Biology subjects

Takahashi, Y.

Publications and source records attributed to Takahashi, Y..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Carotenoid pigments enhance rhodopsin-mediated phototrophy by light-harvesting and photocycle-accelerating

Microbial rhodopsins, photoreceptor proteins widely distributed in marine microorganisms, receive large amount of light energy that sustains marine ecosystems. Although rhodopsins generally harbor retinal as their only chromophore, a recent study reported that carotenoid antennae transfer light energy to the retinal in proteorhodopsins, proton pump rhodopsins abundant in marine environments. Here, using marine bacterial isolates, we detected energy transfer from a carotenoid (myxol) to retinal not only in proteorhodopsin but also in the chloride ion-pumping rhodopsin. Carotenoid binding improved the light utilization efficiency of the proteorhodopsin by accelerating the photocycle, together with facilitating light-harvesting. The carotenoid-binding ability is conserved in rhodopsins of the phylum Bacteroidota, which are widely transcribed in the photic zone. These findings suggest that the distribution of carotenoid-binding rhodopsins is more taxon-specific than previously thought, thus underscoring the importance of carotenoid-binding rhodopsins that provide an extended light utilization strategy in the environmental adaptation of marine bacteria.

microbiology↗

bioRxiv2024

Zero-echo time imaging achieves whole brain activity mapping without ventral signal loss in mice

Functional MRI (fMRI) is an important tool for investigating functional networks. However, the widely used fMRI with T2*-weighted imaging in rodents has the problem of signal lack in the lateral ventral area of forebrain including the amygdala, which is essential for not only emotion but also noxious pain. Here, we scouted the zero-echo time (ZTE) sequence, which is robust to magnetic susceptibility and motion-derived artifacts, to image activation in the whole brain including the amygdala following the noxious stimulation to the hind paw. ZTE exhibited higher spatial and temporal signal-to-noise ratios than conventional fMRI sequences. Electrical sensory stimulation of the hind paw evoked ZTE signal increase in the primary somatosensory cortex. Formalin injection into the hind paw evoked early and latent change of ZTE signals throughout the whole brain including the subregions of amygdala. Furthermore, resting-state fMRI using ZTE demonstrated the functional connectivity, including that of the amygdala. These results indicate the feasibility of ZTE for whole brain fMRI, including the amygdala and we first show acute and latent activity in different subnuclei of the amygdala complex after nociceptive stimulation. Significance statementFunctional MRI (fMRI) is an important tool for investigating functional networks. However, the widely used fMRI in rodents has the problem of signal lack in the lateral ventral area of forebrain including the amygdala, which is essential for not only emotion but also noxious pain. Here, we used zero-echo time (ZTE) sequence, which was robust to susceptibility artifacts, for functional imaging in the whole brain including amygdala. We demonstrated the feasibility and advantages of using ZTE to investigate neuronal activity in mice. Furthermore, we first showed acute and latent activation in different subnuclei of the amygdala complex as well as other regions related to pain after nociceptive stimulation in mice.

neuroscience↗

bioRxiv2024

From Monomers to Oligomers: Structural Mechanism of Receptor-Triggered MyD88 Assembly in Innate Immune Signaling

MyD88 plays a pivotal role in Toll-like receptor (TLR) and interleukin-1 family signaling through its oligomerization upon receptor activation, leading to downstream protein recruitment. The Toll/interleukin-1 receptor domain of MyD88 (TIRMyD88) is responsible for this receptor-mediated oligomerization, but the detailed mechanism involved remains elusive. We investigated the structure of TIRMyD88 oligomers and their interactions with TLRs. Cryoelectron microscopy revealed that tandemly arrayed TIRMyD88 subunits formed an antiparallel double-stranded filament that could further form rings and cylindrical filaments. Moreover, the self-assembly of TIRMyD88 in vitro was markedly accelerated by dimeric rather than monomeric receptor TIRs, possibly reflecting the signal initiation step in vivo. High-speed atomic force microscopy further captured the dynamic processes of oligomerization of TIRMyD88, in addition to its direct interaction with the receptor TIRs. Based on these results, a novel regulatory mechanism of TIRMyD88 oligomerization underlying the signal initiation step was revealed.

biophysics↗

bioRxiv2024

Conserved variation across scales unveils dialectical relationships of micro- and macroevolution

