bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct populations suppress or escalate intake of cocaine paired with aversive quinine
Authors: Powers Rosalie E. , Fogel Peter A. , Reeves Jayson H. , Madrid Pamela , Moschak Travis M.
Published: July 2024

Background

Only a subset of individuals who encounter drugs of abuse become habitual users. Aversive subjective effects like coughing and unpleasant taste are predictors for continued use. While several preclinical studies have explored self-administration involving aversive cues, none have simultaneously introduced aversion with the initial drug self-administration. We aimed to develop a clinically relevant model by pairing intravenous cocaine with intraoral quinine self-administration from the outset and investigating whether repeated exposure to an aversive stimulus would alter its hedonic value under laboratory conditions.

Methods

Twenty-seven male and female Sprague Dawley rats self-administered intravenous/intraoral (cocaine/quinine) for 2 hr/day over 14 days. This was followed by a 1-day quinine-only extinction session, a 3-day return to self-administration, and an intraoral infusion session to assess quinine taste reactivity (TR).

Results

We identified three distinct groups. The first self-administered very little cocaine, while the second sharply escalated cocaine intake. Both groups had similar aversive TR to quinine, suggesting that the escalating group did not habituate to the aversive cue but pursued drug despite it. We also identified a third group with high initial intake that decreased over time. This decrease predicted high aversive TR, and we argue this group may represent individuals who “overindulge” on their first use and subsequently find self-administration to be aversive.

Conclusions

Our novel model mimics real-world variability in initial interactions with drugs of abuse and yields three distinct groups that differ in self-administration patterns and aversive cue valuation.
Vasopressin-to-Oxytocin Receptor Crosstalk in the Preoptic Area Underlying Parental Behaviors in Male Mice
Authors: Inada Kengo , Hagihara Mitsue , Yaguchi Kasane , Irie Satsuki , Inoue Yukiko U. , Inoue Takayoshi , Miyamichi Kazunari
Published: July 2024

The transition to parenthood brings significant changes in behavior toward offspring. For instance, in anticipation of their offspring, male mice shift from infanticidal to caregiving behaviors. While the release of oxytocin from the paraventricular hypothalamus (PVH) plays a critical role in paternal caregiving, it does not fully account for the entire behavioral shift. The specific downstream neurons and signaling mechanisms involved in this process remain obscure. Here, we demonstrate that PVH vasopressin neurons also essentially contribute to a paternal behavioral shift. This vasopressin signal is partially transmitted through oxytocin receptors (OTRs) expressed in the anterior commissure and medial nuclei of the preoptic area. These OTR-expressing neurons receive inputs from both PVH oxytocin and vasopressin neurons and are responsible for expressing paternal caregiving behaviors. Collectively, this non-canonical vasopressin-to-OTR crosstalk within specific limbic circuits acts as a pivotal regulator of paternal behavioral changes in mice.

Highlights

PVH vasopressin neurons are required for and can trigger paternal caregiving behaviors.

Vasopressin-induced paternal behaviors are mediated in part by OTRs in the preoptic area (POA).

POA OTR neurons receive inputs from both PVH oxytocin and vasopressin neurons.

POA OTR neurons play a critical and facilitative role in promoting paternal caregiving behaviors.
Structural basis of the human transcriptional Mediator complex modulated by its dissociable Kinase module
Authors: Chen Shin-Fu , Chao Ti-Chun , Kim Hee Jong , Tang Hui-Chi , Khadka Subash , Li Tao , Lee Dung-Fang , Murakami Kenji , Boyer Thomas G. , Tsai Kuang-Lei
Published: July 2024

The eukaryotic Mediator, comprising a large Core (cMED) and a dissociable CDK8 kinase module (CKM), regulates RNA Polymerase II (Pol II)-dependent transcription. cMED recruits Pol II and promotes pre-initiation complex (PIC) formation in a manner inhibited by the CKM, which is also implicated in post-initiation control of gene expression. Herein we report cryo-electron microscopy structures of the human complete Mediator and its CKM, which explains the basis for CKM inhibition of cMED-activated transcription. The CKM binds to cMED through an intrinsically disordered region (IDR) in MED13 and HEAT repeats in MED12. The CKM inhibits transcription by allocating its MED13 IDR to occlude binding of Pol II and MED26 to cMED and further obstructing cMED-PIC assembly through steric hindrance with TFIIH and the +1 nucleosome. Notably, MED12 binds to the cMED Hook, positioning CDK8 downstream of the transcription start site, which sheds new light on its stimulatory function in post-initiation events.
Preclinical evaluation of pharmacological inhibition of SIRT1 on the growth of tumoral and metastatic granulosa cells
Authors: Cluzet Victoria , Airaud Eloïse , Devillers Marie M , Petit Florence , Leary Alexandra , Pierre Alice , Li Haojian , Day Chi-Ping , Weyemi Urbain , Chauvin Stéphanie , Guigon Céline J
Published: July 2024

Background

Clinical management of patients with recurrent ovarian granulosa cell tumor (GCT) remains poor. Sirtuin-1 (SIRT1), a deacetylase enzyme involved in the regulation of tumor growth and metastasis, may represent a therapeutic target due to the availability of selective pharmacological inhibitors with minimal toxicity.

