Browse Articles

Rapid antimicrobial susceptibility testing using carbon screen printed electrodes in a microfluidic device

Profile of Bik-Kwoon Tye

Visual perception of wind hazards using cycloidal scanning LiDAR system

QnAs with Jeremy J. Michalek and Corey D. Harper

ANGPTL3 regulates the peroxisomal translocation of SmarcAL1 in response to cell growth states

CO ₂ potentiates echinocandin efficacy during invasive candidiasis therapy via dephosphorylation of Hsp90 by Ptc2 in condensates

Carbon dioxide is a signaling cue critical for fungal pathogenesis. Ptc2, a type 2C protein phosphatase (PP2C), serves as a conserved CO 2 sensor in fungi. By combining phosphoproteomic and biochemical assays, we identified Hsp90 as a direct target of Ptc2 at host CO 2 concentrations and Ssb1 as a Ptc2 target protein regardless of CO 2 levels in Candida albicans , the most prevalent human fungal pathogen. Ptc2 forms reversible condensates at elevated CO 2 , which enables the recruitment of Hsp90, but not Ssb1, to condensates, allowing efficient dephosphorylation. This process confers an enhanced susceptibility to caspofungin in vitro and during in vivo infection therapy. Importantly, we demonstrate this phenomenon in non-albicans Candida species. Sequential passages of C. albicans in mice with caspofungin treatment readily induce in vivo drug tolerance, causing therapeutic failure. These evolved strains display increased resistance to caspofungin under host concentrations of CO 2 but remain susceptible in air. Collectively, our study reveals a profound impact of host concentrations of CO 2 on antifungal drug susceptibility and connects this phenotype to therapeutic outcomes and highlights condensate formation as an efficient means that enables selective recruitment of substrates for certain signaling events.

Quality control of hospitals and its effect on hospitalized fatality rate of COVID-19

Rapid restoration of potent neutralization activity against the latest Omicron variant JN.1 via AI rational design and antibody engineering

The rapid evolution of the viral genome has led to the continual generation of new variants of SARS-CoV-2. Developing antibody drugs with broad-spectrum and high efficiency is a long-term task. It is promising but challenging to develop therapeutic neutralizing antibodies (nAbs) through in vitro evolution based on antigen–antibody binding interactions. From an early B cell antibody repertoire, we isolated antibody 8G3 that retains its nonregressive neutralizing activity against Omicron BA.1 and various other strains in vitro. 8G3 protected ACE2 transgenic mice from BA.1 and WA1/2020 virus infection without adverse clinical manifestations and completely cleared viral load in the lungs. Similar to most IGHV3–53 antibodies, the binding sites of 8G3 and ACE2 largely overlap, enabling competition with ACE2 for binding to RBD. By comprehensively considering the binding free energy changes of the antigen–antibody complexes, the biological environment of their interactions, and the evolutionary direction of the antibodies, we were able to select 50 mutants. Among them, 11 were validated by experiments showing better neutralizing activities. Further, a combination of four mutations were identified in 8G3 that increased its neutralization potency against JN.1, the latest Omicron mutant, by approximately 1,500-fold, and one of the mutations led to an improvement in activity against multiple variants to a certain extent. Together, we established a procedure of rapid selection of neutralizing antibodies with potent SARS-CoV-2 neutralization activity. Our results provide a reference for engineering neutralizing antibodies against future SARS-CoV-2 variants and even other pandemic viruses.

The effects of perturbation intensities on backward slip-falls induced by a split-belt treadmill