Variation enables short-term evolution (microevolution), but its role in long-term evolution (macroevolution) is debated. Here, we analyzed a dataset of Drosophila wing variation across six levels of biological organization to demonstrate that microevolutionary variation and macroevolutionary divergence are positively correlated at all levels from variation within an individual to 40 million years of macroevolution. Surprisingly, the strongest relationship was between developmental noise and macroevolutionary divergence--levels thought to be the most distant--whereas the relationship between standing genetic variation and population divergence was modest, despite established theoretical predictions. Our results indicate that the congruence of developmental system with long-term history of fluctuation in adaptive peaks creates dialectical relationships between microevolution and macroevolution.

evolutionary biology↗

bioRxiv2024

Modeling statin-induced myopathy with human iPSCs reveals that impaired proteostasis underlies the myotoxicity and is targetable for the prevention

Statins, HMG-CoA reductase inhibitors, have been widely prescribed to lower circulating low-density lipoprotein cholesterol levels and reduce the risk of cardiovascular disease. Although statins are well tolerated, statin-associated muscle symptoms (SAMS) are the major adverse effect and cause statin intolerance. Therefore, understanding the molecular mechanisms of SAMS and identifying effective strategies for its prevention are of significant clinical importance; however, both remain unclear. Here we establish a model of statin-induced myopathy (SIM) with human induced pluripotent stem cell (hiPSC)-derived myocytes (iPSC-MCs) and investigate the effect of statins on protein homeostasis (proteostasis) that affects skeletal muscle wasting and myotoxicity. We show that treating hiPSC-MCs with statins induces atrophic phenotype and myotoxicity, establishing a hiPSC-based SIM model. We then examine whether statins impair the balance between protein synthesis and degradation. The results show that statins not only suppress protein synthesis but also promote protein degradation by upregulating the expression of the muscle-specific E3 ubiquitin ligase Atrogin-1 in a mevalonate pathway-dependent manner. Mechanistically, blocking the mevalonate pathway inactivates the protein kinase Akt, leading to the inhibition of mTORC1 and GSK3{beta} but the activation of FOXO1. These changes explain the statin-induced impairment in proteostasis. Finally, we show that pharmacological blockage of FOXO1 prevents SIM in hiPSC-MCs, implicating FOXO1 as a key mediator of SIM. Taken together, this study suggests that the mevalonate pathway is critical for maintaining skeletal muscle proteostasis and identifies FOXO1 as a potential target for preventing SIM.

pharmacology and toxicology↗

bioRxiv2024

Genetic heterogeneity induces nonadditive behavioural changes in Drosophila

The formation and dynamics of group behaviours are important topics in ecology and evolution. Although several theoretical studies assume homogeneity among individuals, real-world organisms often display remarkable behavioural diversity within groups. This study investigated the synergistic impact of genetic heterogeneity on group behaviour and reveals the behavioural underpinnings of diversity effects using 83 genetically distinct strains of Drosophila melanogaster. Various indices of foraging behaviour, including movement speed, search comprehensiveness, spatial preference and stopping time, were measured using homogeneous (single strain) and heterogeneous (mixing two distinct strains) groups of flies. The heterogeneous groups exhibited significant increases in spatial preference and stopping time compared with the homogeneous groups, suggesting that genetic heterogeneity induces nonadditive changes in group behaviour. Furthermore, the magnitude and direction of the behavioural change varied among different combinations. Multiple regression analysis showed that the phenotypic distance in some traits between mixed strains could explain the emergence of diversity effects on group behaviour. Specifically, interindividual heterogeneity in the locomotor activity level showed a positive correlation with diversity effects. These results emphasise the importance of intraspecific diversity in group dynamics and suggest that genetic heterogeneity can improve group performance through the acquisition of novel behavioural traits.

animal behavior and cognition↗

bioRxiv2024

Digital Twin Brain Simulator: Harnessing Primate ECoG Data for Real-Time Consciousness Monitoring and Virtual Intervention

