%.

Conclusions

High IDH and 1p19q classification performance was achieved on the NZ retrospective cohort. Performance generalised to the EGD demonstrating the potential for clinical translation. This method makes use of readily available imaging and has high potential impact in glioma diagnostics.

Key Points

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IDH and 1p19q are the main molecular markers in glioma.

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Accurate predictions can be obtained from preoperative MRI without changes to imaging protocols.

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Non-invasive diagnosis will likely enhance treatment planning and facilitate targeted preoperative therapies.

Importance of the Study

The 2021 WHO CNS tumour classification system formalises the increasing recognition of molecular factors like IDH and 1p19q in the prognostication and treatment of glioma. Emerging research shows the potential of artificial intelligence methods applied to preoperative MRI sequences to noninvasively predict molecular status. A limitation of the literature published to date is a lack of generalisation and external validation outside the widely used TCIA dataset. Here we present the performance of an MRI-based IDH and 1p19q classification tool evaluated on a large consecutive cohort from New Zealand and an independent publicly available dataset of MR images from the Netherlands. We demonstrate high predictive performance with robust generalisation, indicating the potential usefulness of this method in the workup of glioma. Reliable preoperative tumour characterisation may facilitate tailored treatment approaches and early decision making without the need for additional imaging.
Biallelic null variants inPNPLA8cause microcephaly through the reduced abundance of basal radial glia
Authors: Nakamura Yuji , Shimada Issei S. , Maroofian Reza , Houlden Henry , Falabella Micol , Fujimoto Masanori , Sato Emi , Takase Hiroshi , Aoki Shiho , Miyauchi Akihiko , Koshimizu Eriko , Miyatake Satoko , Arioka Yuko , Honda Mizuki , Higashi Takayoshi , Miya Fuyuki , Okubo Yukimune , Ogawa Isamu , Scardamaglia Annarita , Miryounesi Mohammad , Alijanpour Sahar , Ahmadabadi Farzad , Herkenrath Peter , Dafsari Hormos Salimi , Velmans Clara , Balwi Mohammed , Vitobello Antonio , Denommé-Pichon Anne-Sophie , Jeanne Médéric , Civit Antoine , Zaki Maha S. , Darvish Hossein , Bakhtiari Somayeh , Kruer Michael , Carroll Christopher J , Karimiani Ehsan Ghayoor , Khailany Rozhgar A , Abdulqadir Talib Adil , Ozaslan Mehmet , Bauer Peter , Zifarelli Giovanni , Seifi Tahere , Zamani Mina , Alam Chadi Al , Pitceathly Robert D S , Haginoya Kazuhiro , Matsunaga Tamihide , Osaka Hitoshi , Matsumoto Naomichi , Ozaki Norio , Ohkawa Yasuyuki , Oki Shinya , Tsunoda Tatsuhiko , Taketomi Yoshitaka , Murakami Makoto , Kato Yoichi , Saitoh Shinji
Published: April 2023

PNPLA8, one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. However, little is known about its role in brain development. Here, we report 12 individuals from 10 unrelated families with biallelic ultra-rare variants inPNPLA8presenting with a wide spectrum of clinical features ranging from developmental and epileptic-dyskinetic encephalopathy (DEDE) to progressive movement disorders. Complete loss of PNPLA8 was associated with the severe end of the spectrum, showing DEDE manifestations and congenital or progressive microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 reduced the number of basal radial glial cells (bRGCs) and upper-layer neurons. By spatial transcriptomic analysis targeting apical radial glial cells (aRGCs), we found the downregulation of bRGC-related gene sets in patient-derived cerebral organoids. Lipidomic analysis revealed a decrease in the amount of lysophosphatidic acid, lysophosphatidylethanolamine, and phosphatidic acid, indicative of the disturbed phospholipid metabolism inPNPLA8knockout neural progenitor cells. Our data suggest that PNPLA8 has a critical role in the bRGC-mediated expansion of the developing human cortex by regulating the fate commitment of aRGCs.
Percutaneous Coronary Intervention of Chronic Total Occlusion is Associated with Higher Inpatient Mortality and Complications Compared to Non-CTO lesions Using the National Inpatient Sample (NIS) Database
Authors: Nathan Allistair , Hashemzadeh Mehrtash , Movahed Mohammad Reza
Published: April 2023

Background

Percutaneous coronary intervention (PCI) in patients with chronic total occlusion (CTO) is commonly performed despite unclear long-term benefits. The goal of this study was to evaluate the post-procedural outcome of patients with CTO intervention.

Methods

The National Inpatient Sample (NIS) database, years 2016-2020, was studied using ICD 10 codes. Patients with CTO intervention were compared to patients without CTO. We evaluated post-procedural mortality and complications.

