Browse Articles

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.

Multiorifice acoustic microrobot for boundary-free multimodal 3D swimming

The emerging new generation of small-scaled acoustic microrobots is poised to expedite the adoption of microrobotics in biomedical research. Recent designs of these microrobots have enabled intricate bioinspired motions, paving the way for their real-world applications. We present a multiorifice design of air-filled spherical microrobots that convert acoustic wave energy to efficient propulsion through a resonant encapsulated microbubble. These microrobots can swim boundary-free in three-dimensional (3D) space while switching between various frequency-dependent locomotion modes. We explore the locomotion dynamics of microrobots with diameters ranging from 10 μm to 100 μm, focusing on their boundary-free 3D swimming and multimodal locomotion in response to acoustic stimuli below 1 MHz. Further, we elucidate the dynamics of these microrobots, featuring a single multiorifice cavity, which contributes to complex acoustic streaming and facilitates swift, unrestricted movements. Finally, we demonstrate that incorporating microrobots with additional nickel and gold layers significantly enhances their steering and visibility in optoacoustic and ultrasound imaging, enabling the development of the next generation of microrobots in healthcare applications.

Targeting EPHB2/ABL1 restores antitumor immunity in preclinical models of ependymoma

Ependymoma (EPN) is a common form of brain tumor in children, often resistant to available cytotoxic therapies. Molecular profiling studies have led to a better understanding of EPN subtypes and revealed a critical role of oncogenes ZFTA–RELA fusion and EPHB2 in supratentorial ependymoma (ST-EPN). However, the immune system’s role in tumor progression and response to therapy remains poorly understood. New treatments for various molecular subtypes of EPN are desperately needed. Using ST-EPN-ZFTA subtype-specific syngeneic mouse models, we found an increased frequency of M2-like tumor-associated macrophages (TAMs), which proportionally increased with tumor size during tumor progression. Transcriptomic profiling of ST-EPN-ZFTA and analysis of a human EPN dataset revealed multiple protein kinases as potential druggable targets. By matching transcriptomic signatures with the target spectrum of FDA-approved drugs, we found that the multikinase inhibitor dasatinib potently inhibited the growth of EPN both in vitro and in vivo, mainly through blocking EPHB2 and ABL1. Treatment with dasatinib reprogrammed the EPN immune microenvironment by polarizing TAMs toward an M1-like phenotype and increasing CD8 T cell activation. Furthermore, dasatinib treatment induced complete regression of established EPN tumors in 78% of the animals and protected survivors against tumor recurrence. Depletion of CD8 cells compromised the durability of EPN responses and reduced overall survival. These data indicate that dasatinib has the potential to be an effective therapy for ST-EPN-ZFTA molecular subgroup of EPN and support further investigation of dasatinib in clinical trials.

Profile of Geoffrey M. Heal

Retrospective SARS-CoV-2 human antibody development trajectories are largely sparse and permissive

Immunological interventions, like vaccinations, are enabled by the predictive control of humoral responses to novel antigens. While the development trajectories for many broadly neutralizing antibodies (bnAbs) have been measured, it is less established how human subtype-specific antibodies develop from their precursors. In this work, we evaluated the retrospective development trajectories for eight anti-SARS-CoV-2 Spike human antibodies (Abs). To mimic the immunological process of BCR selection during affinity maturation in germinal centers (GCs), we performed deep mutational scanning on anti-S1 molecular Fabs using yeast display coupled to fluorescence-activated cell sorting. Focusing only on changes in affinity upon mutation, we found that human Ab development pathways have few mutations which impart changes in monovalent binding dissociation constants and that these mutations can occur in nearly any order. Maturation pathways of two bnAbs showed that while they are only slightly less permissible than subtype-specific Abs, more development steps on average are needed to reach the same level of affinity. Many of the subtype-specific Abs had inherent affinity for antigen, and these results were robust against different potential inferred precursor sequences. To evaluate the effect of differential affinity for precursors on GC outcomes, we adapted a coarse-grained affinity maturation model. This model showed that antibody precursors with minimal affinity advantages rapidly outcompete competitors to become the dominant clonotype.