Methods

We assessed the possible overexpression of SIRT1 during tumorigenesis by Western blot and immunohistochemistry. We tested the effects of SIRT1 inhibition by EX-527 on growth, proliferation, death, migration and gene expression by RNA sequencing and RT-qPCRin vitroon three GCT cell lines (AT29, KGN, COV434). Tumor growth in response to EX-527 treatment was examined in nude mice carrying subcutaneous GCT cell grafts using an electronic caliper and in GCT of AT83 mice by 3D ultrasound imaging system.

Results

SIRT1 abundance increased during tumorigenesis.In vitrotreatment with EX-527 efficiently reduced cell growth, either by inducing apoptosis or by inhibiting proliferation. EX-527 induced alterations in pathways driven by mTOR, Myc and E2F, and in pathways controlling cell metabolism and oxidative stress. The administration of this treatment for 4 weeks efficiently reduced tumor progressionin vivo.

Conclusions

Our study reveals a new therapeutic potential of SIRT1 targeting as a treatment option for patients with recurrent GCT.
Deep learning identifies heterogeneous subpopulations in breast cancer cell lines
Authors: Jost Tyler A. , Gardner Andrea L. , Morgan Daylin , Brock Amy
Published: July 2024

Motivation

Cells exhibit a wide array of morphological features, enabling computer vision methods to identify and track relevant parameters. Morphological analysis has long been implemented to identify specific cell types and cell responses. Here we asked whether morphological features might also be used to classify transcriptomic subpopulations withinin vitrocancer cell lines. Identifying cell subpopulations furthers our understanding of morphology as a reflection of underlying cell phenotype and could enable a better understanding of how subsets of cells compete and cooperate in disease progression and treatment.

Results

We demonstrate that cell morphology can reflect underlying transcriptomic differencesin vitrousing convolutional neural networks. First, we find that changes induced by chemotherapy treatment are highly identifiable in a breast cancer cell line. We then show that the intra cell line subpopulations that comprise breast cancer cell lines under standard growth conditions are also identifiable using cell morphology. We find that cell morphology is influenced by neighborhood effects beyond the cell boundary, and that including image information surrounding the cell can improve model discrimination ability.
Wetland tree barks are dynamic hotspots for microbial trace gas cycling
Authors: Leung Pok Man , Jeffrey Luke C , Bay Sean K , Gomez-Alvarez Paula , Hall Montgomery , Johnston Scott G , Dittmann Johannes , Jirapanjawat Thanavit , Hutchinson Tess F , Coleman Nicholas V , Dong Xiyang , Deschaseaux Elizabeth , Maher Damien T , Greening Chris
Published: July 2024

Wetland tree stems have recently been shown to be a major source of methane emissions. However, the microbial communities associated within these stems (the caulosphere) and their contribution to biogeochemical cycling of methane and other compounds remain poorly understood. Here, we reveal that specialised microbial communities inhabit the bark of multiple Australian tree species and actively mediate the cycling of methane, hydrogen, and other climate-active trace gases. Based on genome-resolved metagenomics, most bark-associated bacteria are hydrogen metabolisers and facultative fermenters, adapted to dynamic redox and substrate conditions. Over three quarters of assembled genomes encoded genes for hydrogen metabolism, including novel lineages of Acidobacteriota, Verrucomicrobiota, and the candidate phylum JAJYCY01. Methanotrophs such as Methylomonas were abundant in certain trees and coexisted with hydrogenotrophic methanogenic Methanobacterium. Bark-associated microorganisms mediated aerobic oxidation of hydrogen, carbon monoxide, and methane at concentrations seen in planta, but under anoxic conditions barks could become a significant source of these gases. Field-based experiments and upscaling analysis suggested that bark communities are quantitatively significant mediators of global biogeochemical cycling, mitigating climatically-active gas emissions from stems and contributing to the net terrestrial sink of atmospheric hydrogen. These findings highlight the caulosphere as an important new research frontier for understanding microbial gas cycling and biogeochemistry.
Structural insights into the recognition of RALF peptides by FERONIA receptor kinase during Brassicaceae Pollination
Authors: Bhalla Hemal , Sudarsanam Karthik , Srivastava Ashutosh , Sankaranarayanan Subramanian
Published: July 2024

Ensuring species integrity and successful reproduction is pivotal for the survival of angiosperms. Members of Brassicaceae family employ a lock and key mechanism involving stigmatic (sRALFs) and pollen RALFs (pRALFs) binding to FERONIA, a Catharanthus roseus receptor-like kinase 1-like (CrRLK1L) receptor, to establish a prezygotic hybridization barrier. In the absence of compatible pRALFs, sRALFs bind to FERONIA, inducing a lock state for pollen tube penetration. Conversely, compatible pRALFs act as a key, facilitating successful fertilization. Competing pRALFs reduce the sRALFs binding to FERONIA in a dose-dependent manner, enabling pollen tube penetration. Despite its crucial role in Brassicaceae hybridization, the structural basis of this binding remains elusive owing to the highly flexible nature of RALF peptides. Using advanced structural modeling techniques and flexible peptide molecular docking, this study reveals that pRALFs and sRALFs bind to negatively charged pockets in FERONIA with varying binding affinities. Our study unveils the structural basis of this binding, shedding light on the molecular mechanism underlying hybridization barriers in Brassicaceae.
Tumor- and immune-derivedN-acetyl-β-D-hexosaminidase drive colorectal cancer and stratify patient risk
Authors: Kawahara Rebeca , Kautto Liisa , Bansal Naaz , Dipta Priya , Chau The Huong , Liquet-Weiland Benoit , Ahn Seong Beom , Thaysen-Andersen Morten
Published: July 2024