Results

PCI in patients with CTO was associated with higher mortality and all post-procedural complications. A total of 2,011,854 patients underwent PCI with 259,574 having CTO. The CTO group had a 3.17% mortality rate vs 2.57% of non-CTO PCI. (OR, 1.24; CI:1.18–1.31; p<0.001). Using multivariate analysis adjusting for age, sex, race, diabetes mellitus, and chronic kidney disease, CTO PCI remained significantly associated with higher mortality (OR, 1.37; 95% CI, 1.3 – 1.45; p<0.001). Patients with CTO compared to non-CTO PCI patients had higher rates of myocardial infarction (OR, 2.85; 95% CI, 2.54 – 3.21; p<0.001), coronary perforation (OR, 6.01; 95% CI, 5.25-6.89; p<0.001), tamponade (OR, 3.36; 95% CI, 2.91-3.88, p<0.001), contrast-induced nephropathy (OR, 2.05; 95% CI, 1.45-2.90), p<0.001), procedural bleeding (OR, 3.57; 95% CI, 3.27-3.89, p<0.001), and acute post-procedural respiratory failure (OR, 2.07; 95% CI, 1.81-2.36, p<0.001). All post-procedural complications were more than 3 times the non-CTO patients (OR, 3.45; 95% CI, 3.24-3.67; p<0.001).

Conclusion

Using a large national inpatient database, PCI performed in patients with CTO was associated with significantly much higher mortality and post-procedural complications compared to PCI in non-CTO patients.
Brain2GAN: Feature-disentangled neural encoding and decoding of visual perception in the primate brain
Authors: Dado Thirza , Papale Paolo , Lozano Antonio , Le Lynn , Wang Feng , van Gerven Marcel , Roelfsema Pieter , Güçlütürk Yağmur , Güçlü Umut
Published: April 2023

A challenging goal of neural coding is to characterize the neural representations underlying visual perception. To this end, multi-unit activity (MUA) of macaque visual cortex was recorded in a passive fixation task upon presentation of faces and natural images. We analyzed the relationship between MUA and latent representations of state-of-the-art deep generative models, including the conventional and feature-disentangled representations of generative adversarial networks (GANs) (i.e.,z- andw-latents of StyleGAN, respectively) and language-contrastive representations of latent diffusion networks (i.e., CLIP-latents of Stable Diffusion). A mass univariate neural encoding analysis of the latent representations showed that feature-disentangledwrepresentations outperform bothzand CLIP representations in explaining neural responses. Further,w-latent features were found to be positioned at the higher end of the complexity gradient which indicates that they capture visual information relevant to high-level neural activity. Subsequently, a multivariate neural decoding analysis of the feature-disentangled representations resulted in state-of-the-art spatiotemporal reconstructions of visual perception. Taken together, our results not only highlight the important role of feature-disentanglement in shaping high-level neural representations underlying visual perception but also serve as an important benchmark for the future of neural coding.

Author summary

Neural coding seeks to understand how the brain represents the world by modeling the relationship between stimuli and internal neural representations thereof. This field focuses on predicting brain responses to stimuli (neural encoding) and deciphering information about stimuli from brain activity (neural decoding). Recent advances in generative adversarial networks (GANs; a type of machine learning model) have enabled the creation of photorealistic images. Like the brain, GANs also have internal representations of the images they create, referred to as “latents”. More recently, a new type of feature-disentangled “w-latent” of GANs has been developed that more effectively separates different image features (e.g., color; shape; texture). In our study, we presented such GAN-generated pictures to a macaque with cortical implants and found that the underlyingw-latents were accurate predictors of high-level brain activity. We then used thesew-latents to reconstruct the perceived images with high fidelity. The remarkable similarities between our predictions and the actual targets indicate alignment in howw-latents and neural representations represent the same stimulus, even though GANs have never been optimized on neural data. This implies a general principle of shared encoding of visual phenomena, emphasizing the importance of feature disentanglement in deeper visual areas.
Microplastics found in Antarctic penguins: chemical reactivity theory to analyze possible toxicity
Authors: Martínez Ana , Barbosa Andrés
Published: April 2023

Micro- and nanoplastics are widespread in the marine environment including polar regions across Antarctica. In Antarctic penguins, eighty percent of microplastics were identified as polyethylene and ten percent as polyester. To analyze the toxicity of these two polymers, oligomers with different numbers of units were used as models. The use of oligomers as polymer models has been used previously with success. We started with the monomer and continued with different oligomers until the chain length was greater than 2 nm. According to the results of quantum chemistry, polyester is a better oxidant than polyethylene, since it is a better electron acceptor. Although there is less polyester than polyethylene in penguins, the presence of polyester may be more harmful than the presence of polyethylene for three reasons: polyester is better electron acceptor and therefore a better oxidant than polyethylene; polyester has negatively charged oxygen atoms and can promote stronger interactions than polyethylene with other molecules; polyester forms stable complexes and can dissociate the guanine-cytosine nucleobase pair. This could affect DNA replication. This theoretical information helps to elucidate the potential damage of micro- and nanoplastics.
Proteomic analysis of peripheral nerve myelin during murine aging
Authors: Helbing Dario Lucas , Kirkpatrick Joanna M. , Reuter Michael , Bischoff Julia , Stockdale Amy , Carlstedt Annemarie , Cirri Emilio , Bauer Reinhard , Morrison Helen
Published: April 2023

