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Fipronil in sub-lethal doses leads to immuno-toxicological effects in broiler birds

PLoS ONE Shafia Tehseen Gul, Muhammad Zergham Tahir, Latif Ahmad et al. Jan 28, 2025 DOI: 10.1371/journal.pone.0315915

Pesticides, including fipronil, are used mainly in agriculture; however, in veterinary and animal husbandry, their potential use is to control the pests responsible for vector-borne diseases. Their residues in agriculture products and direct use on farms are responsible for potentially harming livestock and poultry. So, this study was designed to evaluate the toxico-pathological effects of fipronil on the immune system of poultry birds. One hundred a-day-old chicks were purchased from a local hatchery, and standard housing conditions were provided from brooding till the end of the trail. The temperature at brooding was kept at 33°C; later on, it was maintained at 26–28°C, and the humidity was at 60–70%. Clean water and a basal diet were provided ad libitum. After three days of acclimatization, birds were divided into five experimental groups (A to E), each containing 20 birds. Group A was kept as a control group. Fipronil was administered orally through crop tubing @ 1.5, 2.5, 3.5, and 4.5 mg/kg to groups B-E, respectively. Birds were euthanized humanely on the 15th, 30th, and 45th days of the experiment. Immunological parameters were evaluated, i.e., antibody titers against NDV and SRBCs, phagocytic activity to clear carbon particles, avian incompetence to avian tuberculin, and histopathological alterations in the lymphoid organs. The SAS® University Edition software was used for data analysis. The results indicated decreased antibody titers against NDV in the treatment groups compared to the control. Similarly, antibody response to SRBCs, phagocytic activity in clearing the carbon particles, and sensitivity to avian tuberculin in the treatment groups were also decreased. Results also revealed that the bursa of Fabricius thymus and spleen were also affected due to the toxic effect of fipronil, even at sub-lethal doses.

Erratum: “Ambipolarity of diluted hydrogen in wide-gap oxides revealed by Muon study” [J. Appl. Phys. 132, 105701 (2022)]

Journal of Applied Physics M. Hiraishi, H. Okabe, A. Koda et al. Jan 28, 2025 DOI: 10.1063/5.0253759

Epstein–Barr virus BALF0/1 subverts the Caveolin and ERAD pathways to target B cell receptor complexes for degradation

Proceedings of the National Academy of Sciences Stephanie Pei Tung Yiu, Yifei Liao, Jinjie Yan et al. Jan 28, 2025 DOI: 10.1073/pnas.2400167122

Epstein–Barr virus (EBV) establishes persistent infection, causes infectious mononucleosis, is a major trigger for multiple sclerosis and contributes to multiple cancers. Yet, knowledge remains incomplete about how the virus remodels host B cells to support lytic replication. We previously identified that EBV lytic replication results in selective depletion of plasma membrane (PM) B cell receptor (BCR) complexes, composed of immunoglobulin and the CD79A and CD79B signaling chains. Here, we used proteomic and biochemical approaches to identify that the EBV early lytic protein BALF0/1 is responsible for EBV lytic cycle BCR degradation. Mechanistically, an immunoglobulin heavy chain (HC) cytoplasmic tail KVK motif was required for ubiquitin-mediated BCR degradation, while CD79A and CD79B were dispensable. BALF0/1 subverted caveolin-mediated endocytosis to internalize PM BCR complexes and to deliver them to the endoplasmic reticulum. BALF0/1 stimulated immunoglobulin HC cytoplasmic tail ubiquitination, which together with the ATPase valosin-containing protein/p97 drove ER-associated degradation of BCR complexes by cytoplasmic proteasomes. BALF0/1 knockout reduced the viral load of secreted EBV particles from B cells that expressed a monoclonal antibody against EBV glycoprotein 350 but not a control anti-influenza hemagglutinin antibody and increased viral particle immunoglobulin incorporation. Consistent with downmodulation of PM BCR, BALF0/1 overexpression reduced viability of a diffuse large B cell lymphoma cell line whose survival is dependent upon BCR signaling. Collectively, our results suggest that EBV BALF0/1 downmodulates immunoglobulin upon lytic reactivation to block BCR signaling and support virion release, but await the development of suitable models to test its roles in EBV reactivation in vivo.

