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Background: Long coronavirus disease (COVID; LC) affects millions of people worldwide. The exact mechanisms which result in a broad, undulating and detrimental symptom profile remain unknown. Blood biomarkers associated with LC have been described; however, consensus on these remains elusive, in part due to a lack of continuity between studies on a universally accepted definition of LC. This systematic review aimed to consolidate current knowledge of blood biomarkers associated with the prevalence of LC on the basis of the World Health Organisation (WHO) clinical definition of this condition., Eligibility Criteria for Selecting Studies: Observational, cross-sectional, and randomised control studies published in the English language that studied blood biomarkers associated with the WHO definition of LC. All studies included participants who were ≥ 18 years old and group sizes ≥ 10 participants, and were compared against a control group without any known co-morbidities., Methods: A systematic literature search was conducted according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and prospectively registered on Prospero (ID: CRD42022373121). The Cochrane, Embase, PubMed and Web of Science databases were searched from inception to January 2024. Search results were gathered using Rayyan software and data extracted using Microsoft Excel. The reporting recommendations for tumour markers prognostic studies (REMARK) questionnaire was used to assess the quality of the included studies., Results: A total of 45 observational and one interventional study comprising 4415 participants were included in this review which identified 525 blood biomarkers thought to be associated with LC. Three blood biomarker subtypes were associated with the development of LC: (1) immunological and inflammatory dysfunction, (2) endothelial/vascular dysfunction and (3) metabolic and clotting abnormalities., Discussion and Conclusions: Our data are consistent with previous findings; however, no single biomarker was sufficiently associated with LC prevalence and instead a profile of biomarkers across various physiological systems may be more clinically useful. In all, 196 studies were excluded due to a lack of an adequately healthy comparator group and/or failure to meet the WHO LC definition. This demonstrates a need for further research incorporating a universal LC definition across all disease severity groups and symptom profiles, and longitudinal data reflecting the relapsing and remitting nature of this condition. Further investigation into blood biomarkers of LC, including clear reporting of healthy comparator groups and the investigation of acute and chronic biomarker changes, within the context of medical practice, may support the development of curative/restorative approaches., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The non-essential amino acid serine is a critical nutrient for cancer cells due to its diverse biosynthetic functions. While some tumors can synthesize serine de novo, others are auxotrophic and therefore reliant on serine uptake. Importantly, despite several transporters being known to be capable of transporting serine, the transporters that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (SLC1A5) as a major contributor to serine uptake in cancer cells. ASCT2 is well known as a glutamine transporter in cancer, and our work demonstrates that serine and glutamine compete for uptake through ASCT2. We further show that ASCT2-mediated serine uptake is essential for purine nucleotide biosynthesis and that estrogen receptor α (ERα) promotes serine uptake by directly activating SLC1A5 transcription. Collectively, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target., Competing Interests: Declaration of interests P.K.S. is a member of the SAB or BOD for Applied Biomath, RareCyte. Nanostring, Glencoe Software, and Montai; he is consultant for Merck. None of these activities impact the content of this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Control of cellular identity requires coordination of developmental programs with environmental factors such as nutrient availability, suggesting that perturbing metabolism can alter cell state. Here, we find that nucleotide depletion and DNA replication stress drive differentiation in human and murine normal and transformed hematopoietic systems, including patient-derived acute myeloid leukemia (AML) xenografts. These cell state transitions begin during S phase and are independent of ATR/ATM checkpoint signaling, double-stranded DNA break formation, and changes in cell cycle length. In systems where differentiation is blocked by oncogenic transcription factor expression, replication stress activates primed regulatory loci and induces lineage-appropriate maturation genes despite the persistence of progenitor programs. Altering the baseline cell state by manipulating transcription factor expression causes replication stress to induce genes specific for alternative lineages. The ability of replication stress to selectively activate primed maturation programs across different contexts suggests a general mechanism by which changes in metabolism can promote lineage-appropriate cell state transitions., Competing Interests: Declaration of interests D.B.S. is a co-founder of and holds equity in Clear Creek Bio. M.G.V.H. is on the scientific advisory board of Agios Pharmaceuticals, iTeos Therapeutics, Drioa Ventures, Sage Therapeutics, Lime Therapeutics, Pretzel Therapeutics, and Auron Therapeutics, and is on the advisory board of Developmental Cell. P.P.H. has consulted for Auron Therapeutics. J.S.W. serves as an advisor to and/or has equity in KSQ Therapeutics, Maze Therapeutics, and 5AM Ventures. J.M.R. consults for Maze Therapeutics, Waypoint Bio, and Third Rock Ventures. I.S.H. reports financial support from Kojin Therapeutics and consulting fees for Ono Pharma USA., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Blocking the import of nutrients essential for cancer cell proliferation represents a therapeutic opportunity, but it is unclear which transporters to target. Here we report a CRISPR interference/activation screening platform to systematically interrogate the contribution of nutrient transporters to support cancer cell proliferation in environments ranging from standard culture media to tumours. We applied this platform to identify the transporters of amino acids in leukaemia cells and found that amino acid transport involves high bidirectional flux dependent on the microenvironment composition. While investigating the role of transporters in cystine starved cells, we uncovered a role for serotonin uptake in preventing ferroptosis. Finally, we identified transporters essential for cell proliferation in subcutaneous tumours and found that levels of glucose and amino acids can restrain proliferation in that environment. This study establishes a framework for systematically identifying critical cellular nutrient transporters, characterizing their function and exploring how the tumour microenvironment impacts cancer metabolism., (© 2024. The Author(s).)

