Linking signal input, cell state, and spatial context to inflammatory responses.

Signal integration is central to a causal understanding of appropriately scaled inflammatory responses. Here, we discuss recent progress in our understanding of the stimulus-response linkages downstream of pro-inflammatory inputs, with special attention to (1) the impact of cell state on the specificity of evoked gene expression and (2) the critical role of the spatial context of stimulus exposure. Advances in these directions are emerging from new tools for inferring cell-cell interactions and the activities of cytokines and transcription factors in complex microenvironments, enabling analysis of signal integration in tissue settings.

In vivo CAR T-cell generation in nonhuman primates using lentiviral vectors displaying a multidomain fusion ligand.

Chimeric antigen receptor (CAR) T-cell therapies have demonstrated transformative efficacy in treating B-cell malignancies. However, high costs and manufacturing complexities hinder their widespread use. To overcome these hurdles, we have developed the VivoVec platform, a lentiviral vector capable of generating CAR T cells in vivo.

Post-translational modification-centric base editor screens to assess phosphorylation site functionality in high throughput.

Signaling pathways that drive gene expression are typically depicted as having a dozen or so landmark phosphorylation and transcriptional events. In reality, thousands of dynamic post-translational modifications (PTMs) orchestrate nearly every cellular function, and we lack technologies to find causal links between these vast biochemical pathways and genetic circuits at scale. Here we describe the high-throughput, functional assessment of phosphorylation sites through the development of PTM-centric base editing coupled to phenotypic screens, directed by temporally resolved phosphoproteomics.

Predicting gene-level sensitivity to JAK-STAT signaling perturbation using a mechanistic-to-machine learning framework.

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway integrates complex cytokine signals via a limited number of molecular components, inspiring numerous efforts to clarify the diversity and specificity of STAT transcription factor function. We developed a computational framework to make global cytokine-induced gene predictions from STAT phosphorylation dynamics, modeling macrophage responses to interleukin (IL)-6 and IL-10, which signal through common STATs, but with distinct temporal dynamics and contrasting functions. Our mechanistic-to-machine learning model identified cytokine-specific genes associated with late pSTAT3 time frames and a preferential pSTAT1 reduction upon JAK2 inhibition.

PD-1 Impairs CD8+ T Cell Granzyme B Production in Aged Mice during Acute Viral Respiratory Infection.

CD8+ T cell dysfunction contributes to severe respiratory viral infection outcomes in older adults. CD8+ T cells are the primary cell type responsible for viral clearance. With increasing age, CD8+ T cell function declines in conjunction with an accumulation of cytotoxic tissue-resident memory (TRM) CD8+ T cells.

Proteome-wide base editor screens to assess phosphorylation site functionality in high-throughput.

Signaling pathways that drive gene expression are typically depicted as having a dozen or so landmark phosphorylation and transcriptional events. In reality, thousands of dynamic post-translational modifications (PTMs) orchestrate nearly every cellular function, and we lack technologies to find causal links between these vast biochemical pathways and genetic circuits at scale. Here, we describe "signaling-to-transcription network" mapping through the development of PTM-centric base editing coupled to phenotypic screens, directed by temporally-resolved phosphoproteomics.

Prevalence of COVID-19 and Psychotropic Drug Treatment in Psychiatric In-patients in Germany in 2020: Results from a Nationwide Pilot Survey.

Introduction: In patients with a pre-existing mental disorder, an increased risk for a first manifestation of a psychiatric disorder in COVID-19 patients, a more severe course of COVID-19 and an increased mortality have been described. Conversely, observations of lower COVID-19 incidences in psychiatric in-patients suggested protective effects of psychiatric treatment and/or psychotropic drugs against COVID-19.

Methods: A retrospective multi-center study was conducted in 24 German psychiatric university hospitals.

Isoform-specific optical activation of kinase function reveals p38-ERK signaling crosstalk.

Evolution has diversified the mammalian proteome by the generation of protein isoforms that originate from identical genes, , through alternative gene splicing or post-translational modifications, or very similar genes found in gene families. Protein isoforms can have either overlapping or unique functions and traditional chemical, biochemical, and genetic techniques are often limited in their ability to differentiate between isoforms due to their high similarity. This is particularly true in the context of highly dynamic cell signaling cascades, which often require acute spatiotemporal perturbation to assess mechanistic details.

Predicting gene level sensitivity to JAK-STAT signaling perturbation using a mechanistic-to-machine learning framework.

The JAK-STAT pathway integrates complex cytokine signals via a limited number of molecular components, inspiring numerous efforts to clarify the diversity and specificity of STAT transcription factor function. We developed a computational workflow to make global cytokine-induced gene predictions from STAT phosphorylation dynamics, modeling macrophage responses to IL-6 and IL-10, which signal through common STATs, but with distinct temporal dynamics and contrasting functions. Our mechanistic-to-machine learning model identified select cytokine-induced gene sets associated with late pSTAT3 timeframes and a preferential pSTAT1 reduction upon JAK2 inhibition.

SARS-CoV-2 ORF8 Mediates Signals in Macrophages and Monocytes through MyD88 Independently of the IL-17 Receptor.

SARS-CoV-2 has caused an estimated 7 million deaths worldwide to date. A secreted SARS-CoV-2 accessory protein, known as open reading frame 8 (ORF8), elicits inflammatory pulmonary cytokine responses and is associated with disease severity in COVID-19 patients. Recent reports proposed that ORF8 mediates downstream signals in macrophages and monocytes through the IL-17 receptor complex (IL-17RA, IL-17RC).

Signaling is the pathway to macrophage function.

Tissue and inflammatory contexts are well appreciated to shape macrophage function to promote health or disease. However, there has been minimal progress towards understanding how these contexts modify signaling-to-transcription networks. Integration of mechanistic modeling and data-driven approaches will be crucial for investigating how cell state impacts macrophage decision-making.