“Without a man’s decision, nothing works”: Building resilience to Rift Valley fever in pastoralist communities in Isiolo Kenya

PLoS ONE Irene N. Mutambo, Bernard Bett, Salome A. Bukachi Jan 28, 2025 DOI: 10.1371/journal.pone.0316015

Rift Valley Fever (RVF) is a zoonotic disease that affects both livestock and humans. Men and women in pastoralist communities are vulnerable to RVF risk exposure because of their different roles and reliance on livestock products. This study sought to understand how ownership and decision-making in pastoralist male and female-headed households influence coping mechanisms and resilience to Rift Valley fever (RVF), using the three resilience capacities of absorptive, adaptive, and transformative. This study was conducted in two sub-counties (Garbatulla) and Merti), Isiolo County, Kenya. Data were collected through 16 focus group discussions and 13 key informant interviews with pastoralists and animal and human health stakeholders. The findings indicate that traditionally, men have the final say on decisions related to livestock ownership and make overall household decisions. Pastoralist men and women employ different approaches, including hygiene practices and mosquito nets, community knowledge dissemination, establishment of new businesses, utilization of healthcare, and indigenous medicines, to reduce the effects of RVF in both humans and livestock. They also collaborated with community disease surveillance initiatives to strengthen disease surveillance networks and gain access to county government support. This process fosters resilience, community empowerment, and transformative and sustainable adaptation responses to RVF.

VS2/MoS2 nanocomposite with reverse saturable absorption for optical limiting and nonlinear optical applications

Journal of Applied Physics B. Dandasena, S. Das, Prabhukrupa C. Kumar et al. Jan 28, 2025 DOI: 10.1063/5.0243996

Transition metal dichalcogenides (TMDs) have been widely used as nonlinear optical materials. In the current study, hydrothermally prepared VS2/MoS2 nanocomposite was investigated for the non-linear study through the Z-scan technique. Z-scan is a straightforward method for determining how much a laser beam's phase changes when it passes through a nonlinear substance. This phase change, ΔΦ, is simply connected to the change in index of refraction, Δn, and yields both its sign and magnitude. Furthermore, the change in transmission due to nonlinear absorption that is associated with the change in the absorption coefficient, Δα, can also be independently determined using a Z-scan. X-ray diffraction (XRD) resembles the development of the hexagonal phase of VS2 as well as composite. The crystallite size decreased with the increased amount of Mo precursors. The morphological study confirms the formation of a nano-sheet-like structure for VS2 and a flower-like structure of the VS2/MoS2 composite. The high-resolution transmission electron microscopy(HRTEM) images contain both crystallographic planes, confirming the formation of the composite. The prepared material also shows tunable bandgap properties. The direct bandgap value lies in the range from 3.65 to 3.4 eV. The open aperture transmittance data provide information about the nonlinear absorption phenomenon, and the closed aperture transmittance data provide information about the phase shift of the light, that leads to a nonlinear refractive index (n2). The composite shows both self-focusing and self-defocusing nature. From the Z-scan experimental result, it is found that the saturable absorption (SA) properties of the pristine VS2 changed to reverse saturable absorption (RSA) after the formation of the composite with MoS2. The nonlinear absorption coefficient for VS2, VS2/MoS2-1, VS2/MoS2-2, and VS2/MoS2-3 are −(24.15 ± 0.25), 0.183 ± 127 × 10−4, 0.115 ± 3.96 × 10−4, and 0.139 ± 3.084 × 10−5 cm/W, respectively. The composite shows significant optical limiting properties for 100 mW laser source. The increase in nonlinear susceptibility, nonlinear refractive index, and nonlinear absorption coefficient are useful for optical limiting and nonlinear optical device applications.

