The intratumor microbiome, one of the hallmarks of cancer, plays a crucial role in cancer progression through interaction with the host. However, the underlying mechanisms remain poorly understood. Here we investigated the heterogeneity of host-microbiome interactions at the single-cell level by integrating six single-cell transcriptomic lung cancer datasets using single-cell analysis of host-microbiome interactions (SAHMI). Our findings indicate that primary tumor tissues display a high proportion of fungi-associated cells, whereas metastatic brain tissues predominantly feature bacteria-associated cells. A distinct distribution of fungal and bacterial taxa across various cell types was observed. Notably, the presence of specific bacteria significantly influences the transcriptome of resident host cells, including T cells and macrophages, by modulating pathways related to rRNA processing, cellular responses to stress and stimuli, and the metabolism of RNA and proteins. Finally, specific cell-associated bacteria are significantly correlated with clinical features, such as lung cancer stages and smoking frequency. These single-cell insights into microbiome-host interactions facilitate our understanding of lung cancer development and progression, offering potential microecological and diagnostic insights.

The clinical presentation of histoplasmosis is non-specific and has several mimics as documented in the literature. Regarding cancers, previous reviews emphasized mainly the clinical and radiological similarities between histoplasmosis and pulmonary malignancies. Besides lung cancers, histoplasmosis also masquerades as other malignancies. We identified one hundred and twenty-four cases of histoplasmosis clinically mistaken for malignancies. Of the 124,84 (67.7%) were included in the analyses of demographics, immune status, clinical features, diagnosis, and treatment outcomes. The remainder were excluded as the available data was mainly on diagnosis. Of the eighty-four, histoplasmosis was predominantly misdiagnosed as lung cancers (n = 16, 19.0%), gastrointestinal tumors (n = 15, 17.9%), and lymphomas/hematological malignancies (n = 15, 17.9%). Fifty-four (64.3%) were immunocompromised including 16 (29.6%) who were living with HIV, while the remainder were immunocompetent. We conclude that infective aetiologies like histoplasmosis should be considered or ruled out in patients clinically suspected of malignancy regardless of their immune status.

Various precise gene editing techniques at the DNA/RNA level, driven by clustered regularly interspaced short palindrome repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology, have gained significant prominence. Yet, research on targeted protein editing techniques remains limited. Only a few attempts have been made, including the use of specific proteases and de-O-glycosylating enzymes as editing enzymes. Here, we propose direct editing of N-glycosylated proteins using de-N-glycosylating enzymes to modify N-glycosylation and simultaneously alter the relevant asparagine residue to aspartate in living cells. Selective protein deglycosylation editors were developed by fusing high-affinity protein-targeting peptides with active peptide:N-glycanases (PNGases). Three crucial cell membrane proteins, PD-1, PD-L1, and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein, were chosen to be tested as a proof of concept. N-linked glycans were removed, and the relevant sites were converted from Asn to Asp in living mammalian cells, destabilizing target proteins and accelerating their degradation. Further investigation focused on SARS-CoV-2 spike protein deglycosylation editing. The collaboration of LCB1-PNGase F (PNGF) effectively reduced syncytia formation, inhibited pseudovirus packaging, and significantly hindered virus entry into host cells, which provides insights for coronavirus disease 2019 (COVID-19) treatment. This tool enables editing protein sequences post-de-N-glycosylation in living human cells, shedding light on protein N-glycosylation functions, and Asn to Asp editing in organisms. It also offers the potential for developing protein degradation technologies.

Polydiacetylene (PDA) liposomes have been widely applied for detection due to their distinctive optical properties. However, the liquid phase in which PDA liposomes are dispersed generates several drawbacks, for instance, instability, compromise of detection sensitivity induced by dilution, and separation of target sampling and detection, making it inconvenient for application. In this paper, various functionalized PDA liposomes for detecting target were prepared, which were also immobilized into swelling microneedles to construct a solid-phase detection system. The PDA liposomes-complexed microneedles (PDA/MNs) enable the integration of target sampling and detection in one platform. The effects of the dispersing matrix phase on the detection sensitivity of PDA liposomes were systematically investigated from both environmental and chemical perspectives. PDA/MNs exhibited higher sensitivity than their counterparts in liquid phase. PDA/MNs were optimized and validated for lead ion (Pb2+) and sialic acid (SA) detections. For Pb2+ detection, the limit of detection (LOD) of the PDA/MNs was 13.7 μM and 2.5 times lower than the liquid phase. For SA detection, the LOD of the PDA/MNs was 0.83 μM and 1.7 times lower than the liquid phase. The results suggested that such PDA/MNs were validated to provide a label-free, stable, sensitive, and convenient tool in an all-in-one manner for physiologic target detection.

To rapidly develop hyperstable inhibitors that bind specifically and covalently to functional proteins is critical for diagnostics and therapeutics. Taking targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants as an example, we report a fast and low-cost de novo design strategy on covalent bonding peptides towards the SARS-CoV-2 spike protein receptor-binding domain (RBD), hence blocking its interaction with the human angiotensin-converting enzyme 2 (hACE2). As a proof-of-concept, peptide scaffolds built by ligating the hotspot residues at the hACE2-Omicron RBD interface were docked against RBD, and then the chemically modified peptides were designed by predicting their reactivity against RBD using a modified Amber ff14SB force field. Two peptides (15- and 16-mer peptides) were equipped with sulfonyl fluoride warheads bound with the conserved Y449 residue of RBD via the sulfur (VI) fluoride exchange (SuFEx) click chemistry. With permanent bonding and without dissociation, the two peptides blocked Omicron BA.2 pseudovirus infection with IC50 values of 1.07 μM and 1.56 μM, respectively. Our design approach greatly promotes the discovery of hyper stable inhibitors against SARS-CoV-2 variants and other rapidly evolving viruses, potentially applicable to combat future viral outbreaks efficiently.

