The inherent influence of travel on an emerging feminist icon : Florence Nightingale abroad.

The primary intent of this research is to evaluate and deduce events leading up to, during, and after the travels of Florence Nightingale abroad in Europe and the near East. This work examines the perception of how enforced idleness brought about the madness of many Victorian women while others sought to find freedom outside the home. My scholarship investigates the influences on Florence Nightingale and what encouraged her to step outside the predetermined Victorian life set up by her family. The nineteenth century proved to be a pivotal period in the development of what would later become the women's movement. The goal is to show how Nightingale's heightened education, close relationship with her father, and specifically her extensive travel tendered the courage she needed to succeed in her lifelong call to service. Nightingale spent several years traveling with family friends, Selena and Charles Bracebridge, a couple who gave her unfettered freedom to explore the ancient cities of Rome, Athens, and Alexandria. In her youth she and her family took the Grand Tour and exposed her to Italian and French intellectuals and exiles during the Risorgimento in Italy. Most prior research on Nightingale focused on her life after she gained recognition for her work during the Crimean War and contribution to the fields of medicine and nursing. This focus inadvertently undermines the significance of unfettered movement and intellectual ventures that influenced her determination change the face of modern medicine. This research draws upon mostly primary sources including memoirs, published letters, and travel journals written by Florence Nightingale. The British Library and Wellcome Library of Medicine house two of the most comprehensive collections of Nightingale writing. The Wellcome Library has a wonderful collection of Florence Nightingale papers, including copies from the Verney Collection at the Claydon House. The Verney Collection is the contribution of Parthenope Verney (nee?ü Nightingale) and the most complete collection of Nightingale papers available. The scholarship on this subject has been exciting. Travel became an escape from gender roles and oppression for many Victorian women travelers. They became travel writers or accompanied family and friends on the many tours now available since the end of the Napoleonic Wars. Many female travelers identified with the people of the land as objects of study. They related to the native people because as women they were also objectified in Europe. As I delve deeper into the role of education and travel into women of the period a common thread begins to emerge, the most important being their insatiable thirst for knowledge. Nightingale saw wonders and experiences that no human will ever have these cultures and times are long past. What powerful forces she explored to become a founding feminist, a pioneer in medicine, and a staunch advocate for constant scholarly pursuits. Primary sources reflect the public statements and correspondence of Florence Nightingale. These particular sources are indicated the British Library, the Wellcome Library, and the London Metropolitan Archives. The British Library consisted of a majority of correspondence letters, some within manuscripts and other published. A considerable number of published sources from the archives at the Claydon House that now reside at the Wellcome Library. To this effect, the archives within Wellcome and published works within the British Library have contributed a host of rare and unique sources attributing to this research

Noninvasive ¹³C-octanoic acid breath test shows delayed gastric emptying in patients with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons. However, ALS has been recognized to also involve non-motor systems. Subclinical involvement of the autonomic system in ALS has been described. The recently developed C-13-octanoic acid breath test allows the noninvasive measurement of gastric emptying. With this new technique we investigated 18 patients with ALS and 14 healthy volunteers. None of the patients had diabetes mellitus or other disorders known to cause autonomic dysfunction. The participants received a solid standard test meal labeled with C-13-octanoic acid. Breath samples were taken at 15-min intervals for 5 h and were analyzed for (CO2)-C-13 by isotope selective nondispersive infrared spectrometry. Gastric emptying peak time (t(peak)) and emptying half time (t(1/2)) were determined. All healthy volunteers displayed normal gastric emptying with a mean emptying t(1/2) of 138 +/- 34 (range 68-172) min. Gastric emptying was delayed (t(1/2) > 160 min) in 15 of 18 patients with ALS. Emptying t(1/2) in ALS patients was 218 +/- 48 (range 126-278) min (p < 0.001). These results are compatible with autonomic involvement in patients with ALS, causing delayed gastric emptying of solids and encouraging the theory that ALS is a multisystem disease rather than a disease of the motor neurons only