Structural insights into glucose-6-phosphate recognition and hydrolysis by human G6PC1

Proceedings of the National Academy of Sciences Zhanyi Xia, Chuanyu Liu, Di Wu et al. Jan 28, 2025 DOI: 10.1073/pnas.2418316122

The glucose-6-phosphatase (G6Pase) is an integral membrane protein that catalyzes the hydrolysis of glucose-6-phosphate (G6P) in the endoplasmic reticulum lumen and plays a vital role in glucose homeostasis. Dysregulation or genetic mutations of G6Pase are associated with diabetes and glycogen storage disease 1a (GSD-1a). Studies have characterized the biophysical and biochemical properties of G6Pase; however, the structure and substrate recognition mechanism of G6Pase remain unclear. Here, we present two cryo-EM structures of the 40-kDa human G6Pase: a wild-type apo form and a mutant G6Pase-H176A with G6P bound, elucidating the structural basis for substrate recognition and hydrolysis. G6Pase comprises nine transmembrane helices and possesses a large catalytic pocket facing the lumen. Unexpectedly, G6P binding induces substantial conformational rearrangements in the catalytic pocket, which facilitate the binding of the sugar moiety. In conjunction with functional analyses, this study provides critical insights into the structure, substrate recognition, catalytic mechanism, and pathology of G6Pase.

Pooled prevalence and associated factors of traditional uvulectom among children in Africa: A systematic review and meta-analysis

PLoS ONE Solomon Demis Kebede, Kindu Agmas, Demewoz Kefale et al. Jan 28, 2025 DOI: 10.1371/journal.pone.0316755

Background Traditional childhood uvulectomy (TCU) is an unregulated cultural practice associated with significant health risks, including infections, anemia, aspiration, and oral or pharyngeal injuries. The reuse of unsafe tools such as blades, needles, or thread loops exacerbates the spread of infectious diseases like HIV and hepatitis B. Despite its clinical significance, the pooled prevalence and associated factors of TCU have not been adequately examined through systematic reviews or meta-analyses. Objective This review and meta-analysis aimed to estimate the pooled prevalence and associated factors of TCU in some African countries. Methods This systematic review and meta-analysis adhered to the PRISMA 2020 guidelines. A comprehensive search was performed across multiple databases, including MEDLINE, ScienceDirect, Google Scholar, and African Journals Online, to identify relevant studies. A weighted inverse-variance random-effects model was employed to estimate the pooled prevalence and associated predictors of TCU. Heterogeneity among the included studies was assessed using a forest plot, I2 statistics, and Egger’s test, ensuring the robustness and reliability of the findings. Missing data was handled by random effect model and sensitivity analysis. Data extraction was conducted fromNovember 6 to December 23, 2023. Eligibility criteria Included studies focused on children aged birth to under 15 years, examining TCU defined as the partial or complete removal of the uvula by traditional healers. Participants Eleven primary studies comprising 7,231 children from some countries in Africa were included. Results Pooled estimate of TCU in some African countries was 40.98% (95% CI: 25.04–56.92; I2 = 99.61, P = 0.001). Mothers residing in rural areas were 2.45 times more likely to have a child experienced TCU compared to those in urban areas (AOR = 2.45; 95% CI: 1.59–3.32). Similarly, Mothers with a history of having a previous child who undergo TCU were 8.44 times more likely to seek the procedure for their other children compared to mothers without such a history (AOR = 8.44; 95% CI: 6.27–10.61). However, caution is warranted when interpreting these findings due to the significant heterogeneity reported across the included studies, which may influence the generalizability of the results. Conclusions Nearly two-fifths of children in some African countries experienced TCU, which was influenced by maternal history and rural residency. While most procedures did not result in hospitalization, significant health risks remain. These findings underscore the urgent need for targeted interventions within maternal and child health programs to address TCU and mitigate its associated morbidity in the affected countries across Africa. Prospero I.D. CRD42024498699.

Effects of shear stability and residual stresses in computer glasses

Journal of Applied Physics Edan Lerner Jan 28, 2025 DOI: 10.1063/5.0246245

Numerical investigations of disordered solids often involve employing a fixed simulation-box geometry and periodic boundary conditions, the latter are intended to minimize surface effects. One consequence of this methodological approach is that the resulting solids typically feature residual macroscopic stresses and could feature negative shear moduli, in which case they are deemed unstable to shear. In this work, we review and validate via numerical simulations the statistical theory that explains how the fraction of shear-unstable solids within an ensemble of solids created via the same protocol depends on the system size. We further demonstrate and rationalize how the fraction of disordered soft-sphere packings that are unstable to shear depends on their proximity to the unjamming point at which solidity is lost. Finally, we show that residual-stress-free structural glasses created in a fixed-box geometry have the same vibrational and elastic properties as glasses that do feature residual stresses. This result seemingly contradicts previous work that shows that residual-stress-free samples created using variable box shape feature different vibrational properties. These observations raise questions about the equivalence of constant-stress vs constant box-geometry ensembles in the thermodynamic limit, which are discussed together with future research directions.

