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Giant quantum oscillations in thermal transport in low-density metals via electron absorption of phonons
Oscillations of conductance observed in strong magnetic fields are a striking manifestation of the quantum dynamics of charge carriers in solids. The large charge carrier density in typical metals sets the scale of oscillations in both electrical and thermal conductivity, which characterize the Fermi surface. In semimetals, thermal transport at low-charge carrier density is expected to be phonon dominated, yet several experiments observe giant quantum oscillations in thermal transport. This raises the question of whether there is an overarching mechanism leading to sizable oscillations that survives in phonon-dominated semimetals. In this work, we show that such a mechanism exists. It relies on the peculiar phase-space allowed for phonon scattering by electrons when only a few Landau levels are filled. Our measurements on the Dirac semimetal ZrTe 5 support this counterintuitive mechanism through observation of pronounced thermal quantum oscillations, since they occur in similar magnitude and phase in directions parallel and transverse to the magnetic field. Our phase-space argument applies to all low-density semimetals, topological or not, including graphene and bismuth. Our work illustrates that phonon absorption can be leveraged to reveal degrees of freedom through their imprint on longitudinal thermal transport.
Bioinspired ion-shuttling memristor with both neuromorphic functions and ion selectivity
The fluidic memristor has attracted growing attention as a promising candidate for neuromorphic computing and brain–computer interfaces. However, a fluidic memristor with ion selectivity as that of natural ion channels remains a key challenge. Herein, inspired by the structure of natural biomembranes, we developed an ion-shuttling memristor (ISM) by utilizing organic solvents and artificial carriers to emulate ion channels embedded in biomembranes, which exhibited both neuromorphic functions and ion selectivity. Pinched hysteresis I-V loop curve, scan rate dependency, and distinctive impedance spectra confirmed the memristive characteristics of the as-prepared device. Moreover, the memory mechanism was discussed theoretically and validated by finite-element modeling. The ISM features multiple neuromorphic functions, such as paired-pulse facilitation, paired-pulse depression, and learning–experience behavior. More importantly, the ion selectivity of the ISM was observed, which allowed further emulation of ion-selective neural functions like resting membrane potential. Benefiting from the structural similarity to membrane-embedded ion channels, the ISM opens the door for ion-based neuromorphic computing and sophisticated chemical regulation by manipulating multifarious ions with neuromorphic functions.
The neural bases of the reach–grasp movement in humans: Quantitative evidence from brain lesions
Visually guided grasping is a fundamental building block of animal behavior, the specific neural mechanisms of which remain poorly documented in the human brain. We have mapped the causal contribution of different brain parts to grasping behavior by studying the kinematic parameters of 33 patients with brain tumors, engaged in actions directed toward objects of different sizes. Using motion capture techniques, we analyzed the dynamics of grip aperture and wrist transport. Voxel-based lesion-symptom mapping analysis was applied to correlate lesion volumes with specific behavioral deficits. Results showed that lesions in the anterior and lateral bank of the intraparietal sulcus produced impaired finger scaling related to object size. Conversely, impaired velocity of finger aperture was associated with lesions in the dorsal premotor cortex (PMd). Grip aperture deficits following dominant hemisphere lesions were bilateral and were unilateral when following nondominant hemisphere lesions. Impaired wrist transport during reaching was associated with lesions in the first segment of the superior longitudinal fasciculus. Our work highlights an architecture of the grasping network in humans, with unique species-specific features. We hypothesize a model of human neural architecture in which object geometry for hand preshaping is first coded in the left anterior intraparietal cortex and then shared with the right hemisphere. Execution of the motor program of hand preshaping is then performed by the PMd on the corresponding side.