At the forefront of bridging computational brain modeling with personalized medicine, this study introduces a novel, real-time, electrocorticogram (ECoG) simulator based on the digital twin brain concept. Utilizing advanced data assimilation techniques, specifically a Variational Bayesian Recurrent Neural Network model with hierarchical latent units, the simulator dynamically predicts ECoG signals reflecting real-time brain latent states. By assimilating broad ECoG signals from Macaque monkeys across awake and anesthetized conditions, the model successfully updated its latent states in real-time, enhancing the precision of ECoG signal simulations. Behind the successful data assimilation, a self-organization of latent states in the model was observed, reflecting brain states and individuality. This self-organization facilitated simulation of virtual drug administration and uncovered functional networks underlying changes in brain function during anesthesia. These results show that the proposed model is not only capable of simulating brain signals in real-time with high accuracy, but is also useful for revealing underlying information processing dynamics.

neuroscience↗

bioRxiv2024

Discovery and characterization of stereodefined PMO-gapmers targeting tau

Antisense oligonucleotides (ASOs) are an important class of therapeutics to treat genetic diseases, and expansion of this modality to neurodegenerative disorders has been an active area of research. To realize chronic administration of ASO therapeutics to treat neurogenerative diseases, new chemical modifications improving activity and safety profile are still needed. Furthermore, it is highly desirable to develop a single stereopure ASO with defined activity and safety profile to avoid any efficacy and safety concerns due to the batch-to-batch variation in the composition of diastereomers. Herein, a stereopure PMO-gapmer was developed as a new construct to improve safety and stability by installing charge-neutral PMOs at the wing region and by fully controlling phosphorus stereochemistries. The developed stereopure PMO-gapmer construct was applied to the discovery of ASO candidates for the reduction of microtubule-associated protein tau (MAPT, tau). Sequence screening targeting MAPT followed by screening of optimal phosphorus stereochemistry identified stereopure development candidates. While evaluating the stereopure PMO-gapmers, we observed a dramatic difference in safety profile among stereoisomers in which only one phosphorus stereochemistry differs. These results further highlight the benefits of developing stereopure ASOs as safe and well-characterized candidates for clinical studies.

neuroscience↗

bioRxiv2024

Systematic Discovery of Phage Genes that Inactivate Bacterial Immune Systems

Bacteria have developed numerous defense systems to counter phage infections. However, the extent to which phages possess countermeasures against these defense systems remains unclear. In this study, we combined a phage gene knockout library with a defense system library to analyze the mechanisms by which phages counteract bacterial defense systems. After attempting gene deletions of 105 open reading frames (ORFs) in the DruSM1 phage ({Phi}DruSM1), we successfully generated 73 different ORF knockout phages. By infecting this library with bacteria harboring defense system expression plasmids, we identified inactivators of Druantia type I (Druad1), Brex type I, AVAST type III, Sir2+HerA, DUF4297+HerA, and hhe, as well as an activator of Retron Ec86, in a single phage genome. Synthetic phages incorporating Druad1 effectively eradicated Escherichia coli harboring the robust Druantia type I defense system by altering DNA methylation at m6A sites of the phage. This study highlighted the prevalence of various antidefense mechanisms employed by phages to overcome bacterial defense systems.

microbiology↗

bioRxiv2024

Diurnal regulation of SOS Pathway and Sodium Excretion Underlying Salinity Tolerance of Vigna marina

Vigna marina (Barm.) Merr. is adapted to tropical marine beaches and has an outstanding tolerance to salt stress. Given there are growing demands for cultivating crops in saline soil or with saline water, it is important to understand how halophytic species are adapted to the saline environments. Here we revealed by positron emitting tracer imaging system (PETIS) that V. marina actively excretes sodium from the root during the light period but not in the dark period. The following whole genome sequencing accompanied with forward genetic study identified a QTL region harboring SOS1, encoding plasma membrane Na+/H+ antiporter, which was associated with not only salt tolerance but also ability of sodium excretion. We also found the QTL region contained a large structural rearrangement that suppressed recombination across [~]20 Mbp, fixing multiple gene loci potentially involved in salt tolerance. RNA-seq and promoter analyses revealed SOS1 in V. marina was highly expressed even without salt stress and its promoter shared common cis-regulatory motifs with those exhibiting similar expression profile. Interestingly, the cis-regulatory motifs seemed installed by a transposable element (TE) insertion. Though not identified by genetic analysis, the transcriptome data also revealed SOS2 transcription was under diurnal regulation, explaining the pattern of sodium excretion together with up-regulated expression of SOS1. Furthermore, we demonstrated that, under a condition of mild salt stress, the plants with the diurnally regulated SOS pathway outperformed those with the constitutively activated one.

plant biology↗

bioRxiv2024

The minimal SUF system can substitute for the canonical iron-sulfur cluster biosynthesis systems by using inorganic sulfide as the sulfur source.

