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With a goal of determining an absolute free energy scale for ion hydration, quasi-chemical theory and ab initio quantum mechanical simulations are employed to obtain an accurate value for the bulk hydration free energy of the Na⁺ ion. The free energy is partitioned into three parts: 1) the inner-shell or chemical contribution that includes direct interactions of the ion with nearby waters, 2) the packing free energy that is the work to produce a cavity of size λ in water, and 3) the long-range contribution that involves all interactions outside the inner shell. The interfacial potential contribution to the free energy resides in the long-range term. By averaging cation and anion data for that contribution, cumulant terms of all odd orders in the electrostatic potential are removed. The computed total is then the bulk hydration free energy. Comparison with the experimentally derived real hydration free energy produces an effective surface potential of water in the range −0.4 to −0.5 V. The result is consistent with a variety of experiments concerning acid–base chemistry, ion distributions near hydrophobic interfaces, and electric fields near the surface of water droplets.

Hypoxia in germinal centres regulates B cell class switching via its effects on mTOR complex 1 and activation-induced cytosine deaminase activity. Oxygen restriction in germinal centres Oxygen delivery and local hypoxia have been extensively studied in solid tumours in relation to immunobiology of cancer, but little is known about the microanatomy of oxygen concentrations around cells in different zones of the secondary lymphoid organs. This paper shows that oxygen — the supply of which is central to intermediary metabolism — is naturally restricted in germinal centres and influences B-lymphocyte function. Specifically, Mark Boothby and colleagues show that germinal centre hypoxia regulates antibody class switching via its effects on the activity of mTOR complex 1 and the cytosine deaminase AID. Germinal centres (GCs) promote humoral immunity and vaccine efficacy. In GCs, antigen-activated B cells proliferate, express high-affinity antibodies, promote antibody class switching, and yield B cell memory 1 , 2 . Whereas the cytokine milieu has long been known to regulate effector functions that include the choice of immunoglobulin class 3 , 4 , both cell-autonomous 5 and extrinsic 6 , 7 metabolic programming have emerged as modulators of T-cell-mediated immunity 8 . Here we show in mice that GC light zones are hypoxic, and that low oxygen tension ( ) alters B cell physiology and function. In addition to reduced proliferation and increased B cell death, low impairs antibody class switching to the pro-inflammatory IgG2c antibody isotype by limiting the expression of activation-induced cytosine deaminase (AID). Hypoxia induces HIF transcription factors by restricting the activity of prolyl hydroxyl dioxygenase enzymes, which hydroxylate HIF-1α and HIF-2α to destabilize HIF by binding the von Hippel–Landau tumour suppressor protein (pVHL) 7 . B-cell-specific depletion of pVHL leads to constitutive HIF stabilization, decreases antigen-specific GC B cells and undermines the generation of high-affinity IgG, switching to IgG2c, early memory B cells, and recall antibody responses. HIF induction can reprogram metabolic and growth factor gene expression. Sustained hypoxia or HIF induction by pVHL deficiency inhibits mTOR complex 1 (mTORC1) activity in B lymphoblasts, and mTORC1-haploinsufficient B cells have reduced clonal expansion, AID expression, and capacities to yield IgG2c and high-affinity antibodies. Thus, the normal physiology of GCs involves regional variegation of hypoxia, and HIF-dependent oxygen sensing regulates vital functions of B cells. We propose that the restriction of oxygen in lymphoid organs, which can be altered in pathophysiological states, modulates humoral immunity.

The epidemiological approach to converting radon exposure to effective dose is examined. Based on the definition of the effective dose, the dose conversion is obtained from the equivalence of lung-specific detriment associated with low-LET radiation and with radon exposure. This approach most reliably estimates effective dose per radon exposure on the basis of epidemiological data and implicitly includes the radiation weighting factor required to calculate the effective dose from radon exposure using the dosimetric approach, applying biokinetic and dosimetric models. Consistency between the results of the epidemiological and dosimetric approaches is achieved by using a radiation weighting factor of about 10 for alpha particles instead of the current ICRP value of 20. In contrast, the epidemiological approach implemented in ICRP 65, and referred to as dose conversion convention, was based on direct comparison of total radiation detriment with lung detriment from radon exposure. With the revision of radiation detriments in ICRP 103, this approach can be judged to overestimate the effective dose per radon exposure by about a factor of two because the tissue weighting factor for lung differs from the value of relative detriment to which it relates.

