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To humanize models of liver metabolic disease research, authors develop a microfluidic platform leveraging human hepatic spheroids integrated with microvasculature and circulating monocytes to model hepatic insulin resistance.

Technologies are now in place to obtain large amounts of data for systems biology approaches. What are the most suitable technologies for fast, accurate and high-throughput data collection? And following data collection, how should these data be analysed and validated?

Lopez Zapana, DeBolt et al. apply untargeted proteomics to identify second trimester molecular signatures of spontaneous and medically-indicated preterm birth and assess how BMI shapes these patterns. Distinct proteomic profiles define each subtype, and BMI strongly modifies inflammatory and metabolic pathways linked to preterm birth.

This Protocol presents a detailed guide for generating and analyzing single-cell multiomic data from low-input samples with the Seq-Well S³ platform.

Many diseases are caused by disruptions to the network of biochemical reactions that allow cells to respond to external signals. Here Nilsson et al develop a method to simulate cellular signaling using artificial neural networks to predict cellular responses and activities of signaling molecules.

Analysis of Mycobacterium tuberculosis-specific antibody responses in previously exposed South African cohorts reveals that profile features associated with progression to active tuberculosis are affected by age and sex.

A crucial aspect of cell function in tissues is the biophysical interactions of the cell with the surrounding extracellular matrix. A fascinating report in this issue offers a major advance in the techniques available for investigating how the transmission of cell-generated forces to an underlying substratum is regulated. Application of this approach should provide key insights into such force regulation during cell migration and matrix contraction.

Nziza et al. profile anti-SARS-CoV-2 antibody responses in infants and toddlers after mRNA vaccination and demonstrate a strong functional activation of humoral immunity in this age group when compared with adults and naturally infected children.

Screening a large barcoded library of unique CD19-specific chimaeric antigen receptors with diverse intracellular domains allows for the discovery of receptors that elicit enhanced antitumoural functions.

Convalescent plasma (CP) has been trialed as a therapy for SARS-CoV-2 symptoms, but its heterogenous nature precludes uniform outcomes. Here the authors perform deep profiling of CP, as well as plasma of CP recipients before and after transfer, to find CP-mediated, spike/nucleocapsid-focused modulations of humoral responses in the recipient.

A systems-level look at the activation of joint synovial fibroblasts in rheumatoid arthritis patients in response to different activators and therapeutic kinase inhibitors shows that multivariate inhibitor effects depend on the nature of the activator, not on the disease state per se.

Expression of ADAM8, a metalloprotease disintegrin, correlates with worse prognosis in pancreatic adenocarcinoma (PDAC). Here Schlomann et al. show that ADAM8 promotes PDAC invasiveness, and develop a peptide inhibitor that blocks ADAM8 function and impedes PDAC progression in mouse models.

Distinct routes of immunization elicit different antibody isotypes and functions associated with protection against SIV infection that converge on phagocytosis as a candidate protective mechanism of independent SIV vaccines.

Synthetic gene circuits regulated by small molecules have been used to fine-tune glycosyltransferase expression in CHO cells, providing a method to produce therapeutic monoclonal antibodies with precise glycosylation states.

The extent of antibody protection against SARS-CoV-2 remains unclear. Here, using a cohort of 120 seroconverted individuals, the authors longitudinally characterize neutralization, Fc-function, and SARS-CoV-2 specific T cell responses, which they show to be prominent only in those subjects that elicited receptor-binding domain (RBD)-specific antibody titers above a certain threshold, suggesting that development of T cell responses to be related to anti-RBD Ab production.

The protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccine expressing the SARS-CoV-2 spike protein in non-human primates is demonstrated.

Adoptive transfer of purified IgG from convalescent macaques protects naive macaques against SARS-CoV-2 infection, and cellular immune responses contribute to protection against rechallenge with SARS-CoV-2.

Kaplonek et al. provide a prospective look at ChAdOx1 nCoV-19-vaccinated individuals who go on to experience breakthrough COVID infections. They report an antibody Fc profile characterized by higher FcgR2b and reduced Fcgr3b for individuals who are more susceptible to breakthrough infections.

Cellular heterogeneity is a feature of diverse disease processes, yet is masked in typical biochemical assays. Sarkar et al.develop a microfluidic device to access the contents of single cells in adherent culture, allowing biochemical measurements to be connected with phenotypic information.

Despite major drug discovery efforts, the therapeutic options for glioblastoma (GBM) remain inadequate. Here they analyze patient-derived xenograft model of GBM to quantitatively map distribution and cellular response to the EGFR inhibitor erlotinib, and report heterogeneous erlotinib delivery to intracranial tumors to be inadequate to inhibit EGFR signaling.

Nanoparticle albumin bound paclitaxel (nab-PTX) is widely used in the clinic to treat different cancers, but the effect of albumin on the distribution of the drug in tumours is not clear. Here the authors show that the accumulation of nab-PTX in tumours is affected by signalling molecules involved in nutrient uptake and processing, which could be reprogrammed to increase the drug’s efficacy.

The regulation of microtubule (MT) dynamics in cancer cells within the tumor microenvironment is less understood. Here, the authors develop an imaging platform to examine MT dynamics in live xenograft models and show that pro-tumor macrophages modulate MT coherence and alignment to promote cancer cell migration.

Identifying the cellular targets of small molecules remains a central challenge of chemical biology. The application of an RNAi-based functional genomics approach permitted the clustering of drugs with related targets by 'shRNA signatures', which served as a basis set to assign modes of action to compounds with unknown targets.

New immune biomarkers of exposure to tuberculosis may require a rethink of evidence of Mycobacterium tuberculosis infection and control.

Immunopeptidomics allows identifying the cellular repertoire of MHC-bound peptides, but quantifying them remains challenging. Here, the authors present a method to efficiently generate internal peptide MHC standards and calibration curves, facilitating relative and absolute quantitative immunopeptidomics.

A study of multisystem inflammatory syndrome in children (MIS-C) shows maintenance of elevated levels of monocyte-activating pathogen-specific IgG not seen in children infected with SARS-CoV-2 who do not develop MIS-C.

An immunotherapy consisting of a tumor-antigen targeting antibody, PD-1 blocking antibody, extended half-life recombinant IL-2 and a lymph-node-targeted T cell vaccine mobilized innate and adaptive immunity and eradicated large established tumors in a variety of mouse models.

Microwestern arrays combine the advantages of scalability of reverse phase protein arrays and the information content of western blotting for analyzing protein abundance and modification state with high sensitivity and throughput. The method is demonstrated for analyzing phosphorylation state changes in the EGF receptor signaling network using Bayesian network modeling.

A systems-modelling approach is used to address the question of why cells often respond in a cell type-specific manner to stimulation or pertubations of the signalling network. It shows that the main determinant of cell specificity is the type, strength and combination of upstream signalling events. These cell-type specific signals are integrated by common effectors to create cell type specific outcomes.

Understanding how cytokines interact with multimeric cell receptors to generate signals governing cell behavioral responses is crucial for the development of these promising pharmacological agents. A powerful quantitative approach is reported that was used to analyze the complicated case of binding of the GDNF family member artemin to the heteromeric GFRα3-Ret receptor.

Morshed et al. analyzed the proteome and phosphoproteome of brain tissue from patients with Alzheimer’s disease. The analysis of patient heterogeneity links glia pathologies and signaling pathways to stages of disease progression.