Aging of the peripheral nervous system (PNS) is associated with structural and functional changes that lead to a reduction in regenerative capacity and the development of age-related peripheral neuropathy. Myelin is central to maintaining physiological peripheral nerve function and differences in myelin maintenance, degradation, formation and clearance have been suggested to contribute to age-related PNS changes. Recent proteomic studies have elucidated the complex composition of the total myelin proteome in health and its changes in neuropathy models. However, changes in the myelin proteome of peripheral nerves during aging have not been investigated. Here we show that the proteomes of myelin fractions isolated from young and old nerves show only subtle changes. In particular, we found that the three most abundant peripheral myelin proteins (MPZ, MBP and PRX) do not change in old myelin fractions. We also show a tendency for high-abundance myelin proteins other than these three to be downregulated, with only a small number of ribosome-related proteins significantly downregulated and extracellular matrix proteins such as collagens upregulated. In addition, we illustrate that the peripheral nerve myelin proteome reported in this study is suitable for assessing myelin degradation and renewal during peripheral nerve degeneration and regeneration. Our results suggest that the peripheral nerve myelin proteome is relatively stable and undergoes only subtle changes in composition during mouse aging. We proffer the resultant dataset as a resource and starting point for future studies aimed at investigating peripheral nerve myelin during aging. Said datasets are available in the PRIDE archive under the identifier PXD040719 (aging myelin proteome) and PXD041026 (sciatic nerve injury proteome).
Dopamine receptor type 2-expressing medium spiny neurons in the ventral lateral striatum have a non-REM sleep-induce function
Authors: Kato Tomonobu , Tanaka Kenji F. , Natsubori Akiyo
Published: April 2023

Dopamine receptor type 2-expressing medium spiny neurons (D2-MSNs) in the medial part of the ventral striatum (VS) induce non-REM (NREM) sleep from the wake state in animals. However, it is unclear whether D2-MSNs in the lateral part of the VS (VLS), which is anatomically and functionally different from the medial part of the VS, contribute to sleep-wake regulation. This study aims to clarify whether and how D2- MSNs in the VLS are involved in sleep-wake regulation. Our study found that specifically removing D2-MSNs in the VLS led to an increase in wakefulness time in mice during the dark phase using a diphtheria toxin-mediated cell ablation/dysfunction technique. D2-MSN ablation throughout the VS increased dark phase wakefulness time. These findings suggest that VLS D2-MSNs may induce sleep during the dark phase with the medial part of the VS. Next, our fiber photometric recordings revealed that the population intracellular calcium (Ca2+) signal in the VLS D2-MSNs increased during the transition from wake to NREM sleep. The mean Ca2+signal level of VLS D2-MSNs was higher during NREM and REM sleep than during the wake state, supporting their sleep-inducing role. Finally, optogenetic activation of the VLS D2-MSNs during the wake state always induced NREM sleep, demonstrating the causality of VLS D2-MSNs activity with sleep-induction. Additionally, activation of the VLS D1-MSNs, counterparts of D2-MSNs, always induced wake from NREM sleep, indicating a wake- promoting role. In conclusion, VLS D2-MSNs could have an NREM sleep-inducing function in coordination with those in the medial VS.

Significant statement

The sleep-inducing function of D2-MSNs in the medial part of the ventral striatum (VS) has been previously reported; however, their function in the lateral part of the VS (VLS) has not been elucidated. We demonstrated that the diphtheria toxin-induced ablation of D2-MSNs in the VLS, as well as in the entire VS, increased wakefulness time in mice during the dark phase. VLS D2-MSNs had higher average Ca2+signals during NREM and REM sleep than wake state via fiber photometric recording. Furthermore, optogenetic activation of VLS D2-MSNs during wake state induced NREM sleep in mice. In conclusion, D2-MSNs in the VLS have an NREM sleep-inducing function in coordination with those in the medial VS.
Incomplete dosage balance and dosage compensation in the ZZ/ZW Gila monster (Heloderma suspectum) revealed byde novogenome assembly
Authors: Webster Timothy H. , Vannan Annika , Pinto Brendan J. , Denbrock Grant , Morales Matheo , Dolby Greer A. , Fiddes Ian T. , DeNardo Dale F. , Wilson Melissa A.
Published: April 2023

Reptiles exhibit a variety of modes of sex determination, including both temperature-dependent and genetic mechanisms. Among those species with genetic sex determination, sex chromosomes of varying heterogamety (XX/XY and ZZ/ZW) have been observed with different degrees of differentiation. Karyotype studies have demonstrated that Gila monsters (Heloderma suspectum) have ZZ/ZW sex determination and this system is likely homologous to the ZZ/ZW system in the Komodo dragon (Varanus komodoensis), but little else is known about their sex chromosomes. Here, we report the assembly and analysis of the Gila monster genome. We generated ade novodraft genome assembly for a male using 10X Genomics technology. We further generated and analyzed short-read whole genome sequencing and whole transcriptome sequencing data for three males and three females. By comparing female and male genomic data, we identified four putative Z-chromosome scaffolds. These putative Z-chromosome scaffolds are homologous to Z-linked scaffolds identified in the Komodo dragon. Further, by analyzing RNAseq data, we observed evidence of incomplete dosage compensation between the Gila monster Z chromosome and autosomes and a lack of balance in Z-linked expression between the sexes. In particular, we observe lower expression of the Z in females (ZW) than males (ZZ) on a global basis, though we find evidence suggesting local gene-by-gene compensation. This pattern has been observed in most other ZZ/ZW systems studied to date and may represent a general pattern for female heterogamety in vertebrates.
Repetition plasticity in primary auditory cortex occurs across long timescales for spectrotemporally randomized pure-tones
Authors: Gill Nasiru K. , Francis Nikolas A.
Published: April 2023