Non-invasive prognostic markers are needed to improve survival of colorectal cancer (CRC) patients. Towards this goal, we applied integrative systems glycobiology approaches to tumor tissues and PBMCs from CRC patients and matching controls as well as to a CRC patient-derived cell line. Firstly, quantitative glycomics and glycoproteomics revealed that non-canonical paucimannosidic proteins from monocytic and cancer cell origins are prominent signatures in CRC tumor tissues, and that their expression associates with CRC progression. Guided by these associations, we then showed thatN-acetyl-β-D-hexosaminidase (Hex) facilitates paucimannosidic protein biosynthesis in CRC cells and is intimately involved in processes underpinning CRC metastasis (adhesion, migration, invasion, proliferation). Finally, Hex activity was found to be elevated in PBMCs and plasma from patients with advanced CRC relative to matching controls while plasma Hex activity correlated strongly with CRC patient survival. Our study opens avenues for better prognostication, disease risk stratification and therapeutic interventions in CRC.

Highlights

•

Non-canonical truncated glycans of immune and cancer origins dominate in CRC tumors

•

N-acetyl-β-D-hexosaminidase, a truncating glycoenzyme, drives tumorigenesis in CRC

•

Activity of plasmaN-acetyl-β-D-hexosaminidase stratifies risk in CRC patients
Effect of zinc supplementation on certain serum biochemical parameters in growing pigs
Authors: Borah S. , Soren S , Deka SS , Kalita L , Pame K , Borah B
Published: July 2024

Twenty-four healthy and uniform crossbred (Hampshire × Assam Local) pigs, 4 months of age, were selected to study the effect of 500 ppm Zn supplementation on certain serum biochemical parameters for a period of four months. The animals were divided into three groups (n=8/group): group C (basal diet), group T1(basal diet + 100 ppm Zn + calcium carbonate @ 1.5% DM) and group T2(basal diet + 500 ppm Zn). Serum samples were collected at 15-day intervals and analysed for serum Zn, copper, total serum protein, albumin, globulin, and glucose cholesterol. The serum Zn concentration in the T1group decreased significantly (P<0.01) from day 30 until day 120 of treatment, whereas in the T2group, the level increased significantly (P<0.01) from day 15 onwards. The serum copper concentration did not change groups. The total protein concentration in the serum showed a significant (P<0.01) increasing trend in the T2group from day 45 of treatment, and a significant (P<0.01) decreasing trend was observed in the T1group compared to the C group. The serum globulin concentration decreased significantly (P< 0.05) in the T1group compared with the C and T2groups during the treatment period. An increasing trend in glucose and cholesterol levels was recorded at T2during the treatment period. However, decrease, (P<0.01) in glucose and cholesterol levels was recorded in the T1group from day 30 to day 120 of treatment. The haemoglobin concentration showed a significant (p<0.01) decreasing trend in the T1group from day 45 onwards.
Lack of Synergistic Outcomes with Roflumilast Combined with Levetiracetam or Adipose Stem Cell Secretome After Spinal Cord Injury
Authors: Sousa Carla , Lima Rui , Gomes Eduardo D. , Silva Deolinda , Cibrão Jorge , Pinho Tiffany , Jorge Diogo , Afonso João , Martins-Macedo Joana , Monteiro Andreia , Salgado António J. , Silva Nuno A.
Published: July 2024

The Spinal Cord Injury (SCI) pathophysiology is highly complex, contributing to a poor prognosis and lack of effective treatments. Previously, we demonstrated that Roflumilast (Rof), leads to functional recovery when tested in a SCI contusion model. However, it is unlikely that Rof treatment on its own could fully restore the spinal cord. Therefore, our objective was to scrutinize the synergistic effects of combining Rof with neuroprotective approaches. Herein we tested two therapies, firstly, Rof combined with Levetiracetam (Lev), and in a second phase, the complementary interplay between Rof and Adipose Stem Cells secretome (Sec). We induced SCI using a weight drop trauma model at the T8 level. Functional recovery was assessed according to the Basso, Beattie, and Bresnahan scale, Activity Box Test, Motor Swimming Test, and Von Frei test. Results indicate that the unilateral use of Rof, Lev, or Sec was effective in promoting functional recovery. However, the combination of Rof + Lev or Rof + Sec did not lead to an improvement in functional outcomes when compared to standalone treatments. Moreover, the combination of Rof + Sec actually led to worst functional outcome than the single treatments. Further studies are needed to find a combinatorial treatment that can lead to superior therapeutic effects with potential clinical application.
Physical constraints and biological regulations underlie universal osmoresponses
Authors: Ye Yiyang , Wang Qirun , Lin Jie
Published: July 2024

Microorganisms constantly transition between environments with dramatically different external osmolarities. However, theories of microbial osmoresponse integrating physical constraints and biological regulations are lacking. Here, we propose such a theory, utilizing the separation of timescales for passive responses and active regulations. We demonstrate that regulations of osmolyte production and cell-wall synthesis assist cells in coping with intracellular crowding effects and adapting to a broad range of external osmolarity. Furthermore, we predict a threshold value above which cells cannot grow, ubiquitous across bacteria and yeast. Intriguingly, the theory predicts a dramatic speedup of cell growth after an abrupt decrease in external osmolarity due to cell-wall synthesis regulation. Our theory rationalizes the unusually fast growth observed in fission yeast after an oscillatory osmotic perturbation, and the predicted growth rate peaks match quantitatively with experimental measurements. Our study reveals the physical basis of osmoresponse, yielding farreaching implications for microbial physiology.
Ecology not genetics explains correlated trait divergence during speciation
Authors: de Carvalho Clarissa F. , Planidin Nicholas P. , Villoutreix Romain , Soria-Carrasco Víctor , Riesch Rüdiger , Feder Jeffrey L. , Parchman Thomas L. , Slate Jon , Gompert Zachariah , Nosil Patrik
Published: July 2024