Free-electron resonance transition radiation via Brewster randomness

Free-electron radiation, such as Cherenkov radiation and transition radiation, can generate light at arbitrary frequencies and is fundamental to diverse applications, ranging from electron microscopy, spectroscopy, lasers, to particle detectors. Generally, the features of free-electron radiation are stochastic when electrons interact with random media. Counterintuitively, here, we reveal a type of free-electron radiation that has both its intensity and directionality invariant to specific sorts of long-range structural randomness. Essentially, this invariance is enabled by the Brewster effect and the judiciously engineered phase coherence condition of emitted light, namely that the light induced by electron’s penetration through a layered aperiodic nanostructure is engineered to interfere constructively at the Brewster angle. As such, when each constituent layer with a random thickness fulfills this phase coherence condition, there is always the emergence of free-electron resonance transition radiation at the Brewster angle. At this resonant Brewster angle, we further find that the radiation intensity and directionality could be enhanced by orders of magnitude by readily increasing the interface number. The revealed resonance transition radiation via long-range Brewster randomness may offer a feasible route to explore more enticing photonic applications driven by free electrons, such as light sources at previously unreachable spectral regimes, optical frequency combs, particle detectors, and random lasers.

Performance analysis of palm tree microfibers in concrete

Ethylene-independent modulation of root development by ACC via downregulation of WOX5 and group I CLE peptide expression

In seed plants, the canonical role of 1-aminocyclopropane-1-carboxylic acid (ACC) is to serve as the precursor in the biosynthesis of the phytohormone ethylene, and indeed, ACC treatment is often used as a proxy for ethylene treatment. Increasing evidence suggests that ACC can also act independently of ethylene to regulate various aspects of plant growth and development. Here, we explore the effects of ACC on Arabidopsis thaliana root growth and the mechanisms by which it acts. ACC inhibits growth of the primary root in Arabidopsis seedlings when ethylene signaling is blocked, which becomes evident after 36 h of treatment with ACC. This reduced root growth is in part the result of suppressed cell proliferation in the root meristem resulting from altered expression of a key regulator of stem cell niche activity, WOX5. ACC also promotes lateral root (LR) development, in contrast to ethylene, which inhibits LR formation. Transcriptomic analysis of roots revealed no significant changes in gene expression after 45 min or 4 h of ACC treatment, but longer treatment times revealed a large number of differentially expressed genes, including the downregulation of the expression of a small group of phylogenetically related CLE peptides. Reduced expression of these group 1 CLEs in response to ACC leads to the activation of a transcription factor, LBD18, which promotes LR development. These results suggest that ACC acts to modulate multiple aspects of Arabidopsis root growth independently of ethylene via distinct transcriptional effects in the root meristem and LR precursor cells.

Construction and verification of a nomogram model for the risk of death in sepsis patients

Microtubule inner proteins of <i>Plasmodium</i> are essential for transmission of malaria parasites

Microtubule inner proteins (MIPs) are microtubule-associated proteins that bind to tubulin from the luminal side. MIPs can be found in axonemes to stabilize flagellar beat or within cytoplasmic microtubules. Plasmodium spp. are the causative agents of malaria that feature different parasite forms across a complex life cycle with both unique and divergent microtubule-based arrays. Here, we investigate four MIPs in a rodent malaria parasite for their role in transmission to and from the mosquito. We show by single and double gene deletions that SPM1 and TrxL1, MIPs associated with subpellicular microtubules, are dispensable for transmission from the vertebrate host to the mosquito and back. In contrast, FAP20 and FAP52, MIPs associated with the axonemes of gametes, are essential for transmission to mosquitoes but only if both genes are deleted. In the absence of both FAP20 and FAP52, the B-tubule of the axoneme partly detaches from the A-tubule, resulting in the deficiency of axonemal beating and hence gamete formation and egress. Our data suggest that a high level of redundancy ensures microtubule stability in the transmissive stages of Plasmodium , which is important for parasite transmission.

MedFuseNet: fusing local and global deep feature representations with hybrid attention mechanisms for medical image segmentation

Circadian clock control of interactions between eIF2α kinase CPC-3 and GCN1 with ribosomes regulates rhythmic translation initiation