Repetition plasticity is a ubiquitous property of sensory systems in which repetitive sensation causes either a decrease (“repetition suppression”, i.e. “adaptation”) or increase (“repetition enhancement”, i.e. “facilitation”) in the amplitude of neural responses. Timescales of repetition plasticity for sensory neurons typically span milliseconds to tens of seconds, with longer durations for cortical vs subcortical regions. Here, we used 2-photon (2P) imaging to study repetition plasticity in mouse primary auditory cortex (A1) layer 2/3 (L2/3) during the presentation of spectrotemporally randomized pure-tone frequencies. Our study revealed subpopulations of neurons with repetition plasticity for equiprobable frequencies spaced minutes apart over a 20-minute period. We found both repetition suppression and enhancement in individual neurons and on average across populations. Each neuron tended to show repetition plasticity for 1-2 pure-tone frequencies near the neuron’s best frequency. Moreover, we found correlated changes in neural response amplitude and latency across stimulus repetitions. Together, our results highlight cortical specialization for pattern recognition over long timescales in complex acoustic sequences.
Exposure to childhood maltreatment is associated with changes in sperm small non-coding RNA and DNA methylation profiles
Authors: Tuulari Jetro J. , Bourgery Matthieu , Ahonen Annukka , Ahmedani Ammar , Iversen Jo , Koefoed Thomas Gade , Kataja Eeva-Leena , Karlsson Linnea , Barrès Romain , Karlsson Hasse , Kotaja Noora
Published: April 2023

Background:

Childhood maltreatment exposure (CME) increases the risk of adverse long-term health consequences for the exposed individual. Animal studies suggest that CME may also influence the health and behaviour in the next generation offspring through CME-driven epigenetic changes in the paternal germ line. The contribution of paternal early life stress on the health of the next generation in humans is not fully elucidated.

Methods:

In this study, we measured paternal CME using the Trauma and Distress Scale (TADS) questionnaire and mapped sperm-borne sncRNAs expression by small RNA sequencing (small RNA-seq) and DNA methylation (DNAme) in spermatozoa by reduced-representation bisulfite sequencing (RRBS-seq) in males from the FinnBrain Birth Cohort Study. The study design was a (nested) case-control study, high-TADS (TADS ≥ 39, n = 25 for DNAme and n = 14 for small RNA-seq) and low-TADS (TADS ≤ 10, n = 30 for DNAme and n = 16 for small RNA-seq)). Groups were compared to identify specific epigenetic signatures associated with TADS levels in the spermatozoa of participants.

Results:

Compared to the control group, high CME was associated with altered sperm sncRNA expression and DNAme profiles. Particularly, we identified several tRNA-derived small RNAs (tsRNAs) and miRNAs with markedly changed levels in males with high CME. DNA methylation analysis identified several genomic regions with differentially methylated CpGs between groups. Notably, we identified two epigenetic marks related to brain development with distinct profiles between CME and controls, the miRNA hsa-mir-34c-5p and differential methylation of the region in proximity of FSCN1.

Conclusions:

This study provides further evidence that early life stress influences the paternal germ line epigenome and supports a possible contribution in the development of the central nervous system of the next generation.
Interplay between fecundity, sexual and growth selection on the spring phenology of European beech (Fagus sylvaticaL.)
Authors: Oddou-Muratorio Sylvie , Bontemps Aurore , Gauzere Julie , Klein Etienne
Published: April 2023

Background

Plant phenological traits such as the timing of budburst or flowering can evolve on ecological timescales through response to fecundity and viability selection. However, interference with sexual selection may arise from assortative mating. This study aims to investigate how these three components of selection on spring phenology may combine in European beech populations in contrasting environments (high versus low altitude).

Methods

we monitored the timing of budburst (TBB) in 339 adult beech trees and estimated their fecundity using spatially explicit mating models. Fecundity selection was infered by regressing fecundities on TBB, while sexual selection was inferred by regressing fecundities on mating opportunities (i.e., TBB mismatch). The correlation between mates for flowering time (i.e., assortative mating) was estimated based on paternity analyses. Morever, TBB and growth were surveyed in 3261 seedlings from 40 families grown planted in a common garden, and viability selection was inferred by regressing growth on TBB.

Results

Overall, directional fecundity selection on female fitness favored trees with earlier TBB. Sexual selection acted only on male fitness through assortative mating favoring trees with mean TBB value (stabilizing selection). In the common garden, early budburst was associated with higher seedling growth. The respective intensities of directional and stabilizing selection varied with the environment: at low altitude, directional selection for earlier phenology was modulated by strong assortative mating and by an interaction effect between TBB an size on female fecundity, whereas at high altitude, directional selection for earlier phenology was reinforced by selection through male fecundity.