The formation of new species often involves the correlated divergence of multiple traits and genetic regions. However, the mechanisms by which such trait covariation builds up remain poorly understood. In this context, we consider two non-exclusive hypotheses. First, genetic covariance between traits can cause divergent selection on one trait to promote population divergence in correlated traits (a genetic covariation hypothesis). Second, correlated environmental pressures can generate selection on multiple traits, facilitating the evolution of trait complexes (an environmental covariation hypothesis). Here, we test these hypotheses using cryptic coloration (controlled by an incipient supergene) and chemical traits (i.e.,cuticular hydrocarbons, CHCs) involved in desiccation resistance and mate choice inTimema cristinaestick insects. We first demonstrate that population divergence in color-pattern is correlated with divergence in some (but not all) CHC traits. We show that when correlated population divergence does occur, it is unlikely to be explained by genetic covariation because within-population genetic covariance between color-pattern and CHCs traits is weak. In contrast, we find that correlated variation in climate and host plant likely generates selection jointly on color-pattern and some CHC traits. This supports the environmental covariation hypothesis, likely via the effects of two correlated environmental axes selecting on different traits. Finally, we provide evidence that misalignment between natural and sexual selection also contributes to patterns of correlated trait divergence. Our results shed light into transitions between phases of speciation by showing that environmental factors can promote population divergence in trait complexes, even without strong genetic covariance.
A genome engineered tool set forDrosophilaTGF-β/BMP signaling studies
Authors: Ell Clara-Maria , Safyan Abu , Chayengia Mrinal , Kustermann Manuela M. M. , Lorenz Jennifer , Schächtle Melanie , Pyrowolakis George
Published: July 2024

Ligands of the TGF-β/BMP superfamily are critically involved in the regulation of growth, patterning and organogenesis and can act as long-range morphogens. Essential for understanding TGF-β/BMP signaling dynamics and regulation are tools that allow monitoring and manipulating pathway components expressed at physiological levels and endogenous spatiotemporal patterns. We used genome engineering to generate a comprehensive library of endogenously epitope-or fluorescently-tagged versions of receptors, co-receptors, transcription factors and key feedback regulators of theDrosophilaBMP and Activin signaling pathways. We demonstrate that the generated alleles are biologically active and can be utilized for assessing tissue and subcellular distribution of the corresponding proteins. Further, we show that the genomic platforms can be used forin locusstructure-function andcis-regulatory analyses. Finally, we present a complementary set of protein binder-based tools, which allow visualization as well as manipulation of the stability and subcellular localization of epitope-tagged proteins, providing new tools for the analysis of BMP signaling and beyond.
Evidence of a Slower-Z effect inSchistosoma japonicum
Authors: Mrnjavac Andrea , Vicoso Beatriz
Published: July 2024

Sex-linked and autosomal loci experience different selective pressures and evolutionary dynamics. X (or Z) chromosomes are often hemizygous, as Y (or W) chromosomes often degenerate. Such hemizygous regions can be under greater efficacy of selection, as recessive mutations are immediately exposed to selection in the heterogametic sex (the so-called Faster-X or Faster-Z effect). However, in young non-recombining regions, Y/W chromosomes often have many functional genes, and many X/Z-linked loci are therefore diploid. The sheltering of recessive mutations on the X/Z by the Y/W homolog is expected to drive a Slower-X (Slower-Z) effect for diploid X/Z loci, i.e. a reduction in the efficacy of selection. While the Faster-X effect has been studied extensively, much less is known empirically about the evolutionary dynamics of diploid X or Z chromosomes. Here, we took advantage of published population genomic data in the female-heterogametic human parasiteSchistosoma japonicumto characterize the gene content and diversity levels of the diploid and hemizygous regions of the Z chromosome. We used different metrics of selective pressures acting on genes to test for differences in the efficacy of selection in hemizygous and diploid Z regions, relative to autosomes. We found consistent patterns suggesting reduced Ne, and reduced efficacy of purifying selection, on both hemizygous and diploid Z regions. Moreover, relaxed selection was particularly pronounced for female-biased genes on the diploid Z, as predicted by Slower-Z theory.
A ready-to use workflow for automated, sound-based bird identification and localization
Authors: Buchmann Carsten M. , Schurr Frank M.
Published: July 2024

Field studies of bird communities typically require the fine-scale mapping of individuals. Passive acoustic monitoring combined with localization of individuals is a promising approach to gather such data. While various approaches for identification of species and localization of individuals have been proposed, no fully automated ready-to-use workflow is available so far. We here present a novel approach based on sound recordings with multiple cost-efficient automated recording units (Audiomoths). The workflow uses a well-established AI model (BirdNET; other models possible) for species identification and localizes the sources of all identified bird sounds with high accuracy. Tests with replayed sounds of different bird species in an agricultural landscape show that - after filtering out identifications with low identification confidence - the algorithm localizes more than 90% of the sounds within 5 m of the true location (85 % < 2 m). Recording and localization of wild birds demonstrate the applicability of the approach for avian ecology. This workflow is completely automated and ready-to-use, also for non-experts and can also be used when strong winds affect the speed of sound or if 3D localizations are of interest. By making data on individual bird locations accessible the presented work will help to advance fundamental and applied ecology as well as conservation.
Substrate Rigidity Modulates Segmentation Clock Dynamics in Isolated Presomitic Mesoderm Cells
Authors: Sung Chun-Yen , Kadiyala Usha , Blanchard Owen , Yourston Liam , Walker Derek , Li Linyuan , Fu Jianping , Yang Qiong
Published: July 2024