Sjögren's disease is a chronic autoimmune disease with an unmet need for targeted therapies. The aim of the TWINSS study is to evaluate the safety and efficacy of iscalimab, a monoclonal antibody against CD40, in patients with active Sjögren's disease. This randomised, double-blind, placebo-controlled, phase 2b study, conducted at 71 sites in 23 countries, enrolled patients aged 18 years or older fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology (EULAR) 2016 criteria. In the dose-ranging cohort 1, patients with a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 or higher and a EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or higher were randomly assigned (1:1:1:1) to subcutaneous iscalimab 150 mg, 300 mg, 600 mg, or placebo. In the proof-of-concept cohort 2, patients with an ESSDAI score of less than 5, ESSPRI (dryness or fatigue) score of 5 or higher, and Impact of Dry Eye on Everyday Life score of 30 or higher were randomly assigned (1:1) to iscalimab 600 mg or placebo. The sponsor, investigator, site personnel, and patients were masked to the treatment assignment. The primary objectives were to demonstrate a dose–response relationship of iscalimab based on the change in ESSDAI from baseline to week 24 in cohort 1 by Multiple Comparison Procedure—Modelling (MCP-Mod), and to assess the effect of iscalimab 600 mg on ESSPRI at week 24 in cohort 2. All the efficacy analyses included all patients who were randomly assigned, and safety analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03905525), and is complete. Between Oct 1, 2019, and Feb 28, 2022, 460 patients were screened; 173 patients were assigned to cohort 1 (44 to iscalimab 150 mg, 43 to 300 mg, 43 to 600 mg, and 43 to placebo) and 100 to cohort 2 (50 to each group). In cohort 1, the MCP step showed a significant dose–response relationship for placebo-adjusted ESSDAI change from baseline in one of four models (Linlog model, one-sided p=0·0041). ESSDAI decreased from baseline to week 24 with all three doses of iscalimab; 150 mg and 600 mg doses showed statistically significant improvement (placebo-adjusted least squares [LS] mean difference –3·0 [95% CI –4·9 to –1·1]; p=0·0025 for 150 mg and –2·9 [–4·9 to –1·0]; p=0·0037 for 600 mg). In cohort 2, ESSPRI showed a trend towards improvement with iscalimab 600 mg (placebo-adjusted LS mean change from baseline –0·57 points [95% CI –1·30 to 0·15]; p=0·12). Serious adverse events were reported in nine patients in cohort 1 (one [2%] of 43 in the placebo group, one [2%] of 44 in the iscalimab 150 mg group, three [7%] of 42 in the 300 mg group, four [9%] of 44 in the 600 mg group) and four patients in cohort 2 (two [4%] of 50 in each group). No deaths occurred over the 24-week period. The study met the primary objective of demonstrating a significant dose–response relationship with iscalimab in terms of disease activity at week 24. Iscalimab was well tolerated and showed initial clinical benefit over placebo in two distinct populations of patients with Sjögren's disease, to be confirmed in larger trials. Novartis Pharma.

The measurement performance and characteristics of electronic radon monitors with respect to radiological and environmental parameters are investigated. The study includes a sample of 14 different types of devices from nine manufacturers. The devices are currently available on the market with acquisition costs in the low or medium range. For comparison purposes, a high-end AlphaGUARD device is included in the study as a benchmark for measurement performance of radon monitors. Significant differences in the measurement performance are found between the tested instrument types. Overall, however, it can be concluded that most radon monitors perform acceptably and provide reliable information on radon activity concentrations in homes or workplaces, allowing residents and employers to make decisions about the need for radon protection measures. But it turns out that many radon monitors are supplied by the manufacturer with inadequate calibration, so that the instruments must be additionally calibrated in a reference atmosphere before they can be used. Among the tested radon monitors, there are also types with sufficiently good measuring performance, which represent an inexpensive alternative to high-end devices for radon professionals.