Biosynthesis of iron-sulfur (Fe-S) clusters is indispensable for living cells. Three biosynthesis systems termed NIF, ISC and SUF have been extensively characterized in both bacteria and eukarya. For these L-cysteine is the sulfur source. A bioinformatic survey suggested the presence of a minimal SUF system composed of only two components, SufB* (a putative ancestral form of SufB and SufD) and SufC, in anaerobic archaea and bacteria. Here, we report the successful complementation of an Escherichia coli mutant devoid of the usual ISC and SUF systems upon expression of the archaeal sufB*C genes. Strikingly, this heterologous complementation occurred under anaerobic conditions only when sulfide was supplemented to the culture media. Mutational analysis and structural predictions suggest that the archaeal SufB*C most likely forms a SufB*2C2 complex and serves as the scaffold for de novo Fe-S cluster assembly using the essential Cys and Glu residues conserved between SufB* and SufB, in conjunction with a His residue shared between SufB* and SufD. We also demonstrate artificial conversion of the SufB*2C2 structure to the SufBC2D type by introducing several mutations to the two copies of sufB*. Our study thus elucidates the molecular function of this minimal SUF system and suggests that it is the evolutionary prototype of the canonical SUF system.

microbiology↗

bioRxiv2024

Neurogenomic diversity enhances collective antipredator performance in Drosophila

Collective behavior is a unique social behavior that plays crucial roles in detecting and avoiding predators. Despite a long history of research on the ecological significance, its neural and genetic underpinnings remain elusive. Here we focus on the mesmerizing nature that visual cues from surrounding conspecifics alleviate the fear response to threatening stimuli in Drosophila melanogaster. A large-scale behavioral experiment and genome-wide association analysis utilizing 104 strains with known genomes uncovered the genetic foundation of the emergent behavioral properties of flies. We found genes involved in visual neuron development associated with visual response to conspecifics, and the functional assay confirmed the regulatory significance of lamina neurons. Furthermore, behavioral synchronization combined with interindividual heterogeneity in freezing drove nonadditive, synergistic changes in group performance for predatory avoidance. Our novel approach termed genome-wide higher-level association study (GHAS) identified loci whose within-group genetic diversity potentially contributes to such an emergent effect. Population genetic analysis revealed that selective pressure may favor increased responsiveness to conspecifics, indicating that by-productive genomic diversity within the group leads to a collective phenomenon. This work opens up a new avenue to understand the genomics underpinning the group-level phenotypes and offers an evolutionary perspective on the mechanism of collective behavior.

animal behavior and cognition↗

bioRxiv2024

The gut contractile organoid: a novel model for studying the gut motility regulated by coordinating signals between interstitial cells of Cajal and smooth muscles

The gut undergoes peristaltic movements regulated by intricate cellular interactions. How these interactions emerge in the developing gut remains poorly explored due to a lack of model system. We here developed a novel contractile organoid that is derived from the muscle layer of chicken embryonic hindgut. The organoid contained smooth muscle cells (SMCs) and interstitial cells of Cajal (ICCs; pacemaker) with few enteric neurons, and underwent periodic contractions. The organoid was formed by self-organization with morphological arrangements of ICCs (internal) and SMCs (peripheral), allowing identification of these cells in live. GCaMP-Ca2+ imaging analyses revealed that Ca2+ transients between ICC-ICC, SMC-SMC or SMC-ICC were markedly coordinated. Pharmacological studies further suggested a role of gap junctions in ICC-to-SMC signaling, and also possible mechanical feedback from SMCs contraction to ICCs pace-making activities. In addition, two organoids with different rhythm became synchronized when mediated by SMCs, unveiling a novel contribution of SMCs to ICCs pace-making. The gut contractile organoid developed in this study offers a useful model to understand how the rhythm coordination between/among ICCs and SMCs is regulated and maintained during gut development.

developmental biology↗

bioRxiv2024

Effect of phage variation on Shiga toxin 2 (Stx2) production and the virulence of Stx-producing Escherichia coli