The segmentation clock, a genetic oscillator in the presomitic mesoderm (PSM), is known to be influenced by biochemical signals, yet its potential regulation by mechanical cues remains unclear. The complex PSM microenvironment has made it challenging to isolate the effects of mechanical perturbations on clock behavior. Here we investigated how mechanical stimuli affect clock oscillations by culturing zebrafish PSM cells on PDMS micropost arrays with tunable rigidities (0.6-1200 kPa). We observed an inverse sigmoidal relationship between surface rigidity and both the percentage of oscillating cells and the number of oscillation cycles, with a switching threshold between 3-6 kPa. The periods of oscillating cells showed a consistently broad distribution across rigidity changes. Moreover, these cells exhibited distinct biophysical properties, such as reduced motility, contractility, and sustained circularity. These findings highlight the crucial role of cell-substrate interactions in regulating segmentation clock behavior, providing insights into the mechanobiology of somitogenesis.

Highlights

The oscillatory behaviors of single PSM cells respond to substrate rigidity in a switch-like manner, with a critical threshold between 2.9 kPa and 6 kPa.

As rigidity increases, both the oscillation percentage and the number of cycles decrease, while the period does not show a clear dependency on rigidity.

Oscillating cells exhibit distinct biophysical properties compared to non-oscillating cells, including higher and more sustained circularity, lower motility, and reduced contractility.

Cell aggregates exhibit similar trends in response to rigidity, except for significantly increased oscillation percentages across different rigidity conditions, suggesting a potential interplay between cell-cell communications and rigidity in influencing cell aggregate behavior.
Chaotropic Agent-assisted Supported Lipid Bilayer Formation
Authors: Cawley Jennie L. , Santa Dane E. , Singh Aarshi N. , Odudimu Adeyemi T. , Berger Brett A. , Wittenberg Nathan J.
Published: July 2024

Supported lipid bilayers (SLBs) are useful structures for mimicking cellular membranes, and they can be integrated with a variety of sensors. While there are a variety of methods for forming SLBs, many of these methods come with limitations in terms of the lipid compositions that can be employed and the substrates upon which the SLBs can be deposited. Here we demonstrate the use of an all-aqueous chaotropic agent exchange process that can be used to form SLBs on two different substrate materials: SiO2, which is compatible with traditional SLB formation by vesicle fusion and Al2O3, which is not compatible with vesicle fusion. When examined with quartz crystal microbalance with dissipation monitoring, the SLBs generated by chaotropic agent exchange (CASLBs) have similar frequency and dissipation shifts to SLBs formed by the vesicle fusion technique. The CASLBs block nonspecific protein adsorption on the substrate and can be used to sense protein-lipid interactions. Fluorescence microscopy was used to examine the CASLBs, and we observed long-range lateral diffusion of fluorescent probes, which confirmed the CASLBs were composed of a continuous, planar lipid bilayer. Our CASLB method provides another option for forming planar lipid bilayers on a variety of surfaces, including those that are not amenable to the widely used vesicle fusion method.
IGF-1 Acts through Kiss1-expressing Cells to Influence Metabolism and Reproduction
Authors: Wang Mengjie , Pugh Seamus M. , Daboul Judy , Miller David , Xu Yong , Hill Jennifer W.
Published: July 2024

Objective

Kisspeptin, encoded by theKiss1gene, ties puberty and fertility to energy status; however, the metabolic factors that controlKiss1-expressing cells need to be clarified.

Methods

To evaluate the impact of IGF-1 on the metabolic and reproductive functions of kisspeptin producing cells, we created mice with IGF-1 receptor deletion driven by theKiss1promoter (IGF1RKiss1mice). Previous studies have shown IGF-1 and insulin can bind to each other’s receptor, permitting IGF-1 signaling in the absence of IGF1R. Therefore, we also generated mice with simultaneous deletion of the IGF1R and insulin receptor (IR) inKiss1-expressing cells (IGF1R/IRKiss1mice).

Results

Loss of IGF1R inKiss1cells caused stunted body length. In addition, female IGF1RKiss1mice displayed lower body weight and food intake plus higher energy expenditure and physical activity. This phenotype was linked to higher proopiomelanocortin (POMC) expression and heightened brown adipose tissue (BAT) thermogenesis. Male IGF1RKiss1mice had mild changes in metabolic functions. Moreover, IGF1RKiss1mice of both sexes experienced delayed puberty. Notably, male IGF1RKiss1mice had impaired adulthood fertility accompanied by lower gonadotropin and testosterone levels. Thus, IGF1R inKiss1-expressing cells impacts metabolism and reproduction in a sex-specific manner. IGF1R/IRKiss1mice had higher fat mass and glucose intolerance, suggesting IGF1R and IR inKiss1-expressing cells together regulate body composition and glucose homeostasis.