Discussion

This study showed that selection through female fecundity and seedlings growth predominantly selected for earlier TBB, while sexual selection on male fitness through assortative mating modulated this trend. This interplay between fecundity and sexual selection calls for an integrative approach to predict the evolution of spring phenology under a changing climate.
RareSH2B3coding variants identified in lupus patients impair B cell tolerance and predispose to autoimmunity
Authors: Zhang Yaoyuan , Morris Rhiannon , Lorenzo Ayla May D. , Meng Xiangpeng , Kershaw Nadia J. , Kiridena Pamudika , Brown Grant J. , Burgio Gaétan , Cappello Jean Y. , Shen Qian , Wang Hao , Turnbull Cynthia M. , Lea-Henry Tom , Stanley Maurice , Yu Zhijia , Ballard Fiona , Chuah Aaron , Lee James C. , Hatch Ann-Maree , Headley Alexander P. , Trnka Peter , Mallon Dominic , Fletcher Jeffery T. , Walters Giles D. , Šestan Mario , Jelušić Marija , Cook Matthew C. , Athanasopoulos Vicki , Fulcher David A. , Babon Jeffrey J. , Vinuesa Carola G. , Ellyard Julia I.
Published: April 2023

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them,SH2B3- a negative regulator of cytokine and growth factor receptor signaling – harbors rare coding variants in over 5% of SLE patients. Here we show that unlike the variant found exclusively in healthy controls, mostSH2B3rare variants found in lupus patients are predominantly hypomorphic alleles. Generation of two mouse lines carrying variants orthologous to those found in patients revealed SH2B3 is important to limit the numbers of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role forSH2B3in human B cell tolerance and lupus risk.

Zhanget al. reveal a role for hypomorphic SH2B3 in lupus risk. The study shows rare and damaging variants identified in lupus patients enable breach of B cell immune tolerance checkpoints and suggests involvement for dysregulated IL-4R signaling and BAFF-R expression.
A Mechanistic Reinterpretation of Fast Inactivation in Voltage-Gated Na+Channels
Authors: Liu Yichen , Bassetto Carlos AZ , Pinto Bernardo I , Bezanilla Francisco
Published: April 2023

Fast Inactivation in voltage-gated Na+channels plays essential roles in numerous physiological functions. The canonical hinged-lid model has long predicted that a hydrophobic motif in the DIII-DIV linker (IFM) acts as the gating particle that occludes the permeation pathway during fast inactivation. However, the fact that the IFM motif is located far from the pore in recent high-resolution structures of Nav+channels contradicts thisstatus quomodel. The precise molecular determinants of fast inactivation gate once again, become an open question. Here, we provide a mechanistic reinterpretation of fast inactivation based on ionic and gating current data. In Nav1.4 the actualinactivation gateis comprised of two hydrophobic rings at the bottom of S6. These functionin seriesand closing once the IFM motif binds. Reducing the volume of the sidechain in both rings led to a partially conductive inactivated state. Our experiments also point to a previously overlooked coupling pathway between the bottom of S6 and the selectivity filter.
Inconsistent shifts in warming and temperature variability negatively impact avian fitness
Authors: Taff Conor C. , Shipley J. Ryan
Published: April 2023

Climate change can create challenging conditions for reproduction by creating mismatches between breeding activity, resource availability, and favorable weather. Phenological advancement may mitigate some of these effects, but it can also result in exposing developing offspring to greater temperature variability during reproduction. We combined >300,000 community science breeding records with data on historical temperature to understand how exposure to extreme climatic events (ECEs) has changed for 24 North American songbirds during breeding. More specifically, we wanted to understand if changes in average spring temperature were associated with when the latest cold-snap or earliest heat-wave occurred across the breeding range and the relationship to individual fitness. While average spring temperature increased universally across North America since 1950, the change in timing of ECEs was inconsistent in both direction and magnitude. Moreover, increase in average temperature did not predict the amount of change in average cold-snap and heat-wave timing. Thus, the current relationships between temperature and temperature variability differ from those experienced historically during breeding. After accounting for covariates, we found that 16 of 24 species had reduced reproductive success when a cold-snap occurred during the breeding attempt and 11 of 24 had reduced success when a heat-wave occurred. Four of the five aerial insectivores included showed marked sensitivity to ECEs, as did all the sallying insectivores. For three widespread species, we found evidence for latitudinal differences in susceptibility to temperature extremes. However, the pattern of sensitivity differed for each species, suggesting that life history details might play an important role in species responses to ECEs. Large-scale patterns and consequences of climate change on breeding birds ultimately result from the accumulated effects of individual susceptibility. Our results add to evidence demonstrating that understanding individual and species level sensitivity and linking them to population level processes is critical for predicting vulnerability to changing climates.
Novel Anammox Bacteria Discovered in the Untapped Subsurface Aquifers
Authors: Wu Jiapeng , Yang Yuchun , Gu Ji-Dong , Hong Yiguo
Published: April 2023