Temporally shaped vortex phase laser pulses for two-photon excited fluorescence.

We report temporally shaped vortex phase laser pulses for two-photon excited fluorescence of dyes. The particularly tailored pulses are generated by first utilizing a temporal pulse shaper and subsequently a two-dimensional spatial pulse shaper. Various vortex phase shaped structures are demonstrated by combining different two-dimensional phase patterns.

Reply to Fabbris et al. A Viable Alternative. Comment on "Kohmer et al. Self-Collected Samples to Detect SARS-CoV-2: Direct Comparison of Saliva, Tongue Swab, Nasal Swab, Chewed Cotton Pads and Gargle Lavage. 2021, , 5751".

We thank Fabbris et al. for their remarks [..

[Occupationally acquired SARS-CoV-2 infections among healthcare personnel in Frankfurt am Main from March to August 2020].

Background: Standardised surveillance of COVID-19 infections among healthcare personnel during the current pandemic was and is not available. In particular, the proportion of occupational infections among healthcare personnel and which workers among them are most at risk remains unclear.

Objectives: The aim of this study was to analyse the reported COVID-19 cases among healthcare personnel in Frankfurt/Main during the first six months of the pandemic, to determine the number of occupational infections and thus to allow a better interpretation of the data published by the Robert Koch Institute.

[The SARS-CoV-2 Pandemic in Long-Term Care Facilities for the Elderly: Analysis of Data from Frankfurt am Main, Germany, March 2020 - September 2021].

Background: Residents in long-term care facilities (LTCF) are particularly vulnerable during the SARS-CoV-2 pandemic. In the first wave of the pandemic in many countries, 30-70% of all deaths from or with SARS-CoV-2 were LTCF residents, although their proportion in the population is typically less than 1%. Findings from LTCFs in Frankfurt am Main (March 2020-September 2021) are presented below and discussed in terms of necessary improvements.

SARS-CoV-2 screening strategies for returning international travellers: Evaluation of a rapid antigen test approach.

Background: International travel poses the risk of importing SARS-CoV-2 infections and introducing new viral variants into the country of destination. Established measures include mandatory quarantine with the opportunity to abbreviate it with a negative rapid antigen test (RAT).

Methods: A total of 1,488 returnees were tested for SARS-CoV-2 with both PCR and RAT no earlier than 5 days after arrival.

Mechanisms encoding STAT functional diversity for context-specific inflammatory responses.

Cells integrate complex cytokine cues and other inflammatory stimuli through activation of the signal transducers and activators of transcription (STAT) family of transcription factors to drive the appropriate anti-microbial, inflammatory, and resolving functions. Here, we discuss recent progress in our understanding of mechanisms supporting STAT functional diversity. Signaling component availability and the strength of receptor and STAT interactions emerge as important determinants of immune function.

Self-Collected Samples to Detect SARS-CoV-2: Direct Comparison of Saliva, Tongue Swab, Nasal Swab, Chewed Cotton Pads and Gargle Lavage.

Testing for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by RT-PCR is a vital public health tool in the pandemic. Self-collected samples are increasingly used as an alternative to nasopharyngeal swabs. Several studies suggested that they are sufficiently sensitive to be a useful alternative.

Identification of Cell Surface Molecules That Determine the Macrophage Activation Threshold Associated With an Early Stage of Malignant Transformation.

The ability of immune cells to sense changes associated with malignant transformation as early as possible is likely to be important for the successful outcome of cancer immunosurveillance. In this process, the immune system faces a trade-off between elimination of cells harboring premalignant or malignant changes, and autoimmune pathologies. We hypothesized that the immune system has therefore evolved a threshold for the stage of transformation from normal to fully malignant cells that first provides a threat (danger) signal requiring a response.

[Children in the COVID-19 pandemic and the public health service (ÖGD) : Data and reflections from Frankfurt am Main, Germany].

Background: The measures taken to combat the COVID-19 pandemic have severely restricted the opportunities for the development of children. This paper will discuss the reporting data of children and the public health department's activities against the background of the restrictions of school and leisure time offers as well as sports and club activities.

Materials And Methods: Reporting data from Frankfurt am Main, Hesse, were obtained using a SURVStat query for the calendar weeks 10/2020-28/2021 and from SURVNet (until 30 June 2021).

Antibody-Mediated Neutralization of Authentic SARS-CoV-2 B.1.617 Variants Harboring L452R and T478K/E484Q.

The capacity of convalescent and vaccine-elicited sera and monoclonal antibodies (mAb) to neutralize SARS-CoV-2 variants is currently of high relevance to assess the protection against infections. We performed a cell culture-based neutralization assay focusing on authentic SARS-CoV-2 variants B.1.

CISH attenuates homeostatic cytokine signaling to promote lung-specific macrophage programming and function.

Tissue-specific cytokine stimuli orchestrate specialized homeostatic functions of resident macrophages. In the lung, steady-state signaling by the cytokine GM-CSF is critical for alveolar macrophage (AM) development and function. Here, we showed that CISH, a suppressor of cytokine signaling (SOCS) family member that is acutely induced by diverse cytokine stimuli in many tissues, was expressed constitutively in AMs in response to steady-state GM-CSF signaling.

[COVID-19 with respect to occupational healthcare and public health services].

Background: Healthcare personnel (HCP) have an occupation-related risk of an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and can transmit COVID-19 to patients. The related occupational disease is the BK 3101.

Objective: The frequency of suspected claims of occupation-related SARS-CoV‑2 infections and confirmed claims of COVID-19 occupational diseases, reporting obligations under the German Infection Protection Act (IfSG) and mandatory notification requirements of physicians.