Shiga toxin (Stx)-producing Escherichia coli (STEC) causes serious gastrointestinal illness, including hemorrhagic colitis and hemolytic uremic syndrome. Although all known Stxs (Stx1 and Stx2) are encoded by bacteriophages (Stx phages), the production of Stx2 is known to be a major risk factor for severe STEC infections. The production of Stx2, but not Stx1, is tightly coupled with the induction of Stx phages, and Stx2 production levels vary between STEC strains, even within the same serotype. Here, we analyzed the genomic diversity of all Stx phages in 71 strains representing the entire O145:H28 lineage, one of the major STECs. Our analysis revealed the highly dynamic nature of the Stx phages in O145:H28, including the independent acquisition of similar Stx phages by different sublineages and the frequent changes in Stx phages in the same sublineages due to the gain and loss of Stx phages. Analyses of Stx2 production levels in O145:H28 strains and K-12 lysogens of Stx2 phages of specific groups and types, which were defined by their early region sequences and CI repressors, respectively, revealed that short-tailed Stx2a phages (S-Stx2a phages) confer significantly greater Stx2 production to host strains than long-tailed Stx2a phages (L-Stx2a phages). However, L-Stx2a phages that encode a specific type of CI repressor promoted Stx2 production, comparable to the level of production among S-Stx2a phages, as well as promoted virulence to host strains, exceeding the level among other L-Stx2a phages. We also showed a clear link between the phage induction efficiency, which was primarily determined by the early region of each phage, and the level of Stx2 production by host strains. These results provide important insights into the diversification and dynamism of Stx phages and the relationship between the variations in Stx2 phages and the amount of Stx2 production by their host strains. Author summaryShiga toxin (Stx)-producing Escherichia coli (STEC) is an important human intestinal pathogen that causes severe illnesses. These bacteria produce Stx1, Stx2 or both toxins, but the production of Stx2 is an important measure of the virulence of STEC strains. While both types of Stx are encoded by bacteriophages (Stx phages), Stx2 production is tightly coupled with phage induction, and variations in Stx2 phages have been associated with variations in Stx2 production levels by their host O157:H7 STEC strains. However, in non-O157 STEC strains, the variation in Stx phages and its association with host strain production of Stx2 have not yet been fully analyzed. This systematic study of Stx phages in O145:H28 STEC reveals not only the marked genomic diversity and dynamism of Stx phages in this STEC lineage but also that short-tailed Stx2 phages and a specific group of long-tailed Stx2 phages induce high levels of Stx2 production by host strains, and this increased production is linked to the efficient induction of phages.

microbiology↗

bioRxiv2024

Comparative analyses of adsorbed circulating proteins in the PMMA and PES hemodiafilters in patients on predilution online hemodiafiltration

Acute and chronic inflammation are common in patients with end-stage kidney disease (ESKD). So, the adsorption of pro-inflammatory cytokines by the hollow fiber has been expected to modify the inflammatory dysregulation in ESKD patients. However, it remains to be determined in detail what molecules of fiber materials can preferably adsorb proteins from the circulating circuit. We aimed this study to analyze directly the adsorbed proteins in the polymethyl methacrylate (PMMA) and polyethersulfone (PES) membranes in patients on predilution online hemodiafiltration (OL-HDF). To compare the adsorbed proteins in the PMMA and PES hemodiafilters membrane, we initially performed predilution OL-HDF using the PES (MFX-25Seco) membrane while then switched to the PMMA (PMF-A) membrane under the same condition in three patients. We extracted proteins from the collected hemodiafilters by extraction, then SDS-PAGE of the extracted sample, protein isolation, in-gel tryptic digestion, and nano-LC MS/MS analyses. The concentrations of adsorbed proteins from the PMMA and PES membrane extracts were 35.6{+/-}7.9 {micro}g/{micro}L and 26.1{+/-}9.2 {micro}g/{micro}L. SDS-PAGE analysis revealed distinct variations of adsorbed proteins mainly in the molecular weight between 10 to 25 kDa. By tryptic gel digestion and mass spectrometric analysis, the PMMA membrane exhibited higher adsorptions of {beta}2 microglobulin, dermcidin, retinol-binding protein-4, and lambda-1 light chain than those from the PES membrane. In contrast, amyloid A-1 protein was adsorbed more potently in the PES membrane. Western blot analyses revealed that the PMMA membrane adsorbed interleukin-6 (IL-6) approximately 5 to 118 times compared to the PES membrane. These findings suggest that PMMA-based OL-HDF therapy may be useful in controlling inflammatory status in ESKD patients.