Anaerobic ammonium-oxidation (anammox) reaction is a crucial microbial nitrogen (N) transformation process contributing to the global N cycling. The currently known anammox bacteria are affiliated with two families, the marineCa. Scalinduaceae and the freshwaterCa. Brocadiaceae, in thePlanctomycetes. Here we report a discovery of new groups of anammox bacteria consisting of two new orders, two new families, and six new genera within the classCandidatusBrocadiia, all from geochemically distinct aquifer systems. Up to 25 high-quality metagenome-assembled genomes (MAGs) equipped with the core anammox metabolisms were recovered from 13 metagenomic datasets of aquifers and dominated the anammox bacterial communities in distinct aquifers unexpectedly. The comparatively smaller genome size (< 2.6 Mb) and higher coding density (> 85%) likely confer the survival advantage of them by reducing the energy consumption in cell replication and maintenance to increase the nutrient acquisition efficiency in the typically oligotrophic aquifers. Overall, the highly diversity of novel anammox bacterial lineages in aquifer systems largely expands our knowledge of the taxonomic diversity of anammox bacteria and highlights their global importance in aquifer N cycling.
Assembly of Synaptic Protein-DNA Complexes: Critical Role of Non-Specific Interactions
Authors: Vemulapalli Sridhar , Hashemi Mohtadin , Kolomeisky Anatoly B. , Lyubchenko Yuri L.
Published: April 2023

The synaptic protein-DNA complexes, formed by specialized proteins that bridge two or more distant sites on DNA, are critically involved in various genetic processes. However, the molecular mechanism by which the protein searches for these sites and how it brings them together is not well understood. Our previous studies directly visualized search pathways used by SfiI, and we identified two pathways, DNA threading and site-bound transfer pathways, specific to the site search process for synaptic DNA-protein systems. To investigate the molecular mechanism behind these site search pathways, we assembled complexes of SfiI with various DNA substrates corresponding to different transient states and measured their stability using a single-molecule fluorescence approach. These assemblies corresponded to specific-specific (synaptic), non-specific-non-specific (non-specific), and specific-non-specific (pre-synaptic) SfiI-DNA states. Unexpectedly, there was an elevated stability in pre-synaptic complexes assembled with specific and non-specific DNA substrates has been found. To explain these surprising observations, a theoretical approach that describes the assembly of these complexes and compares the predictions with the experiment is developed. The theory explains this effect by utilizing entropic arguments, according to which, after the partial dissociation, the non-specific DNA template has multiple possibilities of rebinding, effectively increasing the stability. Such difference in the stabilities of SfiI complexes with specific and non-specific DNA explains the utilization of threading and site-bound transfer pathways in the search process of synaptic protein-DNA complexes discovered in the time-lapse AFM experiments.
Targeted spectroscopy in the eye fundus
Authors: Lapointe Nicolas , Akitegetse Cléophace , Poirier Jasmine , Picard Maxime , Sauvageau Patrick , Sauvageau Dominic
Published: April 2023

Abstract

Significance

The assessment of biomarkers in the eye is rapidly gaining traction for the screening, diagnosis and monitoring of ocular and neurological diseases. Targeted ocular spectroscopy is a new technology that enables the user to concurrently image the eye fundus and acquire high quality spectra from a targeted region –1.5 degrees– within the imaged area. The combination of imaging and high-sensitivity spectroscopy provides structural, compositional, and functional information of selected regions of the eye fundus. This opens the door to new, non-invasive approaches to the detection of biomarkers in the eye.

Aim

The aim of this study was to demonstrate the multi-modal functionality and validation of the targeted ocular spectroscopy developed. This was done in vitro, using a reference target and a model eye, and in vivo.

Approach

Images and spectra from different regions of a reference target and a model eye were acquired and analyzed to validate the system. The same eye model was used to obtain fluorescence images and spectra, highlighting the capability of the system to also perform targeted ocular fluorescence spectroscopy. Subsequently, in vivo imaging and diffuse reflectance spectra were acquired to assess blood oxygen saturation in the optic nerve head and the parafovea of healthy subjects.

Results

Tests conducted with the reference target showed that spectral analysis could be accurately performed within specific areas of the imaging space. Moving to the model eye, distinct spectral signatures were observed for the targeted spectral analysis done in the optic disc, the retina and the macula, consistent with the variations in tissue composition and functions between these regions mimicked by the model eye. Further, it was shown that the targeted spectral analysis could also be performed in a fluorescence mode to distinguish various fluorophores present within the imaging space. Finally, in vivo ocular oximetry experiments performed in the optic nerve head and parafovea of healthy patients showed significant differences in blood oxygen saturation between these regions (p = 0.004).

Conclusions

Enabling non-invasive, sensitive diffuse reflectance and fluorescence spectroscopy in specific regions of the eye fundus opens the door to a whole new range of monitoring and diagnostic capabilities, from assessment of oxygenation in glaucoma and diabetic retinopathy to photo-oxidation and photo-degradation in age-related macular degeneration.
The Impact of Severe Ventricular Remodeling on Quality-of-Life Outcomes after Transcatheter Aortic Valve Replacement
Authors: Reddy Pavan , Merdler Ilan , Zhang Cheng , Cellamare Matteo , Ben-Dor Itsik , Satler Lowell F. , Rogers Toby , Weintraub William S. , Waksman Ron
Published: April 2023

Background

Among patients with aortic stenosis, severe ventricular remodeling can limit the augmentation of flow with exertion, even after valve intervention. While long-term mortality risk has been shown be elevated in this patient population, the effect on quality of life (QoL) improvement has not been studied. Our objective was to determine the effect of severe ventricular remodeling on QoL outcomes after transcatheter aortic valve replacement (TAVR).

