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Cross-species comparison of AlphaFold-derived G protein-coupled receptor structures reveals novel melatonin-related receptor in Neurospora crassa

Melatonin, a molecule with diverse biological functions, is ubiquitously present in living organisms. There is significant interest in understanding melatonin signal transduction pathways in humans, particularly due to its critical role in regulating the sleep-wake cycle. However, a knowledge gap remains in fully elucidating the mechanisms by which melatonin influences circadian regulation. To bridge this gap, there is a growing need for a model system to study the role of melatonin in circadian clocks, with Neurospora crassa being a promising candidate. As a first step in this investigation, we focused on identifying melatonin receptors in N. crassa. Given the lack of sequence similarity between potential receptors in this fungus and known human melatonin receptors, we utilized structural similarity analysis through AlphaFold2. This approach led to the identification of a strong candidate gene, gpr-3, which shares structural similarities with human melatonin receptors. Experimental validation confirmed that the removal of GPR-3 from cells results in the absence of melatonin signaling. This proof-of-concept study underscores the potential of N. crassa as a model organism for circadian research and demonstrates the broader applicability of using AlphaFold2, especially when sequence similarity does not lead to candidate genes, for identifying novel receptors across different species.

Symmetry facilitated the evolution of heterospecificity and high-order stoichiometry in vertebrate hemoglobin

Many proteins form paralogous multimers—molecular complexes in which evolutionarily related proteins are arranged into specific quaternary structures. Little is known about the mechanisms by which they acquired their stoichiometry (the number of total subunits in the complex) and heterospecificity (the preference of subunits for their paralogs rather than other copies of the same protein). Here, we use ancestral protein reconstruction and biochemical experiments to study historical increases in stoichiometry and specificity during the evolution of vertebrate hemoglobin (Hb), an α 2 β 2 heterotetramer that evolved from a homodimeric ancestor after a gene duplication. We show that the mechanisms for this evolutionary transition were simple. One hydrophobic substitution in subunit β after the gene duplication was sufficient to cause the ancestral dimer to homotetramerize with high affinity across a new interface. During this same interval, a single-residue deletion in subunit α at the older interface conferred specificity for the heterotetrameric form and the trans -orientation of subunits within it. These sudden transitions in stoichiometry and specificity were possible because the interfaces in Hb are isologous, binding via the same surface patch on interacting subunits, but rotated 180° relative to each other. This architecture amplifies the impacts of individual mutations on stoichiometry and specificity, especially in higher-order complexes, and allows single substitutions to differentially affect heteromeric and homomeric interactions. Our findings suggest that elaborate and specific symmetrical molecular complexes may often evolve via simple genetic and physical mechanisms.

Burnout and organisational stressors among healthcare staff working with adults with intellectual disabilities in Ireland

Background The associations between organisational stressors and burnout among healthcare staff working with adults with intellectual disabilities are underexplored. This study investigated rates of burnout and associated stressors among Irish healthcare workers during the COVID-19 pandemic. Materials and methods A convenience sample of 329 Irish frontline staff supporting adults with intellectual disabilities completed a survey assessing personal, work-related, and client-related burnout, and organisational stressors. Quantitative correlational analysis assessed bivariate and multi-variate associations, while qualitative accounts were analysed thematically. Results Compared to international data, we observed very high levels of personal and work-related burnout, with lower levels of client-related burnout. “Lack of resources” was the stressor holding the strongest association with burnout, followed by “bureaucracy” and “work-home conflict”. Qualitative responses highlighted the negative impact of the pandemic on workload, service quality, and staff wellbeing. Discussion Our findings highlight an important association between organisational stressors and burnout among frontline staff, suggesting the potential benefit of designing organisationally focused interventions to reduce stress and promote staff wellbeing.