Cardiovascular (CV) disease (CVD) is a leading cause of premature death and hospitalization which places a significant strain on health services and economies around the World. Evidence from decades of empirical and observational research demonstrates clear associations between physical activity (PA) and cardiorespiratory fitness (CRF) which can offset the risk of mortality and increase life expectancy and the quality of life in patients. Whilst well documented, the narrative of increased CRF remained pertinent during the coronavirus disease 2019 (COVID-19) pandemic, where individuals with lower levels of CRF had more than double the risk of dying from COVID-19 compared to those with a moderate or high CRF. The need to better understand the mechanisms associated with COVID-19 and those that continue to be affected with persistent symptoms following infection (Long COVID), and CV health is key if we are to be able to effectively target the use of CRF and PA to improve the lives of those suffering its afflictions. Whilst there is a long way to go to optimise PA and CRF for improved health at a population level, particularly in a post-pandemic world, increasing the understanding using a cellular-to-systems approach, we hope to provide further insight into the benefits of engaging in PA., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Caffeine ingestion may influence balance control via numerous mechanisms. Although previously investigated using various study designs and methods, here we aimed to create the first evidence-based consensus regarding the effects of caffeine on the control of upright stance via systematic review (PROSPERO registration CRD42021226939). Embase, PubMed/MEDLINE, SPORTDiscus and Web of Science databases were searched on 27 January 2021 to identify placebo-controlled trials investigating caffeine-induced changes in human standing balance. Reference lists of eligible studies were also searched. Overall, nine studies involving a total of 290 participants were included. All studies were moderate to strong in quality according to the QualSyst tool. Balance-related outcome measures were collected across a range of different participant ages, stances and sensory conditions. The results show that younger participants' balance was generally unaffected by caffeine ingestion. However, a significant balance impairment was observed following caffeine ingestion in all studies involving older participants (average age >65 years). Our results therefore suggest an age-dependent effect of caffeine ingestion on human standing. Further research into this effect is warranted as only one study has directly compared younger and older adults. Nonetheless, an important implication of our findings is that caffeine ingestion may increase fall risk in older adults. Furthermore, based on our findings, caffeine ingestion should be considered as a potential confounding factor when assessing human standing balance, particularly in older adults.

Despite climbing's popularity and an increasing number of female participants, there are limited anthropometric and performance data for this population. This study compares the characteristics of 55 experienced female climbers, divided into three categories (lower [ADV-L] and higher advanced [ADV-H] and elite [ELT]) based on self-reported ability. Data on climbing experience, body dimensions, body composition, flexibility, lower and upper-body power and finger strength were assessed. ELT climbers differed significantly from the ADV groups in age (Mean Difference [MD] = 8.8-9.8 yrs; despite smaller differences in years climbing MD = 1.6-2.4 yrs), greater climbing and hours training per week (MD = 3.0-3.7 h & MD = 0.9-1.6 h, respectively), and greater upper-body power (MD = 12.9-16.6 cm) and finger strength (MD = 51.6-65.4 N). Linear regression analysis showed finger strength and upper body power to be associated with ability, particularly when adjusting for descriptive and anthropometric variables (finger strength R 2  = 53% and 45%; upper-body power R 2  = 60% and 39% for boulder and sport, respectively). The findings support the importance of finger strength and upper-body power; changes in female anthropometric data over the last decade provide insight into the changing nature of the sport.