Methods

All patients undergoing TAVR from 2011-2021 at our institution were included. Groups were divided according to guideline-recommended cutoffs for left ventricular (LV) wall thickness. Normal or mild wall thickness was designated as non-remodeled (NR) and moderate/severe wall thickness defined the remodeled group (REM). The Kansas City Cardiomyopathy Questionnaire (KCCQ) was utilized to assess QoL and the primary outcome was KCCQ change <5 from baseline to 30 days and 1 year.

Results

We analyzed 679 patients (NR: N=389, REM: N=290). Baseline KCCQ overall score [OS] trended higher in the NR group (60.1 vs. 56.6, p=0.053). Echocardiographic baseline differed between NR and REM by septal thickness (1.12 cm vs. 1.44 cm, p<0.001), posterior wall thickness (1.08 cm vs. 1.33 cm, p<0.001), and LV internal diastolic diameter (4.34 cm vs. 4.19 cm, p=0.006). The primary outcome was similar between NR and REM at 30 days (31.6% vs. 28.6%, p=0.449) and at 1 year (27.7% vs. 21.5%, p=0.217). NR and REM experienced similar proportions of worsening or no change, small, moderate, and large improvements in KCCQ score (<5, 5-10, 10-19, ≥20, respectively). Both groups experienced similar domain score changes and NYHA improvement. At one year, NR demonstrated greater reduction in 5MWT time compared to REM (−1.98 s vs. -0.2 s, p=0.028). A subgroup analysis of REM patients did not reveal interaction with cavity size, stroke volume, mitral regurgitation, E/A ratio, valvulo-arterial impedance, or hyperdynamic ejection fraction.

Conclusions

Patients with severe ventricular remodeling and aortic stenosis have similar QoL changes after intervention compared to patients without significant remodeling. Findings from this study support aortic valve intervention irrespective of ventricular remodeling.

What is Known; What the Study Adds

What is Known?

Ventricular remodeling occurs due to aortic stenosis, limiting cardiac output even after valve replacement.

The effect of ventricular remodeling on quality of life after TAVR is unknown.

What the Study Adds

Quality of life improvement occurred in the majority of patients undergoing TAVR, with and without severe ventricular remodeling, and to a similar degree regardless of remodeling.

From a quality-of-life perspective, TAVR should remain a viable consideration for patients with severe ventricular remodeling
APOL1Risk Variants Associate with the Prevalence of Stroke in African American Current and Past Smokers
Authors: Mustra Rakic Jelena , Pullinger Clive R. , Van Blarigan Erin L. , Movsesyan Irina , Oestreicher Stock Eveline , Malloy Mary J. , Kane John P.
Published: April 2023

Introduction

Among African Americans, tobacco smokers have 2.5 times higher risk for stroke compared to non-smokers; the tobacco-related stroke risk being higher than in other races/ethnicities. About one half of African Americans carry at least one of two genetic variants (G1 and G2; rare in other races) of apolipoprotein L1 (apoL1), a component of high-density lipoproteins. Several studies showedAPOL1G1/G2 risk variants associate with stroke. However, the role ofAPOL1variants in tobacco-related stroke is unknown.

Methods

In a cross-sectional study, we examined whetherAPOL1risk variants modify the relationship between smoking and stroke in 513 African American adults (median age 58 years, 52% female) recruited through the University of California, San Francisco Lipid Clinic. Using DNA, plasma, and questionnaires we determinedAPOL1variants, smoking status, and history of stroke. Using unstratified and stratified multivariable logistic regression models we examined the association between smoking history (eversmokers vs.neversmokers) and odds of stroke overall, and among carriers of risk variants and non-carriers, separately.

Results

Among participants, 41% wereever(currentandpast) smokers, 54% were carriers of theAPOL1risk variant, and 41 have had stroke. In all stroke cases, where full medical records were available, stroke types were determined to be an ischemic, and not hemorrhagic, stroke. The association of smoking history and stroke differed byAPOL1genotype status in the unstratified model (Pinteraction term=0.016). Among carriers of risk variants,eversmokers had odds ratio (OR) =2.88 for stroke compared toneversmokers (P=0. 0.038). The OR for stroke comparingevervs.neversmokers showed a dose-response trend among carriers of one risk allele of 2.35 and two risk alleles of 4.96. Among non-carriers, smoking history was not associated with a stroke.

