Atmospheric dispersion management in mid-IR mode-locked oscillators.

The atmospheric dispersion in the mid-infrared transparency windows presents an important albeit often neglected factor when developing ultrashort-pulsed lasers. We show that it can amount to hundreds of fs2 in 2-3 µm window with typical laser round-trip path lengths. Using the Cr:ZnS ultrashort-pulsed laser as a test-bed, we demonstrate the atmospheric dispersion influence on femtosecond and chirped-pulse oscillator performance and show that the humidity fluctuations can be compensated by an active dispersion control, greatly improving stability of mid-IR few-optical cycle laser sources. The approach can be readily extended to any ultrafast source in the mid-IR transparency windows.

High peak power and energy scaling in the mid-IR chirped-pulse oscillator-amplifier laser systems.

The paper introduces a new route towards the ultrafast high laser peak power and energy scaling in a hybrid mid-IR chirped pulse oscillator-amplifier (CPO-CPA) system, without sacrificing neither the pulse duration nor energy. The method is based on using a CPO as a seed source allowing the beneficial implementation of a dissipative soliton (DS) energy scaling approach, coupled with a universal CPA technique. The key is avoiding a destructive nonlinearity in the final stages of an amplifier and compressor elements by using a chirped high-fidelity pulse from CPO. Our main intention is to realize this approach in a Cr2+:ZnS-based CPO as a source of energy-scalable DSs with well-controllable phase characteristics for a single-pass Cr2+:ZnS amplifier. A qualitative comparison of experimental and theoretical results provides a road map for the development and energy scaling of the hybrid CPO-CPA laser systems, without compromising pulse duration. The suggested technique opens up a route towards extremely intense ultra-short pulses and frequency combs from the multi-pass CPO-CPA laser systems that are particularly interesting for real-life applications in the mid-IR spectral range from 1 to 20 µm.

A Study of a Protein-Folding Machine: Transient Rotation of the Polypeptide Backbone Facilitates Rapid Folding of Protein Domains in All-Atom Molecular Dynamics Simulations.

Molecular dynamics simulations of protein folding typically consider the polypeptide chain at equilibrium and in isolation from the cellular components. We argue that in order to understand protein folding as it occurs in vivo, it should be modeled as an active, energy-dependent process, in which the cellular protein-folding machine directly manipulates the polypeptide. We conducted all-atom molecular dynamics simulations of four protein domains, whose folding from the extended state was augmented by the application of rotational force to the C-terminal amino acid, while the movement of the N-terminal amino acid was restrained. We have shown earlier that such a simple manipulation of peptide backbone facilitated the formation of native structures in diverse α-helical peptides. In this study, the simulation protocol was modified, to apply the backbone rotation and movement restriction only for a short time at the start of simulation. This transient application of a mechanical force to the peptide is sufficient to accelerate, by at least an order of magnitude, the folding of four protein domains from different structural classes to their native or native-like conformations. Our in silico experiments show that a compact stable fold may be attained more readily when the motions of the polypeptide are biased by external forces and constraints.

An ancient evolutionary connection between Ribonuclease A and EndoU families.

The ribonuclease A family of proteins is well studied from the biochemical and biophysical points of view, but its evolutionary origins are obscure, as no sequences homologous to this family have been reported outside of vertebrates. Recently, the spatial structure of the ribonuclease domain from a bacterial polymorphic toxin was shown to be closely similar to the structure of vertebrate ribonuclease A. The absence of sequence similarity between the two structures prompted a speculation of convergent evolution of bacterial and vertebrate ribonuclease A-like enzymes. We show that bacterial and homologous archaeal polymorphic toxin ribonucleases with a known or predicted ribonuclease A-like fold are distant homologs of the ribonucleases from the EndoU family, found in all domains of cellular life and in viruses. We also detected a homolog of vertebrate ribonucleases A in the transcriptome assembly of the sea urchin Mesocentrotus franciscanus These observations argue for the common ancestry of prokaryotic ribonuclease A-like and ubiquitous EndoU-like ribonucleases, and suggest a better-grounded scenario for the origin of animal ribonucleases A, which could have emerged in the deuterostome lineage, either by an extensive modification of a copy of an EndoU gene, or, more likely, by a horizontal acquisition of a prokaryotic immunity-mediating ribonuclease gene.

Efficient high-energy Raman soliton generation in a Tm:doped large mode area fiber amplifier.

We report the Tm-doped all-fiber MOPA based on a LMA active fiber generating Raman solitons tunable in the range 1970-2300 nm directly from the LMA fiber. By tuning the chirp of the input pulse we reached more than 90 % energy transfer efficiency to Raman soliton. Solitons with 125 fs duration and up to 24 nJ energy are demonstrated in LMA fiber amplifier. We show experimentally that Raman solitons experience both amplification and absorption in active fiber components of the laser system and that the energy of a Raman soliton generated in an LMA fiber amplifier is limited by the soliton area theorem.

Is Protein Folding a Thermodynamically Unfavorable, Active, Energy-Dependent Process?