Electric fields control water-gated proton transfer in cytochrome c oxidase

Funding Information: ACKNOWLEDGMENTS. This work was funded by the Knut and Alice Wallenberg Foundation (2019.0251 and 2019.0043 to V.R.I.K.). V.R.I.K. also acknowledges support from the German Research Foundation (DFG) via the Collaborative Research Centre (SFB1078) as Mercator Fellow. Computational resources were provided by Funding Information: the Swedish National Infrastructure for Computing (SNIC 2021/1-40, SNIC 2022/1-29) at the Center of High-Performance Computing (PDC), and by the Leibniz-Rechenzentrum. M.W. was supported by the Institute of Biotechnology, University of Helsinki. Funding Information: This work was funded by the Knut and Alice Wallenberg Foundation (2019.0251 and 2019.0043 to V.R.I.K.). V.R.I.K. also acknowledges support from the German Research Foundation (DFG) via the Collaborative Research Centre (SFB1078) as Mercator Fellow. Computational resources were provided by the Swedish National Infrastructure for Computing (SNIC 2021/1-40, SNIC 2022/1-29) at the Center of High-Performance Computing (PDC), and by the Leibniz-Rechenzentrum. M.W. was supported by the Institute of Biotechnology, University of Helsinki. Publisher Copyright: Copyright © 2022 the Author(s). Published by PNAS.Aerobic life is powered by membrane-bound enzymes that catalyze the transfer of electrons to oxygen and protons across a biological membrane. Cytochrome c oxidase (CcO) functions as a terminal electron acceptor in mitochondrial and bacterial respiratory chains, driving cellular respiration and transducing the free energy from O2 reduction into proton pumping. Here we show that CcO creates orientated electric fields around a nonpolar cavity next to the active site, establishing a molecular switch that directs the protons along distinct pathways. By combining large-scale quantum chemical density functional theory (DFT) calculations with hybrid quantum mechanics/ molecular mechanics (QM/MM) simulations and atomistic molecular dynamics (MD) explorations, we find that reduction of the electron donor, heme a, leads to dissociation of an arginine (Arg438)-heme a3 D-propionate ion-pair. This ion-pair dissociation creates a strong electric field of up to 1 V A21 along a water-mediated proton array leading to a transient proton loading site (PLS) near the active site. Protonation of the PLS triggers the reduction of the active site, which in turn aligns the electric field vectors along a second, "chemical," proton pathway. We find a linear energy relationship of the proton transfer barrier with the electric field strength that explains the effectivity of the gating process. Our mechanism shows distinct similarities to principles also found in other energy-converting enzymes, suggesting that orientated electric fields generally control enzyme catalysis.Peer reviewe

The Role of Bile in the Regulation of Exocrine Pancreatic Secretion

As early as 1926 Mellanby (1) was able to show that introduction of bile into the duodenum of anesthetized cats produces a copious flow of pancreatic juice. In conscious dogs, Ivy & Lueth (2) reported, bile is only a weak stimulant of pancreatic secretion. Diversion of bile from the duodenum, however, did not influence pancreatic volume secretion stimulated by a meal (3,4). Moreover, Thomas & Crider (5) observed that bile not only failed to stimulate the secretion of pancreatic juice but also abolished the pancreatic response to intraduodenally administered peptone or soap

Mode-multiplexing deep-strong light-matter coupling

Dressing quantum states of matter with virtual photons can create exotic effects ranging from vacuum-field modified transport to polaritonic chemistry, and may drive strong squeezing or entanglement of light and matter modes. The established paradigm of cavity quantum electrodynamics focuses on resonant light-matter interaction to maximize the coupling strength $\Omega_\mathrm{R}/\omega_\mathrm{c}$, defined as the ratio of the vacuum Rabi frequency and the carrier frequency of light. Yet, the finite oscillator strength of a single electronic excitation sets a natural limit to $\Omega_\mathrm{R}/\omega_\mathrm{c}$. Here, we demonstrate a new regime of record-strong light-matter interaction which exploits the cooperative dipole moments of multiple, highly non-resonant magnetoplasmon modes specifically tailored by our metasurface. This multi-mode coupling creates an ultrabroadband spectrum of over 20 polaritons spanning 6 optical octaves, vacuum ground state populations exceeding 1 virtual excitation quantum for electronic and optical modes, and record coupling strengths equivalent to $\Omega_\mathrm{R}/\omega_\mathrm{c}=3.19$. The extreme interaction drives strongly subcycle exchange of vacuum energy between multiple bosonic modes akin to high-order nonlinearities otherwise reserved to strong-field physics, and entangles previously orthogonal electronic excitations solely via vacuum fluctuations of the common cavity mode. This offers avenues towards tailoring phase transitions by coupling otherwise non-interacting modes, merely by shaping the dielectric environment

Effect of Intraduodenal Bile and Na-Taurodeoxycholate on Exocrine Pancreatic Secretion and on Plasma Levels of Secretin, Pancreatic Polypeptide, and Gastrin in Man

The effect of intraduodenally administered cattle bile (CB) and Na-taurodeoxycholate (TDC) on basal pancreatic secretion and plasma levels of secretin, pancreatic polypeptide (PP), and gastrin were investigated on two separate days in 10 fasting volunteers. Doses of 2-6 g CB and 20&600 mg TDC were given intraduodenally at 65-min intervals. Volume, bicarbonate, lipase, trypsin, amylase, and bilirubin were measured in 10-min fractions of duodenal juice, and GI peptides determined by radioimmunoassay. CB and TDC enhanced significantly and dose-dependently volume, bicarbonate and enzyme secretion, and plasma secretin and PP levels. In contrast, plasma gastrin showed only a marginal increase. We conclude that the hydrokinetic effect of intraduodenal CB and TDC is at least partially mediated by secretin. Gastrin could be ruled out as a mediator of the ecbolic effect, whereas other GI peptides, primarily CCK, and/or neural mechanisms must be considered possible mediators. Both pathways may also play a role in the PP release