Conclusion

In conclusion, current and past smokers who carryAPOL1G1 and/or G2 risk variants may be more susceptible to stroke, in particular ischemic stroke, among African Americans.
Expression pattern of nicotinic acetylcholine receptor subunit transcripts in neurons and astrocytes in the ventral tegmental area and locus coeruleus
Authors: Gao Runbo , Schneider Amelia M. , Mulloy Sarah M. , Lee Anna M.
Published: April 2023

Acetylcholine is the endogenous agonist for the neuronal nicotinic acetylcholine receptor (nAChR) system, which is involved in attention, memory, affective behaviors, and substance use disorders. Brain nAChRs are highly diverse with 11 different subunits that can form multiple receptor subtypes, each with distinct receptor and pharmacological properties. Different neuronal cell types can also express different nAChR subtypes, resulting in highly complex cholinergic signaling. Identifying which nAChR subunit transcripts are expressed in cell types can provide an indication of which nAChR combinations are possible and which receptor subtypes may be most pharmacologically relevant to target. In addition to differences in expression across cell types, nAChRs also undergo changes in expression levels from adolescence to adulthood. In this study, we used fluorescentin situhybridization to identify and quantify the expression of α4, α5, α6, β2 and β3 nAChR subunit transcripts in dopaminergic, GABAergic, glutamatergic, and noradrenergic neurons and astrocytes in the ventral tegmental area (VTA) and locus coeruleus (LC) in adult and adolescent, male and female C57BL/6J mice. There were distinct differences in the pattern of nAChR subunit transcript expression between the two brain regions. LC noradrenergic neurons had high prevalence of α6, β2 and β3 expression, with very low expression of α4, suggesting the α6(non-α4)β2β3 receptor as a main subtype in these neurons. VTA astrocytes from adult mice showed greater prevalence of α5, α6, β2 and β3 transcript compared with adolescent mice. These data highlight the complex nAChR expression patterns across brain region and cell type.
Assessing the need for temporary fishing closures to support sustainability for a small-scale octopus fishery
Authors: Wulfing Sophie , Kadba Ahilya Sudarshan , Baker-Médard Mez , White Easton R.
Published: April 2023

1

The blue octopus (Octopus cyanea) fishery off the southwest coast of Madagascar is important for coastal communities. This fishery is a key economic resource for the local community as blue octopus catch is sold by local fishers to international and local export markets. Thus, it is important to monitor and evaluate the status of octopus to ensure its sustainability. One common octopus management approach is through the use of temporary spatial closures. Models can be a useful support tool to evaluate the status of a population and assess different possible management strategies. To better understand the biology and assess the sustainability of blue octopus, we parameterize a Levkovitch population matrix model using existing catch data. We found that the octopus population was experiencing a 1.8% decline per month at the time of data collection in 2006. However, since 2006, a number of management practices, including temporary closures lasting several weeks to several months have been implemented successfully. In line with these efforts, our model indicates that the fishery has likely been sustained since 2006 due to these annual closures. Our model provides support to the idea that temporary closures have restored this population and that temporary closures provide flexibility in management strategies that local communities can tailor to their economic and social needs. In addition, we were able to estimate several important life history metrics, such as time in each stage, stable stage distribution, reproductive value, and per stage survivability, that can be used in future work. Collectively, our study provides insight into the biology of blue octopus as well as demonstrate how temporary closures can be an effective conservation strategy due to the wide range of implementation options.
CTNSmRNA as a potential treatment for nephropathic cystinosis
Authors: Bondue Tjessa , Berlingerio Sante P. , Siegerist Florian , Sendino-Garví Elena , Schindler Maximilian , Cairoli Sara , Goffredo Bianca M. , Arcolino Fanny O. , Dieker Jürgen , Janssen Manoe , Endlich Nicole , Brock Roland , Gijsbers Rik , Heuvel Lambertus van den , Levtchenko Elena
Published: April 2023

Messenger RNA (mRNA) therapies are emerging in different disease areas, but have not yet reached the kidney field. Our aim was to study the feasibility to correct the genetic defect in nephropathic cystinosis using synthetic mRNA. Cystinosis is a prototype disorder of proximal tubular dysfunction caused by mutations in theCTNSgene, encoding the lysosomal cystine-H+symporter cystinosin, and leading to cystine accumulation in all cells of the body. The kidneys are the first and most severely affected organs, presenting glomerular and proximal tubular dysfunction. Cysteamine is the current therapeutic standard that reduces cellular cystine levels, but has many side effects and does not restore kidney function. Here, we show that synthetic mRNA is safe and effective to reintroduce functional cystinosin using lipofection inCTNS-/-kidney cells and following direct injection inctns-/-zebrafish larvae.CTNSmRNA therapy results in prompt lysosomal expression of the functional protein and decreases cellular cystine accumulation for up to 14 days. In thectns-/-zebrafish,CTNSmRNA therapy improves proximal tubular reabsorption, reduces proteinuria, and restores brush border expression of the multi-ligand receptor megalin. We propose that mRNA-based therapy, if sufficient kidney targeting can be achieved, may be a new approach to treat cystinosis.

Translational statement

Cystinosis is a systemic lysosomal storage disease caused by mutations in theCTNS(cystinosin) gene. It initially affects the kidneys and leads to kidney failure, if left untreated. The current standard therapy, cysteamine, is not curative and has many side-effects. Here we demonstrate the potential of mRNA-based therapy to swiftly restore cystinosin function and ameliorate the kidney phenotype. Future research will focus on mRNA delivery methods and targeting kidney cells in cystinosis rodent models.