Misregulation of the activity of GCN2, the kinase that phosphorylates and inactivates translation initiation factor eIF2α, has been implicated in several health disorders, underscoring the need to determine the mechanisms controlling GCN2 activation. During nutrient starvation, increased uncharged tRNA levels trigger GCN1 and GCN20 proteins to mediate the binding of uncharged tRNA to GCN2 to activate the kinase to phosphorylate eIF2α. Under constant conditions, activation of the Neurospora crassa homolog of GCN2, CPC-3, is controlled by the circadian clock. However, how the circadian clock controls the rhythmic activity of CPC-3 was not known. We found that the clock regulates CPC-3 and GCN1 interaction with ribosomes and show that these interactions are necessary for clock regulation of CPC-3 activity. CPC-3 activity rhythms, and the rhythmic interaction of CPC-3 and GCN1 with ribosomes, are abolished in a temperature-sensitive valyl-tRNA synthetase mutant ( un-3 ts ) that has high levels of uncharged tRNA Val at all times of the day. Disrupting the interaction between GCN1 and uncharged tRNA in the absence of GCN20 altered rhythmic CPC-3 activity, indicating that the clock controls the interaction between uncharged tRNA and GCN1. Together, these data support that circadian rhythms in mRNA translation through CPC-3 activity require rhythms in uncharged tRNA levels that drive the rhythmic interaction between CPC-3 and GCN1 with ribosomes. This regulation uncovers a fundamental mechanism to ensure temporal coordination between peak cellular energy levels and the energetically demanding process of mRNA translation.

Ancient levantine demography follows ecological stochasticity

Variable transduction of thyroid hormone signaling in structures of the mouse brain

L-thyroxine (L-T4) monotherapy is the standard treatment for hypothyroidism, administered daily to normalize TSH levels. Once absorbed, T4 is converted to T3 to alleviate most symptoms. However, this treatment abnormally elevates plasma T4 levels in over 50% of patients. Using L-T4-treated Thyroid Hormone (TH) Action Indicator mice, which express a T3-regulated luciferase (Luc) reporter, we examined whether these T4 elevations disrupt TH signaling. Hypothyroid mice exhibited reduced Luc expression across brain regions, and L-T4 treatment failed to restore T3 signaling uniformly. There was also variability in the activity of type 2 deiodinase (D2), the enzyme that generates most brain T3. Intracerebroventricular T4 administration achieved higher elevation of Luc expression in the mediobasal hypothalamus compared to the cortex, and studies on cultured cortical astrocytes and hypothalamic tanycytes revealed cell-type-specific responses to T4. In tanycytes, exposure to T4 sustained D2 activity, leading to progressive T3 signaling, whereas in astrocytes, T4 exposure triggered a drop in D2 activity, limiting T3 production through a ubiquitin-dependent, self-limiting mechanism. The sustained D2 activity in tanycytes was linked to rapid deubiquitination by USP33, as confirmed using a ubiquitin-specific protease (USP) pan-inhibitor and USP33 knockout mice. In conclusion, the brain’s response to L-T4 treatment is heterogeneous, influenced by cell-specific regulation of D2-mediated T3 production. While cortical astrocytes exhibit limited T3 signaling due to D2 ubiquitination, tanycytes coexpressing USP33 amplify T3 signaling by rescuing ubiquitinated D2 from proteasomal degradation. These findings provide mechanistic insights into the limitations of L-T4 therapy and highlight the need for tailored approaches to managing hypothyroidism.

Spectrochemical differentiation in endometriosis based on infrared spectroscopy advanced data fusion and multivariate analysis

Spatial propagation of temperate phages within and among biofilms

Bacteria form groups composed of cells and a secreted polymeric matrix that controls their spatial organization. These groups—termed biofilms—can act as refuges from environmental disturbances and from biotic threats, including phages. Despite the ubiquity of temperate phages and bacterial biofilms, live propagation of temperate phages within biofilms has not been characterized on cellular spatial scales. Here, we leverage several approaches to track temperate phages and distinguish between lytic and lysogenic host infections. We determine that lysogeny within Escherichia coli biofilms initially occurs within a predictable region of cell group packing architecture on the biofilm periphery. Because lysogens are generally found on the periphery of large cell groups, where lytic viral infections also reduce local biofilm structural integrity, lysogens are predisposed to disperse into the passing liquid and are overrepresented in downstream biofilms formed from the dispersal pool of the original biofilm-phage system. Comparing our results with those for virulent phages reveals that temperate phages have unique advantages in propagating over long spatial and time scales within and among bacterial biofilms.