Conformational free energy landscape of a glutamate transporter and microscopic details of its transport mechanism
Removing glutamate from the synaptic cleft is vital for proper function of the brain. Excitatory amino acid transporters mediate this process by uptaking the neurotransmitter from the synaptic cleft back to the cell after its release. The archaeal homolog, Glt Ph , an aspartate transporter from Pyrococcus horikoshii , presents the best structurally characterized model for this family of transporters. In order to transport, Glt Ph undergoes elevator-like conformational changes between inward-facing (IF) and outward-facing (OF) states. Here, we characterize, at an atomic level, the OF⇌IF transition of Glt Ph in different apo /bound states using a combination of ensemble-based enhanced sampling techniques, employing more than two thousand of coupled simulation replicas of membrane-embedded Glt Ph . The resulting free-energy profiles portray the transition of apo /bound states as a complex four-stage process, while sodium binding alone locks the structure in one of its states. Along the transition, the transport domain (TD) disengages from the scaffold domain (SD), allowing it to move as a piston sliding vertically with respect to the membrane during the elevator-like motion of TD. Lipid interactions with residues comprising the SD–TD interface directly influence the large-scale conformational changes and, consequently, the energetics of transport. Structural intermediates formed during the transition leak water molecules and may correlate to the uncoupled Cl − ion conductance observed experimentally in both prokaryotic and mammalian glutamate transporters. Mechanistic insights obtained from our study provide a structural framework for better development of therapeutic for neurological disorders.
Fluidization and anomalous density fluctuations in 2D Voronoi cell tissues with pulsating activity
Cells not only can be motile by crawling but are also capable of nonmotility active motions like periodic contraction or pulsation. In this work, based on a Voronoi cell model, we show how this nonmotility activity affects the structure, dynamic, and density fluctuations of cellular monolayers. Our model shows that random cell pulsation fluidizes solid epithelial tissues into a hyperuniform fluid state, while pulsation synchronization inhibits the fluidity and causes a reverse solidification. Our results indicate this solidification is a Berezinskii–Kosterlitz–Thouless-type transition, characterized by strong density/dynamic heterogeneity arising from the annihilation of topological defects in the pulsating phase space. The magnitude and length scale of density heterogeneity diverge with the pulsating period, resulting in an opposite giant density fluctuation or anti-hyperuniformity. We propose a fluctuating hydrodynamic theory that can unify the two opposite anomalous fluctuation phenomena. Our findings can help to understand recent experimental observations in Madin-Darby canine kidney monolayers.
Structural basis of SARS-CoV-2 polymerase inhibition by nonnucleoside inhibitor HeE1-2Tyr
Targeting the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 with small molecules is a promising therapeutic strategy against COVID-19, but potent and safe inhibitors are lacking. HeE1-2Tyr, a nonnucleoside inhibitor of Dengue virus RdRp, was also shown to inhibit SARS-CoV-2 RdRp in vitro and to have antiviral activity in cells, but the underlying mechanism remains unclear. Here, we elucidate the molecular mechanism of HeE1-2Tyr-mediated SARS-CoV-2 RdRp inhibition. Biochemical assays confirm that HeE1-2Tyr inhibits RdRp with an IC 50 of 5 µM and show that it competes with RNA binding to RdRp in vitro. Structural analysis using cryo-EM reveals that a stack of three HeE1-2Tyr molecules binds to the RNA binding site of RdRp. The identification of the conserved HeE1-2Tyr binding site and its intriguing inhibition mechanism of three stacked molecules that outcompete RNA may facilitate further development of pan-corona nonnucleoside inhibitors.
A horizontally transferred bacterial gene aids the freezing tolerance of Antarctic bdelloid rotifers
Bdelloid rotifers are well known for their abilities to survive long periods of freezing as well as acquire foreign genes. Recently sequenced genomes of some bdelloid rotifers in England were found to encode several proteins similar to ice-binding proteins (IBPs) that are usually associated with freeze–thaw tolerance. Here, I describe bdelloid rotifers inhabiting an algal patch in Antarctica that have multiple homologs of these genes. Structures of the proteins predicted by AlphaFold show that they are well designed for ice-binding and a recombinant protein made for one of them showed strong ice-binding activity. The existence of multiple copies of these proteins is another characteristic of IBPs. Furthermore, multiple bdelloid rotifers in the algal patch were revived in less than an hour after storage at −25 °C for 24 y, an apparent record for laboratory-controlled studies. Several characteristics of these genes point to bacteria as their source: sequence homology, absence of introns, and a structural peculiarity so far found only in bacteria. The remarkable freezing tolerance of bdelloid rotifers can thus be at least partially attributed to horizontally acquired bacterial genes encoding IBPs.