Abrupt transformation of West Greenland lakes following compound climate extremes associated with atmospheric rivers

Arctic ecosystems are affected by accelerated warming as well as the intensification of the hydrologic cycle, yet understanding of the impacts of compound climate extremes (e.g., simultaneous extreme heat and rainfall) remains limited, despite their high potential to alter ecosystems. Here, we show that the aquatic ecosystems in historically arid West Greenland have undergone an ecological transformation after a series of atmospheric rivers that simultaneously produced record heat and rainfall hit the region in autumn 2022. We analyzed a unique, long-term lake dataset and found that compound climate extremes pushed Arctic lakes across a tipping point. As terrestrial–aquatic linkages were strengthened, lakes synchronously transformed from “blue” lakes with high transparency and low pelagic primary production to “brown” in less than a year, owing to a large influx of dissolved organic material and metals, with iron concentrations increasing by more than two orders of magnitude. The browning of lake waters reduced light penetration by 50% across lakes. The resulting light limitation altered plankton distributions and community structure, including a major reduction in prokaryotic diversity and an increase in algal groups capable of metabolizing organic carbon sources. As a result, lakes shifted from being summer carbon sinks to sources, with a &gt;350% increase in carbon dioxide flux from lakes to the atmosphere. The remarkably rapid, coherent transformation of these Arctic ecosystems underscores the synergistic and unpredictable impacts of compound extreme events and the importance of their seasonal timing, especially in regions with negative moisture balance.

Tree rings and Earth System Models unveil mid-Holocene alpine climate

Advancing forecasting capabilities: A contrastive learning model for forecasting tropical cyclone rapid intensification

Tropical cyclones (TCs), particularly those that rapidly intensify (RI), pose a significant threat due to the uncertainty in forecasting them. RI TC periods, which intensify by at least 13 m/s within 24 h, remain challenging to forecast accurately. Existing models achieve a probability of detection (POD) of 82.6% and a false alarm rate (FARate) of 27.2%. To address this, we developed a contrastive-based RI TC forecasting (RITCF-contrastive) model, utilizing satellite infrared imagery alongside atmospheric and oceanic data. The RITCF-contrastive model was tested on 1,149 TC periods in the Northwest Pacific from 2020 to 2021, achieving a POD of 92.3% and a FARate of 8.9%. RITCF-contrastive improves on previous models by addressing sample imbalance and incorporating TC structural features, leading to a 11.7% improvement in POD and a 3 times reduction in FARate compared to existing deep learning methods. The RITCF-contrastive model not only enhances RI TC forecasting but also offers a unique approach to forecasting these dangerous weather events.

Evolution of complexity through regulatory variation at a single gene

Maternal manipulation in the social Hymenoptera

Gesture counteracts gender stereotypes conveyed through subtle linguistic cues

Despite increased attempts to express equality in speech, biases often leak out through subtle linguistic cues. For example, the subject–complement statement (SCS, “Girls are as good as boys at math”) is used to advocate for equality but often reinforces gender stereotypes (boys are the standard against which girls are judged). We ask whether stereotypes conveyed by SCS can be counteracted by gesture. Two preregistered studies with 8- to 11-y-old children ( N = 320 total) investigate whether an equal gesture—two palms placed at the same height—mitigates the gender stereotype induced by SCS. Children who saw the equal gesture along with SCS were more likely to express egalitarian beliefs than children who saw no gesture or an unequal gesture. Children can extract meaning from gesture when making stereotypical inferences, suggesting that the equal gesture may prove to be an innovative, and simple, intervention to counteract stereotypes introduced by subtle language.