Rapid, inexpensive, robust diagnostics are essential to control the spread of infectious diseases. Current state of the art diagnostics are highly sensitive and specific, but slow, and require expensive equipment. Here we report the development of a molecular diagnostic test for SARS-CoV-2 based on an enhanced recombinase polymerase amplification (eRPA) reaction. eRPA has a detection limit on patient samples down to 5 viral copies, requires minimal instrumentation, and is highly scalable and inexpensive. eRPA does not cross-react with other common coronaviruses, does not require RNA purification, and takes ~45 min from sample collection to results. eRPA represents a first step toward at-home SARS-CoV-2 detection and can be adapted to future viruses within days of genomic sequence availability.

Targeted inhibition of oncogenic pathways can be highly effective in halting the rapid growth of tumors but often leads to the emergence of slowly dividing persister cells, which constitute a reservoir for the selection of drug-resistant clones. In BRAF V600E melanomas, RAF and MEK inhibitors efficiently block oncogenic signaling, but persister cells emerge. Here, we show that persister cells escape drug-induced cell-cycle arrest via brief, sporadic ERK pulses generated by transmembrane receptors and growth factors operating in an autocrine/paracrine manner. Quantitative proteomics and computational modeling show that ERK pulsing is enabled by rewiring of mitogen-activated protein kinase (MAPK) signaling: from an oncogenic BRAF V600E monomer-driven configuration that is drug sensitive to a receptor-driven configuration that involves Ras-GTP and RAF dimers and is highly resistant to RAF and MEK inhibitors. Altogether, this work shows that pulsatile MAPK activation by factors in the microenvironment generates a persistent population of melanoma cells that rewires MAPK signaling to sustain non-genetic drug resistance., Competing Interests: Declaration of Interests P.K.S. is a member of the SAB or BOD of Glencoe Software, Applied Biomath, and RareCyte and has equity in these companies and is on the SAB of and NanoString. In the last five years the Sorger lab has received research funding from Novartis and Merck. P.K.S. declares that none of these relationships are directly or indirectly related to the content of this manuscript. R.W. is a co-founder of T2Biosystems and Lumicell, serves as a scientific advisor for ModeRNA Therapeutics, Tarveda Therapeutics, and Alivio Therapeutics. None of these activities are related to the manuscript. The other authors declare that they have no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Curative cancer therapies are uncommon and nearly always involve multi-drug combinations developed by experimentation in humans; unfortunately, the mechanistic basis for the success of such combinations has rarely been investigated in detail, obscuring lessons learned. Here, we use isobologram analysis to score pharmacological interaction, and clone tracing and CRISPR screening to measure cross-resistance among the five drugs comprising R-CHOP, a combination therapy that frequently cures Diffuse Large B-Cell Lymphomas. We find that drugs in R-CHOP exhibit very low cross-resistance but not synergistic interaction: together they achieve a greater fractional kill according to the null hypothesis for both the Loewe dose-additivity model and the Bliss effect-independence model. These data provide direct evidence for the 50 year old hypothesis that a curative cancer therapy can be constructed on the basis of independently effective drugs having non-overlapping mechanisms of resistance, without synergistic interaction, which has immediate significance for the design of new drug combinations., Competing Interests: AP, CC No competing interests declared, PS is a member of the SAB or Board of Directors of Merrimack Pharmaceuticals, Glencoe Software, Applied Biomath and RareCyte Inc and has equity in these companies. In the last five years the Sorger lab has received research funding from Novartis and Merck. PKS declares that none of these relationships are directly or indirectly related to the content of this manuscript, (© 2019, Palmer et al.)