Conclusions

Overall, our study shows that IGF1R and IR inKiss1have cooperative roles in body length, metabolism, and reproduction.
Reciprocal interactions between CA1 pyramidal and axo-axonic cells control sharp wave-ripple events
Authors: Gilbert Earl T. , Klaver Lianne M.F. , Arndt Kaiser C. , Kim Jongwoon , Jia Xiaoting , McKenzie Sam , English Daniel Fine
Published: July 2024

Diverse sources of inhibition serve to modulate circuits and control cell assembly spiking across various timescales. For example, in hippocampus area CA1 the competition between inhibition and excitation organizes spike timing of pyramidal cells (PYR) in network events, including sharp wave-ripples (SPW-R). Specific cellular-synaptic sources of inhibition in SPW-R remain unclear, as there are >20 types of GABAergic interneurons in CA1. Axo-axonic cells (AAC) are defined by their synaptic targeting of the axon initial segment of pyramidal cells, potently controlling spike output. The impact of AAC activity on SPW-R is controversial, due mainly to ambiguity of AAC identification. Here we monitored and manipulated opto-tagged AACs in behaving mice using silicon probe recordings. We found a large variability of AAC neurons, varying from enhanced to suppressed spiking during SPW-Rs, in contrast to the near-uniform excitation of other parvalbumin-expressing interneurons. AACs received convergent monosynaptic inputs from local pyramidal cell assemblies, which strongly influenced their participation in SPW-Rs. Optogenetic silencing of AACs increased power and duration of SPW-Rs, recruiting a greater number of PYR, suggesting AACs control SPW-R dynamics. We hypothesize that lateral inhibition by reciprocal PYR-AAC interactions thus supports the organization of cell assemblies in SPW-R.
Metagenomic peek into a corn mummy
Authors: Solymosi Norbert , Pap Bernadett , Nagy Sára Ágnes , Tóth Adrienn Gréta , Kevély Flóra Judit , Maróti Gergely , Csabai István , Kóthay Katalin , Magyar Donát
Published: July 2024

Numerous studies have shown that metagenomics has opened up a new dimension in reading the contents of archaeological remains as time capsules. Corn mummies are ritual objects made in ancient Egypt by forming human-shaped figures made of cereal grains grown in a mixture of water and earth. We performed metagenomic analyses on samples from a corn mummy dated to the second half of the 3rd century BC. Alongside a number of clearly modern contaminants, we identified organisms that cannot be excluded as being of historical origin. Besides considerable amounts of bacterial sequences belonging to the generaBacillus, Coprococcus, Metabacillus, NialliaandRoseburia, we also found traces of plants, animals, and humans. Sequences assigned to the genusTriticumshowed the highest similarity to ancientT. turgidumssp.dicoccumspecimens from Egypt and the southern Levant. Sequences classified in the genusPopulusshowed the highest identity with the genome ofP. nigra. The fragments that were identified as being of Lepidopteran origin showed the greatest similarity to the genomes of the Sphingidae. Haplotype analysis ofH. sapienssequences suggests haplogroups L3 and E, based on the mitogenome and Y chromosome, respectively, which are the two common lineages in sub-Saharan Africa today.
EPILEPTOGENESIS INHIBITS THE CIRCADIAN CLOCK AND RESHAPES THE DIURNAL TRANSCRIPTOMIC RHYTHMICITY IN THE MOUSE HIPPOCAMPUS
Authors: Benvenutti Radharani , Bruno Danielle C. F. , Gallas-Lopes Matheus , Venø Morten T. , Bruxel Estela Maria , Strickland Tammy , Ramsook Arielle , Wadgaonkar Aditi , Jiang Yiyue , Sanz-Rodriguez Amaya , Sinkkonen Lasse , Alvim Marina K.M. , Yasuda Clarissa L. , Rogerio Fabio , Cendes Fernando , Henshall David C. , Curtis Annie M. , Kobow Katja , Lopes-Cendes Iscia , Reschke Cristina R.
Published: July 2024

Epileptogenesis is the process that leads the brain into epileptic activity. Clinical evidence shows that ∼90% of people with epilepsy present rhythmicity in the timing of their seizures presentation. However, whether the circadian clock is a key player during epileptogenesis remains unknown. Here, we triggered epileptogenesis in mice by the intra-amygdala injection of kainic acid and profiled by RNA sequencing their hippocampal diurnal mRNA rhythmicity. We show that epileptogenesis largely reshapes the hippocampal transcriptomic rhythmicity and that the molecular clock machinery is inhibited due to the disruption of the core clock geneBmal1. We identified relevant dysregulated pathways and their dynamics in epileptogenesis, predicting a key role for microglial-driven neuroinflammation. We predicted the genes thatBmal1is directly controlling over time. Finally, we sought for translational relevance evidence by performing RNA sequencing in hippocampal samples resected from patients with mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS) and cross-analyzing datasets.
Epigenetic changes regulating the epithelial-mesenchymal transition in human trophoblast differentiation
Authors: Ackerman William E. , Rigo Mauricio M. , DaSilva-Arnold Sonia C. , Do Catherine , Tariq Mariam , Salas Martha , Castano Angelica , Zamudio Stacy , Tycko Benjamin , Illsley Nicholas P.
Published: July 2024