pathology↗

bioRxiv2024

Most axonal mitochondria in cortical pyramidal neuronslack mitochondrial DNA and consume ATP

In neurons of the mammalian central nervous system (CNS), axonal mitochondria are thought to be indispensable for supplying ATP during energy-consuming processes such as neurotransmitter release. We have previously shown that glutamatergic excitatory cortical pyramidal neurons (CPNs) are characterized by a striking compartmentalization of mitochondrial structure. Axonal mitochondria are maintained at a small uniform size ([~]1 microns length) by high levels of MFF-dependent fission, whereas dendritic mitochondria form a highly fused network of mitochondria throughout the entire dendritic arbor(1, 2). Here, we tested whether these striking structural differences reflect functional and molecular compartmentalization. Using four independent techniques, we reveal that in CPNs as well as in two subtypes of GABAergic inhibitory cortical interneurons and neuromodulatory dopaminergic neurons of the substantia nigra, the majority of axonal, but not dendritic, mitochondria lack mitochondrial DNA (mtDNA) in vivo. We also show that axonal mitochondria are depleted in both mtDNA-encoded mRNAs and proteins compared to dendritic mitochondria. Timelapse imaging establishes that most mitochondria entering nascent dendritic and axonal processes from the soma are small and lack mtDNA. Using dynamic, optical imaging of genetically encoded sensors for ATP and pH targeted to the mitochondrial matrix, we demonstrate that in axons of CPNs, but not in their dendrites, mitochondrial F1F0-ATP synthase (Complex V) functions in a reverse way, hydrolyzing ATP and extruding H+ out of the matrix to maintain mitochondrial membrane potential. Our results indicate that in neurons of the mammalian CNS, the majority of axonal mitochondria lack mtDNA and likely do not play a major role in ATP generation, despite playing other functions such as regulation of neurotransmission via presynaptic Ca2+ buffering(1, 3-5).

neuroscience↗

bioRxiv2023

A broad antibody class engages the influenza virus hemagglutinin head at its stem interface

Influenza infection and vaccination impart strain-specific immunity that protects against neither seasonal antigenic variants nor the next pandemic. However, antibodies directed to conserved sites can confer broad protection. Here we identify and characterize a class of human antibodies that engage a previously undescribed, conserved epitope on the influenza hemagglutinin (HA) protein. Prototype antibody S8V1-157 binds at the normally occluded interface between the HA head and stem. Antibodies to this HA head-stem interface epitope are non-neutralizing in vitro but protect against lethal influenza infection in mice. Antibody isotypes that direct clearance of infected cells enhance this protection. Head-stem interface antibodies bind to most influenza A serotypes and seasonal human variants, and are present at low frequencies in the memory B cell populations of multiple human donors. Vaccines designed to elicit these antibodies might contribute to "universal" influenza immunity.

microbiology↗

bioRxiv2023

Overcoming antibody-resistant SARS-CoV-2 variants with bispecific antibodies constructed using non-neutralizing antibodies

A current challenge is the emergence of SARS-CoV-2 variants, such as BQ.1.1 and XBB.1.5, that can evade immune defenses, thereby limiting antibody drug effectiveness. Emergency-use antibody drugs, including the widely effective bebtelovimab, are losing their benefits. One potential approach to address this issue are bispecific antibodies which combine the targeting abilities of two antibodies with distinct epitopes. We engineered neutralizing bispecific antibodies in the IgG-scFv format from two initially non-neutralizing antibodies, CvMab-6 (which binds to the receptor-binding domain [RBD]) and CvMab-62 (targeting a spike protein S2 subunit epitope adjacent to the known anti-S2 antibody epitope). Furthermore, we created a bispecific antibody by incorporating the scFv of bebtelovimab with our anti-S2 antibody, demonstrating significant restoration of effectiveness against bebtelovimab-resistant BQ.1.1 variants. This study highlights the potential of neutralizing bispecific antibodies, which combine existing less effective anti-RBD antibodies with anti-S2 antibodies, to revive the effectiveness of antibody therapeutics compromised by immune-evading variants.

microbiology↗