Purpose: Periods of intensified training are associated with immune disturbances, The aim was to investigate the effects of supplementation with Chlorella pyrenoidosa (Chlorella) on secretory IgA (sIgA) responses to 2 days intensified training., Methods: Twenty-six subjects (age 29.1 ± 8.7 years; VO 2max 53.7 ± 11.7 ml kg min -1 ) provided resting saliva samples for determination of sIgA, at baseline (week-0) and following 4, 5, and 6 weeks (weeks-4, -5, -6) of daily supplementation with 6 g/day Chlorella (n = 13) or placebo (PLA, n = 13). During week-4 a 2-day intensified training period was undertaken [morning and afternoon sessions each day, respectively: VO 2max test; high-intensity interval training (HIIT, 3 × 30 s Wingate sprints); 90 min at ~60% VO 2max ; 3 × 30 s HIIT]., Results: Chlorella increased resting sIgA secretion rate (trial × time, P = 0.016: no change with PLA but increases with Chlorella at week-4, week-5 and week-6, P = 0.020, <0.001, and 0.016). PLA vs Chlorella: week-0 = 54 ± 33 vs 57 ± 37 µg/min; week-4 = 54 ± 35 vs 83 ± 57 µg/min; week-5 = 63 ± 46 vs 98 ± 47 µg/min; week-6 = 58 ± 35 vs 85 ± 59 µg/min. Minimal acute changes in sIgA were seen in response to individual exercise bouts, but it was higher at some times in the Chlorella group (for bouts 2 and 3)., Conclusion: Supplementation with Chlorella has beneficial effects on resting sIgA, which might be beneficial during periods of intensified training.

Phenotypic screens allow the identification of small molecules with promising anticancer activity, but the difficulty in characterizing the mechanism of action of these compounds in human cells often undermines their value as drug leads. Here, we used a loss-of-function genetic screen in human haploid KBM7 cells to discover the mechanism of action of the anticancer natural product ophiobolin A (OPA). We found that genetic inactivation of de novo synthesis of phosphatidylethanolamine (PE) mitigates OPA cytotoxicity by reducing cellular PE levels. OPA reacts with the ethanolamine head group of PE in human cells to form pyrrole-containing covalent cytotoxic adducts and these adducts lead to lipid bilayer destabilization. Our characterization of this unusual cytotoxicity mechanism, made possible by unbiased genetic screening in human cells, suggests that the selective antitumor activity displayed by OPA may be due to altered membrane PE levels in cancer cells.

We introduce an approach for detection of drug-protein interactions that combines a new yeast three-hybrid screening for identification of interactions with affinity chromatography for their unambiguous validation. We applied the methodology to the profiling of clinically approved drugs, resulting in the identification of previously known and unknown drug-protein interactions. In particular, we were able to identify off-targets for erlotinib and atorvastatin, as well as an enzyme target for the anti-inflammatory drug sulfasalazine. We demonstrate that sulfasalazine and its metabolites, sulfapyridine and mesalamine, are inhibitors of the enzyme catalyzing the final step in the biosynthesis of the cofactor tetrahydrobiopterin. The interference with tetrahydrobiopterin metabolism provides an explanation for some of the beneficial and deleterious properties of sulfasalazine and furthermore suggests new and improved therapies for the drug. This work thus establishes a powerful approach for drug profiling and provides new insights in the mechanism of action of clinically approved drugs.

The identification of all protein targets of a given drug or bioactive molecule within the human body is a prerequisite for an understanding of its beneficial and deleterious activities. Current approaches to reveal protein targets often fail to reveal physiologically relevant interactions. Here we review a recently introduced yeast-based approach for the identification of the binding partners of small molecules. We discuss the advantages and limitations of the approach using the clinically approved drug sulfasalazine as an example.

Bioconjugations often rely on adaptor molecules to cross-link different biomolecules. In this work, we introduce the molecular adaptor covalin, which is a protein chimera of two self-labeling proteins with nonoverlapping substrate specificity. Covalin permits a selective and covalent heteroconjugation of biomolecules displaying appropriate functional groups. Examples for the use of covalin include the specific heteroconjugation of a reporter enzyme to an antibody and of molecular probes to the surface of living cells. The efficiency and specificity of covalin-based bioconjugations together with the availability of a large variety of substrates create immediate and ubiquitous applications for covalin in bioconjugate chemistry.