The phenotype of human placental extravillous trophoblast (EVT) at the end of pregnancy reflects both first trimester differentiation from villous cytotrophoblast (CTB) and later gestational changes, including loss of proliferative and invasive capacity. Invasion abnormalities are central to two major placental pathologies, preeclampsia and placenta accreta spectrum, so characterization of the corresponding normal processes is crucial. In this report, our gene expression analysis, using purified human CTB and EVT cells, highlights an epithelial- mesenchymal transition (EMT) mechanism underlying CTB-EVT differentiation and provides a trophoblast-specific EMT signature. In parallel, DNA methylation profiling shows that CTB cells, already hypomethylated relative to non-trophoblast cell lineages, show further genome- wide hypomethylation in the transition to EVT. However, a small subgroup of genes undergoes gains of methylation (GOM) in their regulatory regions or gene bodies, associated with differential mRNA expression (DE). Prominent in this GOM-DE group are genes involved in the EMT, including multiple canonical EMT markers and the EMT-linked transcription factorRUNX1, for which we demonstrate a functional role in modulating the migratory and invasive capacities of JEG3 trophoblast cells. This analysis of DE associated with locus-specific GOM, together with functional studies of an important GOM-DE gene, highlights epigenetically regulated genes and pathways acting in human EVT differentiation and invasion, with implications for obstetric disorders in which these processes are dysregulated.
Alcohol induces p53-mediated apoptosis in neural crest by stimulating an AMPK-mediated suppression of TORC1, S6K, and ribosomal biogenesis
Authors: Huang Yanping , Flentke George R. , Smith Susan M.
Published: July 2024

Prenatal alcohol exposure is a leading cause of permanent neurodevelopmental disability and can feature distinctive craniofacial deficits that partly originate from the apoptotic deletion of craniofacial progenitors, a stem cell lineage called the neural crest (NC). We recently demonstrated that alcohol causes nucleolar stress in NC through its suppression of ribosome biogenesis (RBG) and this suppression is causative in their p53/MDM2-mediated apoptosis. Here, we show that this nucleolar stress originates from alcohol’s activation of AMPK, which suppresses TORC1 and the p70/S6K-mediated stimulation of RBG. Alcohol-exposed cells of the pluripotent, primary cranial NC line O9-1 were evaluated with respect to their S6K, TORC1, and AMPK activity. The functional impact of these signals with respect to RBG, p53, and apoptosis were assessed using gain-of-function constructs and small molecule mediators. Alcohol rapidly (<2hr) increased pAMPK, pTSC2, and pRaptor, and reduced both total and pS6K in NC cells. These changes persisted for at least 12hr to 18hr following alcohol exposure. Attenuation of these signals via gain- or loss-of-function approaches that targeted AMPK, S6K, or TORC1 prevented alcohol’s suppression of rRNA synthesis and the induction of p53-stimulated apoptosis. We conclude that alcohol induces ribosome dysbiogenesis and activates their p53/MDM2-mediated apoptosis via its activation of pAMPK, which in turn activates TSC2 and Raptor to suppress the TORC1/S6K-mediated promotion of ribosome biogenesis. This represents a novel mechanism underlying alcohol’s neurotoxicity and is consistent with findings that TORC1/S6K networks are critical for cranial NC survival.
Biomolecular condensates are characterized by interphase electric potentials
Authors: Posey Ammon E. , Bremer Anne , Erkamp Nadia A. , Pant Avnika , Knowles Tuomas P.J. , Dai Yifan , Mittag Tanja , Pappu Rohit V.
Published: July 2024

Biomolecular condensates form via processes that combine phase separation and reversible associations of multivalent macromolecules. Condensates can be two- or multi-phase systems defined by coexisting dense and dilute phases. Here, we show that solution ions can partition asymmetrically across coexisting phases defined by condensates formed by intrinsically disordered proteins or homopolymeric RNA molecules. Our findings were enabled by direct measurements of the activities of cations and anions within coexisting phases of protein and RNA condensates. Asymmetries in ion partitioning between coexisting phases vary with protein sequence, condensate type, salt concentration, and ion type. The Donnan equilibrium set up by asymmetrical partitioning of solution ions generates interphase electric potentials known as Donnan and Nernst potentials. Our measurements show that the interphase potentials of condensates are of the same order of magnitude as membrane potentials of membrane-bound organelles. Interphase potentials quantify the degree to which microenvironments of coexisting phases are different from one another. Importantly, and based on condensate-specific interphase electric potentials, which are membrane-like potentials of membraneless bodies, we reason that condensates are mesoscale capacitors that store charge. Interphase potentials lead to electric double layers at condensate interfaces. This helps explain recent observations of condensate interfaces being electrochemically active.
Familiarity of an environment prevents song suppression in isolated zebra finches
Authors: Zai A.T. , Rodrigues D. I. , Stepien A.E. , Lorenz C. , Giret N. , Adam Iris , Hahnloser R.H.R.
Published: July 2024

Despite the wide use of zebra finches as an animal model to study vocal learning and production, little is known about impacts on their welfare caused by routine experimental manipulations such as changing their social context. Here we conduct a post-hoc analysis of singing rate, an indicator of positive welfare, to gain insights into stress caused by social isolation, a common experimental manipulation. We find that isolation in an unfamiliar environment reduces singing rate for several days, indicating the presence of an acute stressor. However, we find no such decrease when social isolation is caused by either removal of a social companion or by transfer to a familiar environment. Furthermore, during repeated brief periods of isolation, singing rate remains high when isolation is induced by removal of social companions, but it fails to recover from a suppressed state when isolation is induced by recurrent transfer to an unknown environment. These findings suggest that stress from social isolation is negligible compared to stress caused by environmental changes and that frequent short visits of an unfamiliar environment are detrimental rather than beneficial. Together, these insights can serve to refine experimental studies and design paradigms maximizing the birds’ wellbeing and vocal output.
The Role of Coenzyme Q10 in Cardiovascular Disease Treatment: An Updated 2024 Systematic Review and Meta-Analysis of Prospective Cohort Studies (1990-2024)
Authors: Borges Julian Yin Vieira
Published: July 2024