Host antiviral strategies have been studied for a long time, and the antibody response and T cell response represent the classic host antiviral strategies. In a recent study published in Nature Microbiology, Yang and colleagues discovered a novel antiviral mechanism of Interferon-induced transmembrane protein-1 (IFITM1) in inhibiting Epstein–Barr virus (EBV) infection by blocking virus entry receptor Ephrin receptor A2 (EphA2). Along with the past research, this finding hints at the importance of discovering broader host protective factors.

Neoplasms arising from neuroendocrine cells form a heterogeneous group known as neuroendocrine tumors (NETs), which possess both endocrine and neural characteristics. These tumors can occur in various organs throughout the body, with the most prominent sites being the gastrointestinal tract, pancreas, and lungs. Despite their relatively low incidence, NETs have gained significant attention due to their unique biology and clinical behavior. This review intends to provide a widespread gestalt of the present perception of NETs, including their epidemiology, etiology, pathogenesis, classification, clinical presentation, diagnostic modalities, treatment options, and prognosis. Treatment strategies for NETs depend on tumor grade, stage, location, and functional status. Surgical resection remains the pillar of curative treatment for localized disease; on the other hand, systemic therapies take account of targeted therapies like tyrosine kinase inhibitors (TKIs), peptide receptor radionuclide therapy (PRRT), somatostatin analogs, and immunotherapy have shown promising results in advanced cases. In conclusion, this review provides an up-to-date summary of our current knowledge regarding neuroendocrine tumors. Further research is needed to better understand the underlying molecular mechanisms driving tumor development and progression. This will aid in developing novel therapeutic strategies targeting specific pathways involved in NET pathogenesis to improve patient outcomes.

Serological tests have an important and irreplaceable role in the diagnosis of infectious diseases, both for individual patients and society. They indirectly identify the causative pathogen through the capture of antibodies, which contrasts with the direct detection by antigen and molecular biology tests that are also limited to active infections. Within point-of-care platforms, serodiagnostic assays can support immediate decisions in patient care and contain the spread of disease as they do not require highly trained personnel or dedicated infrastructure. By employing serodiagnosis, health officials can proactively respond and eliminate emerging health risks. Larger sample numbers can be screened in other formats for surveillance as well as securing donated blood supplies. Furthermore, an assay can be designed to detect any immunoglobulin from IgM to IgG and its subclasses, to IgA and IgE. However, most serological assays employ natural proteins as the defining antibody-capturing reagent, which compromises their performance by limiting the two critical parameters of a serodiagnostic test: specificity and sensitivity. To surpass this natural limitation, we have repurposed the β-barrel of fluorescent proteins to receive epitope sequences that dependably produce high-performing designer immunological reagents. Consequently, serodiagnosis can be conducted more accurately at a lower cost.

During the continuing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the Omicron variant of concern emerged in the second half of 2021 and has been dominant since November of that year. Along with its sublineages, it has maintained a prominent role ever since. The Nsp5 main protease (Mpro) of the Omicron virus is characterized by a single dominant mutation, P132H. Here we determined the X-ray crystal structures of the P132H mutant (or O-Mpro) as a free enzyme and in complex with the Mpro inhibitor, the alpha-ketoamide 13b-K, and we conducted enzymological, biophysical, as well as theoretical studies to characterize the O-Mpro. We found that O-Mpro has a similar overall structure and binding with 13b-K; however, it displays lower enzymatic activity and lower thermal stability compared to the WT-Mpro (with “WT” referring to the prototype strain). Intriguingly, the imidazole ring of His132 and the carboxylate plane of Glu240 are in a stacked configuration in the X-ray structures determined here. Empirical folding free energy calculations suggest that the O-Mpro dimer is destabilized relative to the WT-Mpro due to less favorable van der Waals interactions and backbone conformations in the individual protomers. All-atom continuous constant-pH molecular dynamics (MD) simulations reveal that His132 and Glu240 display coupled titration. At pH 7, His132 is predominantly neutral and in a stacked configuration with respect to Glu240 which is charged. In order to examine whether the Omicron mutation eases the emergence of further Mpro mutations, we also analyzed the P132H+T169S double mutant, which is characteristic of the BA.1.1.2 lineage. However, we found little evidence of a correlation between the two mutation sites.

Central Asia, a crucible of prehistoric and historical Trans-Eurasian interactions, has been pivotal in shaping cultural exchanges, population dynamics, and genetic admixture. Recent insights from ancient DNA studies have shed light on the extensive population turnover within this region, encompassing a spectrum of groups from Paleolithic hunter-gatherers to Holocene herders and the nomadic pastoralist empires of historical times. The genomic analysis of ancient pathogens across the Eurasian steppe has further deepened our understanding of pathogen origins, clonal expansions, and the intricate processes of host-pathogen coevolution in relation to varying pathogen exposures and their spread. We consolidate the latest findings pertaining to the ancient human and pathogen genomes of Central Asia, elucidating their profound influence on the genomic tapestry of contemporary Central Asians. A notable gap in the current genomic databases for Central Asia is underscored, particularly within the scope of genomics-driven precision medicine. We stress the urgent need for the development of extensive, region-specific genomic resources that hold promise for revealing the genetic blueprints underlying human traits and diseases, refining polygenic scoring models for predictive medicine, and bolstering genomic research endeavors across Central Asia.