Band asymmetry–driven nonreciprocal electronic transport in a helimagnetic semimetal α-EuP <sub>3</sub>

Proceedings of the National Academy of Sciences Alex Hiro Mayo, Darius-Alexandru Deaconu, Hidetoshi Masuda et al. Jan 28, 2025 DOI: 10.1073/pnas.2405839122

Chiral magnetic textures give rise to unconventional magnetotransport phenomena such as the topological Hall effect and nonreciprocal electronic transport. While the correspondence between topology or symmetry of chiral magnetic structures and such transport phenomena has been well established, a microscopic understanding based on the spin-dependent band structure in momentum space remains elusive. Here, we demonstrate how a chiral magnetic superstructure introduces an asymmetry in the electronic band structure and triggers a nonreciprocal electronic transport in a centrosymmetric helimagnet α-EuP 3 . The magnetic structure of α-EuP 3 is highly tunable by a magnetic field and closely coupled to its semimetallic electronic band structure, enabling a systematic study across chiral and achiral magnetic phases on the correspondence between nonreciprocal transport and electronic band asymmetry. Our findings reveal how a microscopic change in the magnetic configuration of charge carriers can lead to nonreciprocal electronic transport, paving the way for designing chiral magnets with desirable properties.

Comparison of inductively coupled plasma mass spectrometry and molybdenum blue colorimetry for total phosphorus determination in freshwater invertebrates

PLoS ONE Molly S. Costanza-Robinson, Baker J. Angstman, Qiting Cai et al. Jan 28, 2025 DOI: 10.1371/journal.pone.0317871

Molybdenum blue colorimetry (MBC) is the dominant, well-established method used for determining total P in environmental media, including in organismal tissues. However, other elemental methods for P determination are available, including inductively coupled plasma mass spectrometry (ICP-MS). Given the extensive literature using MBC to determine P in organismal samples, it is important to assess P analyses by ICP-MS and MBC to ensure that the two methods produce comparable data. In this work, we compared ICP-MS and MBC for total P determination in freshwater invertebrates, including the potential for analytical interferences, by applying both methods to three standard reference materials (SRMs) and 106 freshwater invertebrate samples. Average total P recoveries for SRMs were slightly higher for ICP-MS (99.8 ± 5.2%) than MBC (96.5 ± 5.4%), but both methods indicated good accuracy. Total P in invertebrates determined using the two methods was strongly linearly correlated (r = 0.96) with a slope of 1.01. On the whole, total P measured using ICP-MS exceeded that measured by MBC, but average pair-wise differences in %P were biologically negligible (0.044 ± 0.054). %P for SRMs and invertebrate samples run on ICP-MS in kinetic energy discrimination and standard modes compared favorably (e.g., SRM P recovery of 102% by both methods), indicating negligible influence of polyatomic ions on ICP-MS analysis. Similarly, analysis of P spike recoveries by ICP-MS (100.2 ± 3.4%) and MBC (107.0 ± 2.8%) were both considered acceptable. We conclude that ICP-MS represents a reliable and comparable alternative to MBC for determining total P in freshwater invertebrates while also offering the opportunity to measure additional biologically relevant elements in a single analysis.

Global modeling of iodine Hall thruster performance and discharge properties

Journal of Applied Physics Francesco M. Bianchi, Alfio E. Vinci, Laurent Garrigues Jan 28, 2025 DOI: 10.1063/5.0244131

A 0D model for an iodine-fed Hall thruster is presented. A complete set of reactions is used to account for iodine plasma chemistry phenomena and trace the presence of multiple neutrals and ionized species. The model is developed using novel assumptions based on experimental data trends as derived from the literature. The simulation domain is divided into two zones in order to refine the iodine molecule dissociation process localized in the low electron temperature region found upstream in the channel. After validating a xenon version of the model against SPT-100 characteristics, numerical results are compared against experimental data relative to a low-power iodine-fed Hall thruster. Discharge current and thrust are predicted with satisfactory quantitative agreement, and overall trends are effectively captured. The numerical results indicate a relatively large portion of ionized molecules, while negative ions appear to occur in non-negligible amount upstream in the thruster channel.

