The SARS-CoV-2 Omicron with increased fitness is spreading rapidly worldwide. Analysis of cryo-EM structures of the Spike (S) from Omicron reveals amino acid substitutions forging interactions that stably maintain an active conformation for receptor recognition. The relatively more compact domain organization confers improved stability and enhances attachment but compromises the efficiency of the viral fusion step. Alterations in local conformation, charge and hydrophobic microenvironments underpin the modulation of the epitopes such that they are not recognized by most NTD- and RBD-antibodies, facilitating viral immune escape. Structure of the Omicron S bound with human ACE2, together with the analysis of sequence conservation in ACE2 binding region of 25 sarbecovirus members as well as heatmaps of the immunogenic sites and their corresponding mutational frequencies sheds light on conserved and structurally restrained regions that can be used for the development of broad-spectrum vaccines and therapeutics.

Fluorescent probes in the second near-infrared window (NIR-II) allow high-resolution bioimaging with deep-tissue penetration. However, existing NIR-II materials often have poor signal-to-background ratios because of the lack of target specificity. Herein, an activatable NIR-II nanoprobe for visualizing colorectal cancers was devised. This designed probe displays H S-activated ratiometric fluorescence and light-up NIR-II emission at 900-1300 nm. By using this activatable and target specific probe for deep-tissue imaging of H S-rich colon cancer cells, accurate identification of colorectal tumors in animal models were performed. It is anticipated that the development of activatable NIR-II probes will find widespread applications in biological and clinical systems.

Near-infrared (NIR)-II fluorescence agents hold great promise for deep-tissue photothermal therapy (PTT) of cancers, which nevertheless remains restricted by the inherent nonspecificity and toxicity of PTT. In response to this challenge, we herein develop a hydrogen sulfide (H2S)-activatable nanostructured photothermal agent (Nano-PT) for site-specific NIR-II fluorescence-guided PTT of colorectal cancer (CRC). Our in vivo studies reveal that this theranostic Nano-PT probe is specifically activated in H2S-rich CRC tissues, whereas it is nonfunctional in normal tissues. Activation of Nano-PT not only emits NIR-II fluorescence with deeper tissue penetration ability than conventional fluorescent probes but also generates high NIR absorption resulting in efficient photothermal conversion under NIR laser irradiation. Importantly, we establish NIR-II imaging-guided PTT of CRC by applying the Nano-PT agent in tumor-bearing mice, which results in complete tumor regression with minimal nonspecific damages. Our studies thus shed light on the development of cancer biomarker-activated PTT for precision medicine.

Non-technical summary In the quest to understand how the circulatory system adjusts microvascular function to meet local metabolic demand, we focused on the retina whose circulatory system consists exclusively of microvessels. Since voltages induced by extracellular signals play a key role in generating vasomotor responses, we characterized the movement of voltage within the retinal microvasculature. To do this, we quantified voltage transmission between pairs of recording pipettes located at well-defined sites in capillary/arteriole plexuses freshly isolated from the rat retina. We found that the retinal microvasculature is not simply a homogeneous syncytium, but has a complex electrotonic architecture with differing efficacies of voltage transmission. Furthermore, we discovered that the electrotonic architecture is not static, but is modulated by angiotensin. This newly appreciated action reveals that vasoactive signals can alter the functional organization of the microvasculature and, thereby, regulate the spatial extent of the circulatory system's response to voltage-changing inputs.Abstract The capillary/arteriole complex is the key operational unit regulating local perfusion to meet metabolic demand. However, much remains to be learned about how this multicellular unit is functionally organized. To help address this challenge, we characterized the electrotonic architecture of the retinal microvasculature, which is particularly well adapted for the decentralized control of blood flow. In this study, we quantified the transmission of voltage between pairs of perforated-patch pipettes sealed onto abluminal cells located on microvascular complexes freshly isolated from the adult rat retina. These complexes consisted of capillaries, as well as tertiary and secondary arterioles. Dual recording experiments revealed that voltage spreading axially through a capillary, tertiary arteriole or secondary arteriole is transmitted very efficiently with a decay rate of only ∼5% per 100 μm. However, the retinal microvasculature is not simply a well-coupled syncytium since we detected significant voltage dissipation with radial abluminal cell-to-endothelium transmission and also at branch points between a capillary and its tertiary arteriole and between tertiary and secondary arterioles. Consistent with capillaries being particularly well-suited for the task of transmitting voltages induced by vasoactive signals, radial transmission is most efficient in this portion of the retinal microvasculature. Dual recordings also revealed that angiotensin II potently inhibits axial transmission. As a functional consequence, the geographical extent of the microvasculature's response to voltage-changing inputs is markedly restricted in the presence of angiotensin. In addition, this effect of angiotensin established that the electrotonic architecture of the retinal microvasculature is not static, but rather, is dynamically modulated by vasoactive signals. Abbreviations AT 1 , angiotensin receptor type 1; C m , membrane capacitance; K ATP ...

A molecular design strategy is established to access diverse enzyme-activated probes that are excitable and emit in the NIR (I and II) region with favorable Stokes shifts, enabling targeted cancer imaging by real-time monitoring enzyme activities.

NIR light responsive nanoplatforms hold great promise for on‐demand drug release in precision cancer medicine. However, currently available systems utilize “always‐on” photothermal transducers that lack target specificity, and thus inaccurately differentiate tumors from normal tissues. Developed here is a theranostic nanoplatform featuring H2S‐mediated in situ production of NIR photothermal agents for imaging‐guided and photocontrolled drug release. The system targets H2S‐rich cancers. This nanoplatform shows H2S‐activatable NIR‐II emission and NIR light controllable release of the drug Camptothecin‐11. Upon administering the system to HCT116 tumor‐bearing mice, the tumor is greatly suppressed with minimal side effects, arising from the synergy of the cancer‐specific and NIR light activated therapy. This theranostic nanoplatform thus sheds light on precision medicine with guidance through NIR‐II imaging.

Activatable molecular probes hold great promise for targeted cancer imaging. However, the hydrophobic nature of most conventional probes makes them generate precipitated agglomerate in aqueous media, thereby annihilating their responsiveness to analytes and precluding their practical applications for bioimaging. This study reports the development of two small molecular probes with unprecedented aggregation enhanced responsiveness to H 2 S for in vivo imaging of H 2 S-rich cancers. The subtle modulation of the equilibrium between hydrophilicity and lipophilicity by N-methylpyridinium endows these designed probes with the capability of spontaneously self-assembling into nanoprobes under physiological conditions. Such probes in an aggregated state, rather than a molecular dissolved state, show NIR fluorescence light up and photoacoustic signals turn on upon H 2 S specific activation, allowing in vivo visualization and differentiation of cancers based on differences in H 2 S content. Thus, our study presents an effective design strategy which should pave the way to molecular design of optimized probes for precision cancer diagnostics.

An unusual ceria dispersion was achieved by using the confined space between template and silica walls in as-prepared mesoporous silica, for the first time. The new adsorbents exhibit high adsorptive desulfurization activity and, more importantly, excellent stability and reusability, which is impossible to realize with conventional adsorbents.