PLOS Biology: New Articles

1. Loss of neuropeptidergic regulation of cholinergic transmission induces homeostatic compensation in muscle cells to preserve synaptic strength

   by Jiajie Shao, Jana F. Liewald, Wagner Steuer Costa, Christiane Ruse, Jens Gruber, Mohammad S. Djamshedzad, Wulf Gebhardt, Alexander Gottschalk

   Chemical synaptic transmission at the neuromuscular junction (NMJ) is regulated by electrical activity of the motor circuit, but may also be affected by neuromodulation. Here, we assessed the role of neuropeptide signaling in the plasticity of NMJ function in Caenorhabditis elegans. We show that the CAPS (Ca²⁺-dependent activator protein for secretion) ortholog UNC-31, which regulates exocytosis of dense core vesicles, affects both pre- and post-synaptic functional properties, as well as NMJ-mediated locomotion. Despite reduced evoked acetylcholine (ACh) transmission, the loss of unc-31 results in a more vigorous response to presynaptic stimulation, i.e., enhanced muscle contraction and Ca²⁺ transients. Based on expression profiles, we identified neuropeptides involved in both cholinergic (FLP-6, FLP-15, NLP-9, NLP-15, NLP-21, and NLP-38) and GABAergic motor neurons (FLP-15, NLP-15), that mediate normal transmission at the NMJ. In the absence of these peptides, neurons fail to upregulate their ACh output in response to increased cAMP signaling; for flp-15; nlp-15 double mutants, we observed overall increased postsynaptic currents, indicating that these neuropeptides may be inhibitory. We also identified proprotein convertases encoded by aex-5/kpc-3 and egl-3/kpc-2 that act synergistically to generate these neuropeptides. We propose that postsynaptic homeostatic scaling, mediated by increased muscle activation, likely through excitability, might compensate for the reduced cholinergic transmission in mutants affected for neuropeptide signaling, thus maintaining net synaptic strength. We show that in the absence of UNC-31 muscle excitability is modulated by upregulating the expression of the muscular L-type voltage-gated Ca²⁺ channel EGL-19. Our results unveil a role for neuropeptidergic regulation in synaptic plasticity, linking changes in presynaptic transmission to compensatory changes in muscle excitability.
2. Explosion of formulaic research articles, including inappropriate study designs and false discoveries, based on the NHANES US national health database

   by Tulsi Suchak, Anietie E. Aliu, Charlie Harrison, Reyer Zwiggelaar, Nophar Geifman, Matt Spick

   With the growth of artificial intelligence (AI)-ready datasets such as the National Health and Nutrition Examination Survey (NHANES), new opportunities for data-driven research are being created, but also generating risks of data exploitation by paper mills. In this work, we focus on two areas of potential concern for AI-supported research efforts. First, we describe the production of large numbers of formulaic single-factor analyses, relating single predictors to specific health conditions, where multifactorial approaches would be more appropriate. Employing AI-supported single-factor approaches removes context from research, fails to capture interactions, avoids false discovery correction, and is an approach that can easily be adopted by paper mills. Second, we identify risks of selective data usage, such as analyzing limited date ranges or cohort subsets without clear justification, suggestive of data dredging, and post-hoc hypothesis formation. Using a systematic literature search for single-factor analyses, we identified 341 NHANES-derived research papers published over the past decade, each proposing an association between a predictor and a health condition from the wide range contained within NHANES. We found evidence that research failed to take account of multifactorial relationships, that manuscripts did not account for the risks of false discoveries, and that researchers selectively extracted data from NHANES rather than utilizing the full range of data available. Given the explosion of AI-assisted productivity in published manuscripts (the systematic search strategy used here identified an average of 4 papers per annum from 2014 to 2021, but 190 in 2024–9 October alone), we highlight a set of best practices to address these concerns, aimed at researchers, data controllers, publishers, and peer reviewers, to encourage improved statistical practices and mitigate the risks of paper mills using AI-assisted workflows to introduce low-quality manuscripts to the scientific literature.
3. A standardized nomenclature for the rods and cones of the vertebrate retina

   by Tom Baden, Juan M. Angueyra, Jenny M. Bosten, Shaun P. Collin, Bevil R. Conway, Fabio Cortesi, Karin Dedek, Thomas Euler, Iñigo Novales Flamarique, Anna Franklin, Silke Haverkamp, Almut Kelber, Stephan C.F. Neuhauss, Wei Li, Robert J. Lucas, Daniel C. Osorio, Karthik Shekhar, Dario Tommasini, Takeshi Yoshimatsu, Joseph C. Corbo

   Vertebrate photoreceptors have been studied for well over a century, but a fixed nomenclature for referring to orthologous cell types across diverse species has been lacking. Instead, photoreceptors have been variably—and often confusingly—named according to morphology, presence/absence of ‘rhodopsin’, spectral sensitivity, chromophore usage, and/or the gene family of the opsin(s) they express. Here, we propose a unified nomenclature for vertebrate rods and cones that aligns with the naming systems of other retinal cell classes and that is based on the photoreceptor type’s putative evolutionary history. This classification is informed by the functional, anatomical, developmental, and molecular identities of the neuron as a whole, including the expression of deeply conserved transcription factors required for development. The proposed names will be applicable across all vertebrates and indicative of the widest possible range of properties, including their postsynaptic wiring, and hence will allude to their common and species-specific roles in vision. Furthermore, the naming system is open-ended to accommodate the future discovery of as-yet unknown photoreceptor types.
4. Old cytokine, new tricks: A refined model of interferon’s antiviral activity

   by John W. Schoggins

   Interferon is a central component of the vertebrate antiviral immune response, thought to act through induction of hundreds of interferon-stimulated genes, with some redundancy. Recent findings suggest a more refined ‘limited set’ model, in which distinct viruses are targeted by small subsets of the induced gene repertoire. Interferon is a central component of the vertebrate antiviral immune response, thought to act through induction of hundreds of interferon-stimulated genes, with some redundancy. This Perspective highlights recent findings that suggest a more refined ‘limited set’ model, in which distinct viruses are targeted by small subsets of the induced gene repertoire.
5. Circadian rhythms are more resilient to pacemaker neuron disruption in female <i>Drosophila</i>

   by Aishwarya Ramakrishnan Iyer, Eva Scholz-Carlson, Evardra Bell, Grace Biondi, Shlesha Richhariya, Maria P. Fernandez

   The circadian system regulates the timing of multiple molecular, physiological, metabolic, and behavioral phenomena. In Drosophila, as in other species, most of the research on how the timekeeping system in the brain controls the timing of behavioral outputs has been conducted in males, or sex has not been included as a biological variable. A critical set of circadian pacemaker neurons in Drosophila release the neuropeptide pigment-dispersing factor (PDF), which functions as a key output factor in the network with complex effects on other clock neurons. Lack of Pdf or its receptor, PdfR, results in most flies displaying arrhythmicity in activity–rest cycles under constant conditions. However, our results show that female circadian rhythms are less affected by mutations in both Pdf and PdfR. CRISPR-Cas9-mediated mutagenesis of Pdf, specifically in ventral lateral neurons (LN_vs), also has a greater effect on male rhythms. We tested the influence of M-cells on the circadian network and showed that speeding up the molecular clock specifically in M-cells led to sexually dimorphic phenotypes, with a more pronounced effect on male rhythmic behavior. Our results suggest that the female circadian system is more resilient to manipulations of M-cells and the PDF pathway, suggesting that circadian timekeeping is more distributed across the clock neuron network in females.