BCL6 coordinates muscle mass homeostasis with nutritional states

Proceedings of the National Academy of Sciences Hui J. Wang, Weiwei Fan, Sihao Liu et al. Jan 28, 2025 DOI: 10.1073/pnas.2408896122

Nutritional status is a determining factor for growth during development and homeostatic maintenance in adulthood. In the context of muscle, growth hormone (GH) coordinates growth with nutritional status; however, the detailed mechanisms remain to be fully elucidated. Here, we show that the transcriptional repressor B cell lymphoma 6 (BCL6) maintains muscle mass by sustaining GH action. Muscle-specific genetic deletion of BCL6 at either perinatal or adult stages profoundly reduces muscle mass and compromises muscle strength. Conversely, muscle-directed viral overexpression of BCL6 significantly reverses the loss of muscle mass and strength. Mechanistically, we show that BCL6 transcriptionally represses the suppressor of cytokine signaling 2 to sustain the anabolic actions of GH in muscle. Additionally, we find that GH itself transcriptionally inhibits BCL6 through the Janus kinase and signal transducer and activator of transcription 5 (JAK/STAT5) pathway. Supporting the physiologic relevance of this feedback regulation, we show the coordinated suppression of muscle Bcl6 expression with the induction of GH in the fasted state. These findings reveal the complexity of the feedback controls modulating GH signaling and identify BCL6 as a key homeostatic regulator coordinating muscle mass with nutrient availability. Moreover, these studies open avenues for targeted therapeutic strategies to combat muscle-wasting conditions.

Factors influencing medication adherence among hypertensive patients in primary care settings in Central Vietnam: A cross-sectional study

PLoS ONE Ho Anh Hien, Nguyen Minh Tam, Huynh Van Minh et al. Jan 28, 2025 DOI: 10.1371/journal.pone.0307588

Background Medication adherence plays a crucial role in effectively managing hypertension, a significant public health concern, especially in regions like Central Vietnam. This study aimed to assess medication adherence levels among hypertensive patients in primary care settings and explore the factors influencing adherence within this specific population. Methods We conducted a cross-sectional study to evaluate medication adherence and its determinants among individuals with hypertension in Central Vietnam. Medication adherence was assessed using the 5-item version of the Medication Adherence Report Scale self-report. We collected data on the demographics, medical history, lifestyle, hypertension knowledge, along with the patient beliefs and perceptions about hypertension. Logistic regression analysis was employed to identify the key factors associated with their medication adherence. Results Our study revealed that only half of the hypertensive patients adhered to their prescribed medication regimens. Several factors significantly influenced their medication adherence, including age, ethnicity, educational level, home blood pressure monitoring, healthy diet, time since hypertension diagnosis, hypertension knowledge, and patient beliefs. According to the logistic regression analysis, a healthy diet and patient beliefs emerged as primary predictors of medication adherence. Patients who strongly believed in the necessity of medication demonstrated better adherence, while concerns about overuse and harm were linked to lower adherence levels. Conclusions This study highlighted the suboptimal levels of medication adherence among hypertensive patients in primary care settings in Central Vietnam. It underscored the urgent need for tailored interventions to address this issue. For the sake of better medication adherence, healthcare providers were suggested to prioritize patient education, address patient beliefs and concerns about medication, and promote the practice of home blood pressure monitoring.