Postdoc publications and citations link to academic retention and faculty success

Postdoctoral training is a career stage often described as a demanding and anxiety-laden time when many promising PhDs see their academic dreams slip away due to circumstances beyond their control. We use a unique dataset of academic publishing and careers to chart the more or less successful postdoctoral paths. We build a measure of academic success on the citation patterns two to five years into a faculty career. Then, we monitor how students’ postdoc positions—in terms of relocation, change of topic, and early well-cited papers—relate to their early-career success. One key finding is that the postdoc period seems more important than the doctoral training to achieve this form of success. This is especially interesting in light of the many studies of academic faculty hiring that link Ph.D. granting institutions and hires, omitting the postdoc stage. Another group of findings can be summarized as a Goldilocks principle: It seems beneficial to change one’s direction, but not too much.

Cortical reorganization following dorsal spinal injuries in newborn monkeys reveals a critical period in the development of the somatosensory cortex

Lesions of the dorsal columns of the spinal cord in adult macaque monkeys lead to the loss of hand inputs and large-scale expansion of the face inputs in the hand region of the somatosensory cortex. Inputs from alternate spinal pathways do not reactivate the deafferented regions of area 3b. Here, we determined how transections of the dorsal columns done within a few days after birth affect the developing somatosensory cortex. Dorsal columns were transected between the 3rd and 12th postnatal day (PND), and the somatosensory cortex was mapped when the macaques were over 3 y old. There were two distinct outcomes depending on the age at the time of the lesion. In monkeys lesioned between the 3rd and 5th PND, neurons in the entire hand region of area 3b and the adjacent somatosensory cortex responded to touch on the hand. An alternate spinal pathway must have replaced the lost pathway. In monkeys lesioned between the 9th and 12th PND, neurons in the deafferented hand region did not respond to touch on the hand. There was medialward expansion of the face representation into the deafferented cortex and a lateral expansion of the arm representation as in lesioned adults. Thus, different mechanisms underlie the reorganization of area 3b and the adjacent somatosensory cortex following identical spinal cord injuries sustained as early or late newborns. The results suggest that alternate spinal cord pathways can develop within a critical period before the 9th PND, but not later.

Nav1.8, an analgesic target for nonpsychotomimetic phytocannabinoids

Pain impacts billions of people worldwide, but treatment options are limited and have a spectrum of adverse effects. The search for safe and nonaddictive pain treatments has led to a focus on key mediators of nociceptor excitability. Voltage-gated sodium (Nav) channels in the peripheral nervous system—Nav1.7, Nav1.8, and Nav1.9—play crucial roles in pain signaling. Among these, Nav1.8 has shown promise due to its rapid recovery from inactivation and role in repetitive firing, with recent clinical studies providing proof-of-principal that block of Nav1.8 can reduce pain in humans. We report here that three nonpsychotomimetic cannabinoids—cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN)—effectively inhibit Nav1.8, suggesting their potential as analgesic compounds. In particular, CBG shows significant promise due to its ability to effectively inhibit excitability of peripheral sensory neurons. These findings highlight the therapeutic potential of cannabinoids, particularly CBG, as agents that may attenuate pain via block of Nav1.8, warranting further in vivo studies.

Electrifying the brain capillary Ca ²⁺ signal

Falling racial inequality and rising educational inequality in US prison admissions for drug, violent, and property crimes

Using administrative and survey data, we show that there has been a sea change in the contours of American imprisonment. At the end of the twentieth century, inequality in the prison admission rates of Black and White Americans was comparable to inequality in the prison admission rates of people with and without a college education. However, educational inequality is now much greater than racial inequality in prison admissions for all major crime types. Violent offenses have replaced drug offenses as the primary driver of Black prison admissions and Black–White inequality in the prison admission rate. The prison admission rate of Black Americans has fallen, but the prison admission rate of White Americans with no college education has dramatically increased for all offense categories. These findings, which are robust to adjustments for changing selection into college attendance, contribute to a growing body of evidence documenting narrowing racial inequality and widening educational inequality in Americans’ life chances.