MUC5AC filaments illuminate the structural diversification of respiratory and intestinal mucins
Secreted mucins are multimegadalton glycoprotein polymers that share the function of protecting mucosal tissues but diversified for activities in different organs of the body. Structural studies of secreted mucins are complicated by the enormous sizes, flexibility, and complex supramolecular assembly modes of these glycoproteins. The two major respiratory mucins are MUC5AC and MUC5B. Here, we present structures of a large amino-terminal segment of MUC5AC in the form of helical filaments. These filaments differ from filamentous and tubular structures observed previously for the intestinal mucin MUC2 and the partial mucin homolog VWF. Nevertheless, the MUC5AC helical filaments support the proposed mechanism, based on MUC2 and VWF, for how noncovalent interactions between mucin monomers guide disulfide crosslinking to form polymers. The high-resolution MUC5AC structures show how local and limited changes in amino acid sequence can profoundly affect higher-order assembly while preserving the overall folds and polymerization activity of mucin glycoproteins. Differences in supramolecular assembly are likely to be functionally significant considering the divergence of mechanical properties and physiological requirements between respiratory and intestinal mucins. Determining the high-resolution structures of respiratory mucins provides a foundation for understanding the mechanisms by which they clean and protect the lungs. Moreover, the MUC5AC structure enables visualization of the sites of human amino acid sequence variation and disease-associated mutations.
The effect of salt additives on the glycine crystallization pathway revealed by studying one crystal nucleation at a time
Molecular-level understanding of the early stage of crystallization remains a significant challenge. For a wide range of fundamental research and applications, it is of great importance to understand the mechanism of crystal polymorph selections in different solvents or in the presence of additives. We studied glycine crystallization in aqueous solution with or without the addition of sodium chloride (NaCl), one crystal nucleation at a time, using the recently developed single-crystal nucleation spectroscopy (SCNS). It has been reported that glycine forms γ-glycine when salt is added to aqueous solution, and the mechanism has been considered as a classical nucleation where γ-glycine forms directly as a crystal nucleus. Our study shows that metastable polymorph β-glycine forms first in aqueous solution both with or without NaCl through a nonclassical nucleation pathway. NaCl can stabilize the metastable β-glycine over several hours and also prevent it from converting to α-glycine. Eventually γ-glycine nucleates on the surface of β-glycine and then grows while dissolving the mother β-glycine. The crystal habit of β-glycine suggests that the stabilization by NaCl occurs at its polar face. SCNS provides crucial information to accelerate the investigation of the early stage of crystallization toward the rational control of polymorphisms.
Hypercholesterolemia-induced LXR signaling in smooth muscle cells contributes to vascular lesion remodeling and visceral function
Vascular smooth muscle cells (VSMC) are the most abundant cell type in the artery’s media layer and regulate vascular tone and lesion remodeling during atherogenesis. Like monocyte-derived macrophages, VSMCs accumulate excess lipids and contribute to the total intimal foam cell population in human coronary plaques and mouse aortic atheroma. While there are extensive studies characterizing the contribution of lipid metabolism in macrophage immunometabolic responses in atherosclerotic plaques, the role of VSMC lipid metabolism in regulating vascular function and lesion remodeling in vivo remains poorly understood. Here, we report that the liver X receptor (LXR) signaling pathway in VSMC is continuously activated during atherogenesis. Notably, we found that LXR deficiency in SMCs under hypercholesterolemic conditions influenced lesion remodeling by altering the fate of dedifferentiated SMCs and promoting the accumulation of VSMC-derived transitional cells. This phenotypic switching was accompanied by reduced indices of plaque stability, characterized by a larger necrotic core area and reduced fibrous cap thickness. Moreover, SMC-specific LXR deficiency impaired vascular function and caused visceral myopathy characterized by maladaptive bladder remodeling and gut lipid malabsorption. Mechanistically, we found that the expression of several genes involved in cholesterol efflux and FA synthesis including Abca1 , Srebf1 , Scd1 , Scd2 , Acsl3, and Mid1ip1 was downregulated in mice lacking LXRαβ in SMCs, likely contributing to the phenotypic switching of VSMC in the atherosclerotic lesions.