Photocaged Hoechst enables subnuclear visualization and cell selective staining of DNA in vivo

Selective targeting of DNA by means of fluorescent labelling has become a mainstay in the life sciences. While genetic engineering serves as a powerful technique and allows for the visualization of nucleic acid by using DNA-targeting fluorescent fusion proteins in a cell-type and subcellular specific manner, it relies on the introduction of foreign genes. On the other hand, DNA-binding small fluorescent molecules can be used without genetic engineering but they are not spatially restricted. Here, we report a photocaged version of the DNA dye Hoechst33342 (pcHoechst), which can be uncaged using UV to blue light for the selective staining of chromosomal DNA in subnuclear regions of live cells. Expanding its application to a vertebrate model organism, we demonstrate uncaging in epithelial cells and short-term cell tracking  in vivo  in zebrafish. We envision pcHoechst as a valuable tool for targeting and interrogating DNA with precise spatiotemporal resolution in living cells and wild-type organisms

6- and 8-Prenylnaringenin, Novel Natural Histone Deacetylase Inhibitors Found in Hops, Exert Antitumor Activity on Melanoma Cells

Background/Aims: Prenylnaringenins are natural prenylflavonoids with anticancer properties. However, the underlying mechanisms have not been elucidated yet. Here we report a novel mode of action of 6- and 8-prenylnaringenin (PN) on human melanoma cells: Inhibition of cellular histone deacetylases (HDACs). Methods: We performed in silico and in vitro analyses using 6-PN or 8-PN to study a possible interaction of 6-PN or 8-PN with HDAC as well as Western blot and FACS analyses, real-time cell proliferation and cell viability assays to assess the impact of 6-PN and 8-PN on human metastatic melanoma cells. Results: In silico, 6-PN and 8-PN fit into the binding pocket of HDAC2, 4, 7 and 8, binding to the zinc ion of their catalytic center that is essential for enzymatic activity. In vitro, 100 µmol/L of 6-PN or 8-PN inhibited all 11 conserved human HDAC of class I, II and IV. In clinical oncology HDAC inhibitors are currently investigated as new anticancer compounds. In line, treatment of SK-MEL-28 cells with 6-PN or 8-PN induced a hyperacetylation of histone complex H3 within 2 h. Further, 6-PN or 8-PN mediated a prominent, dose-dependent reduction of cellular proliferation and viability of SK-MEL-28 and BLM melanoma cells. This effect was apoptosis-independent and accompanied by down-regulation of mTOR-specific pS6 protein via pERK/pP90 in SK-MEL-28 cells. Conclusion: The identification of a broad inhibitory capacity of 6-PN and 8-PN for HDAC enzymes with antiproliferative effects on melanoma cells opens the perspective for clinical application as novel anti-melanoma drugs and the usage as innovative lead structures for chemical modification to enhance pharmacology or inhibitory activities

Intensified concurrent chemoradiotherapy with 5-fluorouracil and irinotecan as neoadjuvant treatment in patients with locally advanced rectal cancer

This study aimed to evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy intensified with irinotecan in patients with locally advanced rectal cancer. Eligible patients had nonmetastatic disease at a locally advanced stage that made R0 resection and sphincter preservation uncertain. They received preoperative radiation over 6 weeks to 45 Gy and boost of 5.4 Gy and concurrent continuous infusion 5-fluorouracil 250 mg m−2 day−1 and weekly irinotecan 40 mg m−2. In all, 37 patients entered the study. T stage at baseline as determined by ultrasound was T2/T3/T4 in 2/19/16 patients; 31 patients had lymph node involvement. The predominant toxicity was diarrhoea (grade 3/4 in 10/2 patients). Haematologic toxicity and surgical complications were moderate. Among 36 patients undergoing surgery, 32 (89%) had R0 resection and 23 (64%) sphincter preservation. Pathologic complete response (pCR) was achieved in eight (22%) of 36 patients, and 10 patients (28%) had only microscopic residual disease. At 4 years, overall survival was 66%, disease-free survival 73%, local relapse rate 7%, and distant failure rate 24%. Extent of resection and postoperative nodal status were significant predictors of overall and disease-free survival. Intensified neoadjuvant chemoradiotherapy with irinotecan can be safely administered and results in a high pCR rate