Interstitial nitrogen-modified (Y1−<i>x</i>Sm<i>x</i>)2Fe14BN<i>y</i> compounds toward enhanced operating frequency and reduced power loss

Journal of Applied Physics Chao Meng, Zenan Zhang, Zhaochen Liu et al. Jan 28, 2025 DOI: 10.1063/5.0244861

Soft magnetic materials with high operating frequency and low power loss are crucial for electricity transmission and utilization. However, finding an effective method to improve the operating frequency while minimizing power loss in these materials remains a significant challenge. Herein, we synthesized the (Y1−xSmx)2Fe14B (0≤x≤1) compounds and introduced nitrogen atoms into their interstitial crystal sites via the gas–solid reaction, remarkably improving their operating frequency and reducing power loss. For the compounds with x = 0.15, the operating frequency increased from 1.7 to 5.5 MHz, with the imaginary part of relative permeability decreased from 6.1 to 1.6. The power loss decreased from 1607.7 to 664.1kW/m3, and loss separation indicated that eddy current loss Peddy was significantly suppressed by nitriding from 1397.7 to 547.9kW/m3. The conductivity decreased by approximately 43% by nitriding, from 9380.9 to 5359.0 S/m. These results demonstrate that tuning power loss through nitrogenation of rare-earth transition metal intermetallic compounds is an effective method for developing new high-frequency and low power loss soft magnetic materials.

Preventing inappropriate signals pre- and post-ligand perception by a toggle switch mechanism of ERECTA

Proceedings of the National Academy of Sciences Liangliang Chen, Michal Maes, Alicia M. Cochran et al. Jan 28, 2025 DOI: 10.1073/pnas.2420196122

Dynamic control of signaling events requires swift regulation of receptors at an active state. By focusing on the Arabidopsis ERECTA (ER) receptor kinase, which perceives peptide ligands to control multiple developmental processes, we report a mechanism preventing inappropriate receptor activity. The ER C-terminal tail (ER_CT) functions as an autoinhibitory domain: Its removal confers higher kinase activity and hyperactivity during inflorescence and stomatal development. ER_CT is required for the binding of a receptor kinase inhibitor, BKI1, and two U-box E3 ligases, PUB30 and PUB31, that trigger activated ER to degradation through ubiquitination. We further identify ER_CT as a phosphodomain transphosphorylated by the coreceptor BAK1. The phosphorylation impacts the tail structure, likely releasing ER from autoinhibition. The phosphonull version enhances BKI1 association, whereas the phosphomimetic version promotes PUB30/31 association. Thus, ER_CT acts as an off–on–off toggle switch, facilitating the release of BKI1 inhibition, enabling signal activation, and swiftly turning over the receptors afterward. Our results elucidate a mechanism that fine-tunes receptor signaling via a phosphoswitch module, maintaining the receptor at a low basal state while ensuring robust yet transient activation upon ligand perception.

Coupling characteristics of optical skyrmions based on localized spoof plasmons (LSP)

Journal of Applied Physics Xiaoqiao Sun, Songmei Ni, Longfei Guo et al. Jan 28, 2025 DOI: 10.1063/5.0249416

In this work, we theoretically investigate the coupling characteristics of optical skyrmions based on localized spoof plasmons (LSPs). First, the single LSP optical skyrmion is realized and resonance modes attributed to different topological features are analyzed. Second, the coupling effect is observed through decreasing the distance between the adjacent LSP optical skyrmions. The coupling LSP optical skyrmions can preserve the topological behaviors, and particularly, three coupling modes (mode-a, mode-b, and mode-c) can be observed. Mode-a presents uniform magnetic field distributions, while mode-b and mode-c can be observed with asymmetric magnetic field distributions. Finally, the ten-coupling LSP optical skyrmions supported by space-coiling cylinders and square structures are realized and the robust topological features are discussed. The results may contribute to the future investigation on designing optical skyrmion crystals and advanced optical devices.

Layer-specific control of inhibition by NDNF interneurons

Proceedings of the National Academy of Sciences Laura Bella Naumann, Loreen Hertäg, Jennifer Müller et al. Jan 28, 2025 DOI: 10.1073/pnas.2408966122

Neuronal processing of external sensory input is shaped by internally generated top–down information. In the neocortex, top–down projections primarily target layer 1, which contains NDNF (neuron-derived neurotrophic factor)-expressing interneurons and the dendrites of pyramidal cells. Here, we investigate the hypothesis that NDNF interneurons shape cortical computations in an unconventional, layer-specific way, by exerting presynaptic inhibition on synapses in layer 1 while leaving synapses in deeper layers unaffected. We first confirm experimentally that in the auditory cortex, synapses from somatostatin-expressing (SOM) onto NDNF neurons are indeed modulated by ambient Gamma-aminobutyric acid (GABA). Shifting to a computational model, we then show that this mechanism introduces a distinct mutual inhibition motif between NDNF interneurons and the synaptic outputs of SOM interneurons. This motif can control inhibition in a layer-specific way and introduces competition between NDNF and SOM interneurons for dendritic inhibition onto pyramidal cells on different timescales. NDNF interneurons can thereby control cortical information flow by redistributing dendritic inhibition from fast to slow timescales and by gating different sources of dendritic inhibition.