Urban highways are barriers to social ties
Urban highways are common, especially in the United States, making cities more car-centric. They promise the annihilation of distance but obstruct pedestrian mobility, thus playing a key role in limiting social interactions locally. Although this limiting role is widely acknowledged in urban studies, the quantitative relationship between urban highways and social ties is barely tested. Here, we define a Barrier Score that relates massive, geolocated online social network data to highways in the 50 largest US cities. At the granularity of individual social ties, we show that urban highways are associated with decreased social connectivity. This barrier effect is especially strong for short distances and consistent with historical cases of highways that were built to purposefully disrupt or isolate Black neighborhoods. By combining spatial infrastructure with social tie data, our method adds a dimension to demographic studies of social segregation. Our study can inform reparative planning for an evidence-based reduction of spatial inequality, and more generally, support a better integration of the social fabric in urban planning.
S-nitrosylation-triggered secretion of mycobacterial PknG leads to phosphorylation of SODD to prevent apoptosis of infected macrophages
The tuberculosis-causing agent Mycobacterium tuberculosis (M.tb) establishes its niche inside macrophages by secretion of several virulence factors and engaging many host factors. Mycobacterial infection of macrophages results in a proinflammatory trigger–mediated secretion of TNFα. Protein kinase G (PknG), a Serine/Threonine kinase, is essential for mycobacterial survival within the macrophage. Pathogenic mycobacteria, upon infection, can trigger the secretion of proinflammatory cytokine TNFα, but whether secreted PknG plays any role in TNFα secretion at early stages of infection remains undeciphered. Moreover, at early infection stages, prevention of macrophage apoptosis is vital to successful mycobacterial pathogenesis. Our studies show that mycobacteria-secreted PknG can dampen the expression and concomitant secretion of proinflammatory TNFα. During early infection, M.tb infection–induced generation of reactive nitrogen intermediates (RNI) leads to S-nitrosylation of PknG on Cys109, thereby enabling its secretion into macrophages. Upon M.tb infection, secreted S-nitrosylated PknG phosphorylates macrophage Silencer of Death Domains (SODD) at Thr405, as identified through our phosphoproteomic studies. Thereafter, phosphorylated SODD, through an irreversible binding with the TNFR1 death domain, prevents Caspase8 activation and concomitant extrinsic apoptotic trigger. Moreover, alveolar macrophages from mice infected with PknG-knockout M.tb also exhibited SODD phosphorylation and hindered Caspase8 activation to prevent extrinsic macrophage apoptosis. Therefore, this work exhibits S-nitrosylation-mediated secretion of PknG to induce phosphorylation of macrophage SODD, which, through irreversible interaction with TNFR1, prevented extrinsic macrophage apoptosis at the early stages of infection.
Structural basis of DNA replication fidelity of the Mpox virus
The Mpox virus (MPXV) is an orthopoxvirus that caused a global outbreak in 2022. The poxvirus DNA polymerase complex is responsible for the replication and integrity of the viral genome; however, the molecular mechanisms underlying DNA replication fidelity are still unclear. In this study, we determined the cryoelectron microscopy (cryo-EM) structures of the MPXV F8–A22–E4 polymerase holoenzyme in its editing state, in complex with mismatched primer–template DNA and DNA containing uracil deoxynucleotide. We showed that the MPXV polymerase has a similar replication-to-edit transition mechanism to proofread the mismatched nucleotides like the B-family DNA polymerases of other species. The unique processivity cofactor A22–E4 undergoes conformational changes in different working states and might affect the proofreading process. Moreover, we elucidated the base excision repair (BER) function of E4 as a uracil-DNA glycosylase and the coupling mechanism of genome replication and BER, characteristic of poxviruses. Our findings greatly enhance our molecular understanding of DNA replication fidelity of orthopoxviruses and will stimulate the development of broad-spectrum antiviral drugs.
The mechanism of electrical conduction in glassy semiconductors
We argue that the dominant charge carrier in glassy semiconducting alloys is a compound particle in the form of an electron or hole bound to an intimate pair of topological lattice defects; the particle is similar to the polaron solution of the Su–Schrieffer–Heeger Hamiltonian. The spatial component of the density of states for these special polarons is determined by the length scale of spatial modulation of electronegativity caused by a separate set of standalone topological defects. The latter length scale is fixed by the cooperativity size for structural relaxation; the size is largely independent of temperature in the glass but above melting, it decreases with temperature. Thus we predict that the temperature dependence of the electrical conductivity should exhibit a jump in the slope near the glass transition; the size of the jump is predicted to increase with the fragility of the melt. The predicted values of the jump and of the conductivity itself are consistent with experiment.