Normal brain function hinges on energy-intensive processes. Consequently, alterations to the brain’s metabolic state are common hallmarks in several pathological conditions. Phosphorus Magnetic Resonance Spectroscopy ( 31 P MRS) is a noninvasive method for measuring key markers of brain energy metabolism, including adenosine triphosphate (ATP), inorganic phosphate (Pi), and phosphocreatine (PCr), as well as markers for cell membrane phospholipid turnover, phosphomonoester (PME) and phosphodiester (PDE). Preclinical rodent 31 P MRS has so far been done under anesthesia - with isoflurane being one of the most commonly used anesthetic agents. The use of isoflurane in 31 P MRS is a concern, as anesthetics are known to affect neuronal activity and energy metabolism in the brain. Its use therefore comes with a risk of perturbing brain physiology. Awake mouse MRS avoids this and allows the effect of isoflurane to be quantified. Thus, we here compare mouse brain 31 P MRS in awake MR-habituated mice and isoflurane anesthesia. We find that 31 P metabolite levels differ between the awake state and isoflurane anesthesia in mice. Our findings show that low-dose isoflurane anesthesia reduces PCr levels in the mouse brain and is accompanied by decreases in intracellular pH and decreased PME levels.

Hip fracture risk rises 100 to 1000-fold over 60 years of ageing. Loss of resistance to bending is not a major feature of normal ageing of the femoral neck. Another cause of fragility is local buckling or elastic instability. Bones adapt to their local experience of mechanical loading. The suggestion that bipedalism allows thinning of the underloaded superolateral femoral neck cortex arises from the failure of walking to transmit much mechanical load to this region. We aimed to measure whether elastic instability increases greatly with age since it might trigger hip fracture in a sideways fall. We measured with computed tomography the distribution of bone in the mid-femoral neck of 77 proximal femurs from people who died suddenly aged 20–95 years. We then calculated the critical stress, from the geometric properties and density of the cortical zone most highly loaded in a sideways fall, as a threshold for elastic instability. With normal ageing, this thin cortical zone in the upper femoral neck became substantially thinner. Relative to mean values at age 60 years, female cortical thickness declined by 6·4% (SD 1·1) per decade (p<0·0001), and critical stress by 13·2% (4·3) per decade (p=0·004) in the superoposterior octant compressed most in a sideways fall. Similar, but significantly smaller, effects were evident in men (p=0·004). This thinning compromised the capacity of the femur to absorb energy independently of osteoporosis. Patients with hip fracture had further reduced stability. As women age, hip fragility increases because underloading of the superolateral cortex leads to atrophic thinning. Because walking does not sufficiently load the upper femoral neck, the fragile zones in healthy bones may need strengthening, for example with more well targeted exercise.

Background microRNAs (miRNAs) are considered promising cancer biomarkers, showing high reliability, sensitivity and stability. Our study aimed to identify associations between whole blood miRNA profiles, presence of circulating tumor cells (CTCs) and clinical outcome in post-operative early breast cancer patients (EBC) to assess the utility of miRNAs as prognostic markers in this setting. Method A total of 48 post-operative patients, recruited in frame of the SUCCESS A trial, were included in this retrospective study and tested with a panel of 8 miRNAs (miR-10b, −19a, − 21, − 22, −20a, − 127, − 155, −200b). Additional 17 female healthy donors with no previous history of cancer were included in the study as negative controls. Blood samples were collected at different time points (pre-adjuvant therapy, post-adjuvant therapy, 2 years follow up), total RNA was extracted and the relative concentration of each miRNA was measured by quantitative PCR and compared in patients stratified on blood collection time or CTC detection. Furthermore, we compared miRNA profiles of patients, for each time point separately, and healthy donors. CTCs were visualized and quantified with immunocytochemistry analysis. Data were analyzed using non-parametric statistical tests. Results In our experimental system, miR-19a, miR-22 and miR-127 showed the most promising results, differentiating patients at different time points and from healthy controls, while miR-20a, miR-21 and miR-200b did not show any difference among the different groups. miR-10b and miR-155 were never detectable in our experimental system. With respect to patients’ clinical characteristics, we found a significant correlation between miR-200b and lymph node status and between miR-20a and tumor type. Furthermore, miR-127 correlated with the presence of CTCs. Finally, we found a borderline significance between Progression Free Survival and miR-19a levels. Conclusions This pilot study suggests that profiling whole blood miRNAs could help to better stratify post-operative EBC patients without any sign of metastasis to prevent later relapse or metastatic events.