ANKRD11 binding to cohesin suggests a connection between KBG syndrome and Cornelia de Lange syndrome

Ankyrin Repeat Domain-containing Protein 11 ( ANKRD11 ) is a causative gene for KBG syndrome, a significant risk factor for Cornelia de Lange syndrome (CdLS), and a highly confident autism spectrum disorder gene. Mutations of ANKRD11 lead to developmental abnormalities in multiple organs/tissues including the brain, craniofacial and skeletal bones, and tooth structures with unknown mechanism(s). Here, we find that ANKRD11, via a short peptide fragment in its N-terminal region, binds to the cohesin complex with a high affinity, implicating why ANKRD11 mutation can cause CdLS. The crystal structure of the ANKRD11 peptide in complex with cohesin, together with biochemical experiments, revealed that ANKRD11 competes with CCCTC-binding factor in binding to the cohesin complex. Importantly, a single point mutation in ANKRD11 (Tyr347 to Ala) specifically disrupted the interaction between ANKRD11 and cohesin and perturbed gene expressions in a mouse embryonic stem cell model. Mice carrying the ANKRD11 Y347A mutation display neural and craniofacial anomalies, which mirror clinical phenotypes observed in KBG syndrome patients. Thus, our study reveals how ANKRD11 functions together with cohesin to regulate gene expression and also provides insights into the molecular mechanisms underpinning developmental disorders caused by ANKRD11 mutations.

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

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.

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

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

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.

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

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

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.

Band asymmetry–driven nonreciprocal electronic transport in a helimagnetic semimetal α-EuP ₃

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

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.

BCL6 coordinates muscle mass homeostasis with nutritional states

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

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.

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

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.

Layer-specific control of inhibition by NDNF interneurons

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>

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

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?

Intercellular mRNA transfer alters the human pluripotent stem cell state

Intercellular transmission of messenger RNA (mRNA) is being explored in mammalian species using immortal cell lines. Here, we uncover an intercellular mRNA transfer phenomenon that allows for the adaptation and reprogramming of human primed pluripotent stem cells (hPSCs). This process is induced by the direct cell contact-mediated coculture with mouse embryonic stem cells under the condition impermissible for primed hPSC culture. Mouse-derived mRNA contents are transmitted into adapted hPSCs only in the coculture. Transfer-specific mRNA analysis shows the enrichment for divergent biological pathways involving transcription/translational machinery and stress-coping mechanisms, wherein such transfer is diminished when direct cell contacts are lost. After 5 d of coculture with mouse embryonic stem cells, surface marker analysis and global gene profiling confirmed that mRNA transfer-prone hPSC efficiently gains a naïve-like state. Furthermore, transfer-specific knockdown experiments targeting mouse-specific transcription factor-coding mRNAs in hPSC show that mouse-derived Tfcp2l1 , Tfap2c, and Klf4 are indispensable for human naïve-like conversion. Thus, interspecies mRNA transfer triggers cellular reprogramming in mammalian cells. Our results support that episodic mRNA transfer can occur in cell cooperative and competitive processes, which provides a fresh perspective on understanding the roles of mRNA mobility for intra- and interspecies cellular communications.

A periplasmic protein modulates the proteolysis of peptidoglycan hydrolases to maintain cell wall homeostasis in <i>Escherichia coli</i>

Bacterial cell wall assembly and remodeling require activities of peptidoglycan (PG) hydrolases as well as PG synthases. In particular, the activity of DD-endopeptidases, which cleave the 4-3 peptide crosslinks in PG, is essential for PG expansion in gram-negative bacteria. Maintaining optimal levels of DD-endopeptidases is critical for expanding PG without compromising its integrity. In Escherichia coli , the levels of major DD-endopeptidases, MepS and MepH, along with the lytic transglycosylase MltD, are controlled by the periplasmic protease Prc and its outer membrane adaptor NlpI. However, the mechanisms regulating the turnover of these PG hydrolases have remained unclear. In this study, we identified a periplasmic protein, BipP (formerly YhjJ), that negatively controls the NlpI-Prc system. Further analyses indicate that BipP exerts this control by interacting with NlpI and inhibiting its substrate recognition in response to low DD-endopeptidase activity, providing insight into the homeostatic control of PG hydrolysis and cell wall expansion.