Logic-based machine learning predicts how escitalopram attenuates cardiomyocyte hypertrophy
Cardiomyocyte hypertrophy is a key clinical predictor of heart failure. High-throughput and AI-driven screens have the potential to identify drugs and downstream pathways that modulate cardiomyocyte hypertrophy. Here, we developed LogiRx, a logic-based mechanistic machine learning method that predicts drug-induced pathways. We applied LogiRx to discover how drugs discovered in a previous compound screen attenuate cardiomyocyte hypertrophy. We experimentally validated LogiRx predictions in neonatal cardiomyocytes, adult mice, and two patient databases. Using LogiRx, we predicted antihypertrophic pathways for seven drugs currently used to treat noncardiac disease. We experimentally validated that escitalopram (Lexapro) and mifepristone inhibit hypertrophy of cultured cardiomyocytes in two contexts. The LogiRx model predicted that escitalopram prevents hypertrophy through an “off-target” serotonin receptor/PI3Kγ pathway, mechanistically validated using additional investigational drugs. Further, escitalopram reduced cardiomyocyte hypertrophy in a mouse model of hypertrophy and fibrosis. Finally, mining of both FDA and University of Virginia databases showed that patients with depression on escitalopram have a lower incidence of cardiac hypertrophy than those prescribed other serotonin reuptake inhibitors that do not target the serotonin receptor. Mechanistic machine learning by LogiRx discovers drug pathways that perturb cell states, which may enable repurposing of escitalopram and other drugs to limit cardiac remodeling through off-target pathways.
On the shape of air bubbles trapped in ice
Water usually contains dissolved gases, and because freezing is a purifying process these gases must be expelled for ice to form. Bubbles appear at the freezing front and are then trapped in ice, making pores. These pores come in a range of sizes from microns to millimeters and their shapes are peculiar; never spherical but elongated, and usually fore-aft asymmetric. We show that these remarkable shapes result of a delicate balance between freezing, capillarity, and mass diffusion. A nonlinear ordinary differential equation suffices to describe the bubbles, which features two nondimensional numbers representing the supersaturation and the freezing rate, and two additional parameters representing simultaneous freezing and nucleation treated as the initial condition. Our experiments provide us with a large variety of pictures of bubble shapes. We show that all of these bubbles have their rounded tip well described by an asymptotic regime of the differential equation and that most bubbles can have their full shape quantitatively matched by a full solution. This method enables the measurement of the freezing conditions of ice samples, and the design of freeze-cast porous materials. Furthermore, the equation exhibits a bifurcation that explains why some bubbles grow indefinitely and make long cylindrical “ice worms,” well known to glaciologists.
Effects of binding partners on thermal reversion rates of photoswitchable molecules
The binding of photoswitchable molecules to partners forms the basis of many naturally occurring light-dependent signaling pathways and various photopharmacological and optogenetic tools. A critical parameter affecting the function of these molecules is the thermal half-life of the light state. Reports in the literature indicate that, in some cases, a binding partner can significantly influence the thermal half-life, while in other cases it has no effect. Here, we present a unifying framework for quantitatively analyzing the effects of binding partners on thermal reversion rates. We focus on photoswitchable protein/binder interactions involving LOV domains, photoactive yellow protein, and CBCR GAF domains with partners that bind either the light or the dark state of the photoswitchable domain. We show that the effect of a binding partner depends on the extent to which the transition state for reversion resembles the dark state or the light state. We quantify this resemblance with a ϕ switching value, where ϕ switching = 1 if the conformation of the part of the photoswitchable molecule that interacts with the binding partner closely resembles its dark state conformation and ϕ switching = 0 if it resembles its light state. In addition to providing information on the transition state for switching, this analysis can guide the design of photoswitchable systems that retain useful thermal half-lives in practice. The analysis also provides a basis for the use of simple kinetic measurements to determine effective changes in affinity even in complex milieu.