Itaconate mechanism of action and dissimilation in <i>Mycobacterium tuberculosis</i>

Proceedings of the National Academy of Sciences Manisha Priya, Sonu Kumar Gupta, Anil Koundal et al. Jan 28, 2025 DOI: 10.1073/pnas.2423114122

Itaconate, an abundant metabolite produced by macrophages upon interferon-γ stimulation, possesses both antibacterial and immunomodulatory properties. Despite its crucial role in immunity and antimicrobial control, its mechanism of action and dissimilation are poorly understood. Here, we demonstrate that infection of mice with Mycobacterium tuberculosis increases itaconate levels in lung tissues. We also show that exposure to itaconate inhibits M. tuberculosis growth in vitro, in macrophages, and mice. We report that exposure to sodium itaconate (ITA) interferes with the central carbon metabolism of M. tuberculosis . In addition to the inhibition of isocitrate lyase (ICL), we demonstrate that itaconate inhibits aldolase and inosine monophosphate (IMP) dehydrogenase in a concentration-dependent manner. Previous studies have shown that Rv2498c from M. tuberculosis is the bona fide (S)-citramalyl-CoA lyase, but the remaining components of the pathway remain elusive. Here, we report that Rv2503c and Rv3272 possess itaconate:succinyl-CoA transferase activity, and Rv2499c and Rv3389c possess itaconyl-CoA hydratase activity. Relative to the parental and complemented strains, the ΔRv3389c strain of M. tuberculosis was attenuated for growth in itaconate-containing medium, in macrophages, mice, and guinea pigs. The attenuated phenotype of ΔRv3389c strain of M. tuberculosis is associated with a defect in the itaconate dissimilation and propionyl-CoA detoxification pathway. This study thus reveals that multiple metabolic enzymes are targeted by itaconate in M. tuberculosis. Furthermore, we have assigned the two remaining enzymes responsible for the degradation of itaconic acid into pyruvate and acetyl-CoA. Finally, we also demonstrate the importance of enzymes involved in the itaconate dissimilation pathway for M. tuberculosis pathogenesis.

Adaptive evolutionary trajectories in complexity: Transitions between unicellularity and facultative differentiated multicellularity

Proceedings of the National Academy of Sciences Hanna Isaksson, Peter Lind, Eric Libby Jan 28, 2025 DOI: 10.1073/pnas.2411692122

Multicellularity spans a wide gamut in terms of complexity, from simple clonal clusters of cells to large-scale organisms composed of differentiated cells and tissues. While recent experiments have demonstrated that simple forms of multicellularity can readily evolve in response to different selective pressures, it is unknown if continued exposure to those same selective pressures will result in the evolution of increased multicellular complexity. We use mathematical models to consider the adaptive trajectories of unicellular organisms exposed to periodic bouts of abiotic stress, such as drought or antibiotics. Populations can improve survival in response to the stress by evolving multicellularity or cell differentiation—or both; however, these responses have associated costs when the stress is absent. We define a parameter space of fitness-relevant traits and identify where multicellularity, differentiation, or their combination is fittest. We then study the effects of adaptation by allowing populations to fix mutations that improve their fitness. We find that while the same mutation can be beneficial to populations of different complexity, e.g., strict unicellularity or life cycles with stages of differentiated multicellularity, the magnitudes of their effects can differ and alter which is fittest. As a result, we observe adaptive trajectories that gain and lose complexity. We also show that the order of mutations, historical contingency, can cause some transitions to be permanent in the absence of neutral evolution. Ultimately, we find that continued exposure to a selective driver for multicellularity can either lead to increasing complexity or a return to unicellularity.

Can science-based interventions tamp down polarization?

Proceedings of the National Academy of Sciences M. Mitchell Waldrop Jan 28, 2025 DOI: 10.1073/pnas.2500158122