Background and Objectives

With the increasing need for clinicians to develop novel treatment strategies for the treatment of CVDs, the future lies in developing personalized nutrient recommendations based on an individual’s needs. CoQ10, a key component of the mitochondrial electron transport chain, has emerged as a potential ally with proven cardioprotective effects. This study investigates the efficacy of Coenzyme Q10 (CoQ10) nutrient supplementation in improving mitochondrial function, systolic performance and other parameters in patients with cardiovascular diseases (CVDs).

Methods

A systematic review and meta-analysis included data from PubMed, Embase, and the Cochrane Library up to January 2024. Inclusion criteria were randomized controlled trials (RCTs) involving adults with CVDs, comparing CoQ10 with placebo or standard care. Data extraction and quality assessment were performed using PRISMA guidelines, the Cochrane Collaboration’s RoB2 tool, AMSTAR 2, and GRADE. Primary outcome: mitochondrial function (ATP production, respiratory capacity). Secondary outcome: systolic function (ejection fraction).

Findings

From initial reference list of 46 selected studies, 22 were extracted presenting the encompassing a total sum of 11,372 subjects that were included in the meta-analysis with a total follow-up time ranging from 2 to 144 months (12 years). The results revealed that CoQ10 supplementation significantly improved ejection fraction (mean difference: 5.6%, 95% CI: 3.2% to 8.0%, p<0.001, I²=25%). The I² statistic for ejection fraction was 25%, indicating low heterogeneity among the studies included in the meta-analysis. Mitochondrial function showed increased ATP production (SMD: 0.82, 95% CI: 0.60 to 1.04, p<0.001, I²=30%) and enhanced respiratory capacity (SMD: 0.75, 95% CI: 0.53 to 0.97, p<0.001, I²=28%). The I² statistics for ATP production and mitochondrial respiratory capacity were 30% and 28%, respectively, suggesting low to moderate heterogeneity among the included studies. Sensitivity analyses confirmed the robustness of the results, with consistent effect sizes and confidence intervals across both fixed-effect and random-effects models, and no significant changes upon excluding high-risk studies. Publication bias was low, as indicated by funnel plots and Egger’s test (p=0.12).

Limitations

Larger-scale RCTs are needed to confirm findings and determine the optimal dosage and duration of CoQ10 therapy.

Conclusion

CoQ10 has demonstrated to improve mitochondrial function, systolic performance, and other important cardiovascular health parameters in CVD patients. The evidence here presented strongly supports clinicians in the prescription of CoQ10 supplementation due to its proven efficacy in improving treatment outcomes and mitochondrial function in patients with CVDs.
Incidence, symptoms and medical care for influenza virus and respiratory syncytial virus illnesses among older adults in Eastern China: Findings from the China Ageing Respiratory Infections Study (CARES), 2015-2017
Authors: Leung Nancy H. L. , Zhang Hongjun , Zhang Jun , Tang Fenyang , Luan Lin , Zheng Benfeng , Chen Guoqing , Li Changcheng , Dai Qigang , Xu Cuiling , Chen Yuyun , Chu Daniel K. W. , Song Ying , Zhang Ran , Kim Lindsay , Wendlandt Rachael , Zhu Huachen , Havers Fiona , Yu Hongjie , Shifflett Pat , Greene Carolyn M. , Cowling Benjamin J. , Thompson Mark G. , Iuliano A. Danielle
Published: July 2024

Introduction

Few studies have examined the incidence of virologic-confirmed influenza virus and respiratory syncytial virus (RSV) infections in community-dwelling older adults.

Methods

We enrolled adults aged 60–89 years in Jiangsu Province, China and followed them weekly from December 2015–September 2017 to identify acute respiratory illnesses (ARI), collect illness information and respiratory specimens for laboratory testing.

Results

1,527 adults were enrolled, 0·4% reported ever receiving influenza vaccination. 95 PCR-confirmed influenza ARIs and 22 RSV ARIs were identified, among whom 4–5% required hospitalization. One death associated with RSV ARI while none for influenza ARIs was observed. From December 2015-August 2016, the cumulative incidences of influenza and RSV ARIs were 0·8% (95% CI:0·3–1·4) and 0·5% (95% CI:0·1–1·0), respectively. From September 2016-August 2017, the cumulative incidences were 6·1% (95% CI:4·7–7·7) and 1·0% (95% CI:0·5–1·6); the influenza and RSV ARI-associated hospitalization incidences were 0·3% (95% CI:0–0·8) and 0·1% (95% CI:0–0·2). Feverishness was more common in influenza (55%) than RSV ARIs (30%, p=0·03). Influenza (12·5 days, p=0·02) and RSV ARI symptoms (14·1 days, p=0·15) lasted longer compared to PCR-negative/other ARIs (11·0 days). Antibiotic use was more common for influenza (65%, p=0·02) and RSV (70%, p=0·04) ARIs than other ARIs (51%).

Conclusions

We observed a higher incidence of influenza relative to RSV infections among community-dwelling older adults compared to prior studies. Our findings suggest older adults may benefit from receiving influenza and RSV vaccines to reduce the occurrence of illnesses.