Environmental justice beyond race: Skin tone and exposure to air pollution
Recent research, focused mostly on the United States and Western Europe, shows that marginalized communities often face greater environmental degradation. However, the ethnoracial categories used in these studies may not fully capture environmental inequality in the Global South. Moving beyond conventional ethnoracial variables, this study presents findings exploring the link between skin tone and fine particulate matter (PM 2.5 ) exposure in Colombia. By matching household geolocations from a large-scale longitudinal survey with satellite-based PM 2.5 estimates, we find that skin tone predicts both initial pollution exposure levels and their changes over time. Although average exposure levels remained stable during our study period, the environmental justice (EJ) landscape in Colombia contemporaneously underwent a complete transformation. In 2010, lighter-skinned individuals faced higher PM 2.5 exposure, but darker-skinned individuals experienced steeper increases in the following years. By 2016, the EJ gap had reversed, with people with the darkest skin tones exposed to PM 2.5 levels nearly one SD higher than those faced by people with the lightest skin tones. These patterns remain robust when controlling for a comprehensive set of theoretically relevant covariates, including ethnoracial self-identification and income. Disproportionate exposure to pollution from fires partially explains the observed disparities. Decomposition analysis shows that this variable, local collective action, and economic marginalization account for a sizeable share of the EJ gap. However, one-third of the gap remains unexplained by observable characteristics. With climate change intensifying fire incidence, the disproportionate disease burdens that vulnerable groups face might deepen unless policy measures are taken to reverse this trend.
Decoding planetary surfaces by counting cracks
Planets are often covered with thin cracked shells. From mud films to lithospheres of rock or ice, fracture networks form two-dimensional (2D) tessellations of convex polygons whose geometry encodes their genesis. Here, we chart the geometry of 2D fracture mosaics across the solar system, and decode their formative conditions using a new dynamical crack model. We show that mosaics can be projected onto a Symbolic Ternary Diagram, where the relative proportions of “T,” “X,” and “Y” junctions are uniquely related to contributions from distinct modes of fracture. Most planetary mosaics cluster in a region associated with hierarchical fracture networks, where sequential cracking favors formation of T junctions. Exceptions to this rule may betray the presence of water. Europa’s fracture networks stand apart due to the predominance of X junctions; this is a special feature of ice, where healing of cracks by refreezing of water allows new fractures to overprint older ones. Several fracture networks on Mars appear as outliers due to the high proportion of Y junctions. These patterns—previously interpreted as ancient mudcracks and frozen polar terrain, based on geological evidence—are consistent with the twisting of crack junctions by cyclic volume change. Our findings suggest that counting cracks could aid in the identification of other water-influenced planetary environments.
Prodrug activation in malaria parasites mediated by an imported erythrocyte esterase, acylpeptide hydrolase (APEH)
The continued emergence of antimalarial drug resistance highlights the need to develop new antimalarial therapies. Unfortunately, new drug development is often hampered by undesirable drug-like properties of lead compounds. Prodrug approaches temporarily mask undesirable compound features, improving bioavailability and target penetration. We have found that lipophilic diester prodrugs of phosphonic acid antibiotics, such as fosmidomycin (Fsm), exhibit significantly higher antimalarial potency than their parent compounds [R.L. Edwards et al. , Sci. Rep. 7 , 8400 (2017)]. However, the activating enzymes for these prodrugs were unknown. Here, we show that an erythrocyte enzyme, acylpeptide hydrolase (APEH), is the major activating enzyme of multiple lipophilic ester prodrugs. Surprisingly, this enzyme is taken up by the malaria parasite, Plasmodium falciparum , where it localizes to the parasite cytoplasm and retains enzymatic activity. Using a fluorogenic ester library, we characterize the structure–activity relationship of APEH and compare it to that of P. falciparum esterases. We show that parasite-internalized APEH plays an important role in the activation of substrates with branching at the alpha carbon, in keeping with its exopeptidase activity. Our findings highlight a mechanism for antimicrobial prodrug activation, relying on a host-derived enzyme to yield activation at a microbial target. Mutations in prodrug-activating enzymes are a common mechanism for antimicrobial drug resistance [E. S. Istvan et al. , Nat. Commun. 8 , 14240 (2017); K. M. V. Sindhe et al. , mBio 11 , e02640-19 (2020); J. H. Butler et al. , Acs Infect Dis. 6 , 2994–3003 (2020)]. Leveraging an internalized host enzyme would circumvent this, enabling the design of prodrugs with higher barriers to drug resistance.