The prevailing current view of protein folding is the thermodynamic hypothesis, under which the native folded conformation of a protein corresponds to the global minimum of Gibbs free energy G. We question this concept and show that the empirical evidence behind the thermodynamic hypothesis of folding is far from strong. Furthermore, physical theory-based approaches to the prediction of protein folds and their folding pathways so far have invariably failed except for some very small proteins, despite decades of intensive theory development and the enormous increase of computer power. The recent spectacular successes in protein structure prediction owe to evolutionary modeling of amino acid sequence substitutions enhanced by deep learning methods, but even these breakthroughs provide no information on the protein folding mechanisms and pathways. We discuss an alternative view of protein folding, under which the native state of most proteins does not occupy the global free energy minimum, but rather, a local minimum on a fluctuating free energy landscape. We further argue that ΔG of folding is likely to be positive for the majority of proteins, which therefore fold into their native conformations only through interactions with the energy-dependent molecular machinery of living cells, in particular, the translation system and chaperones. Accordingly, protein folding should be modeled as it occurs in vivo, that is, as a non-equilibrium, active, energy-dependent process.

Cascade Transformations of 1-R-Ethynyl-9,10-anthraquinones with Amidines: Expanding Access to Isoaporphinoid Alkaloids.

The interaction of acetamidine and phenylamidine with peri-R-ethynyl-9,10-anthraquinones in refluxing n-butanol leads to the formation of cascade transformations products: addition/elimination/cyclization-2-R-7H-dibenzo[de,h]quinolin-7-ones and(or) 2-R-3-aroyl-7H-dibenzo[de,h]quinolin-7-ones. The anti-inflammatory and antitumor properties of the new 2-R-7H-dibenzo[de,h]quinolin-7-ones were investigated in vivo, in vitro, and in silico. The synthesized compounds exhibit high anti-inflammatory activity at dose 20 mg/kg (intraperitoneal injection) in the models of exudative (histamine-induced) and immunogenic (concanavalin A-induced) inflammation. Molecular docking data demonstrate that quinolinones can potentially intercalate into DNA similarly to the antitumor drug doxorubicin.

Advanced Solid-State Lasers 2019: focus issue introduction.

This joint issue of Optics Express and Optical Materials Express features 17 state-of-the art articles written by authors who participated in the international conference Advanced Solid-State Lasers held in Vienna, Austria, from September 29 to October 3, 2019. This introduction provides a summary of these articles that cover numerous areas of solid-state lasers from materials research to sources and from design to experimental demonstration.

The Comparative Immunotropic Activity of Carrageenan, Chitosan and Their Complexes.

The immunotropic activity of polyelectrolyte complexes (PEC) of κ-carrageenan (κ-CGN) and chitosan (CH) of various compositions was assessed in comparison with the initial polysaccharides in comparable doses. For this, two soluble forms of PEC, with an excess of CH (CH:CGN mass ratios of 10:1) and with an excess of CGN (CH: CGN mass ratios of 1:10) were prepared. The ability of PEC to scavenge NO depended on the content of the κ-CGN in the PEC. The ability of the PEC to induce the synthesis of pro-inflammatory (tumor necrosis factor-α (TNF-α)) and anti-inflammatory (interleukine-10 (IL-10)) cytokines in peripheral blood mononuclear cell was determined by the activity of the initial κ-CGN, regardless of their composition. The anti-inflammatory activity of PEC and the initial compounds was studied using test of histamine-, concanavalin A-, and sheep erythrocyte immunization-induced inflammation in mice. The highest activity of PEC, as well as the initial polysaccharides κ-CGN and CH, was observed in a histamine-induced exudative inflammation, directly related to the activation of phagocytic cells, i.e., macrophages and neutrophils.

Efficient half-harmonic generation of three-optical-cycle mid-IR frequency comb around 4 µm using OP-GaP.

We report a broadband mid-infrared frequency comb with three-optical-cycle pulse duration centered around 4.2 µm, via half-harmonic generation using orientation-patterned GaP (OP-GaP) with ~43% conversion efficiency. We experimentally compare performance of GaP with GaAs and lithium niobate as the nonlinear element, and show how properties of GaP at this wavelength lead to generation of the shortest pulses and the highest conversion efficiency. These results shed new light on half-harmonic generation of frequency combs, and pave the way for generation of short-pulse intrinsically-locked frequency combs at longer wavelengths in the mid-infrared with high conversion efficiencies.

Social defeat stress exacerbates the blood abnormalities in Opisthorchis felineus-infected mice.

A model of chronic opisthorchiasis combined with social stress is examined; this situation is more likely for humans and animals than a separate impact of the infectious factor. For this purpose, we evaluated the effects of Opisthorchis felineus ("OP" group) and 30-day social stress (confrontations between males, "SS" group) alone and in combination ("OP + SS" group) in inbred C57BL/6 male mice and compared these effects according to the parameters listed below. The animals exposed to neither factor formed the control group ("CON"). All animals were assayed for blood biochemical parameters, changes in blood cell composition, and pattern of bone marrow hematopoiesis. By the end of the experiment, we have observed crucial effects of the two factors on the blood and liver of "OP" and "OP + SS". Eosinophil and basophil counts increased and relative segmented neutrophil and monocyte counts decreased in "OP + SS" mice on the background of activated myelopoiesis, mainly determined by social stress. Despite depressed erythropoiesis, "OP" mice displayed no changes in the relative peripheral erythrocyte counts. On the contrary, social stress, which stimulated erythropoiesis in "SS" and "OP + SS" mice, was accompanied by a decrease in the relative erythrocyte counts and hematocrit. Hepatosplenomegaly was observed on the background of these two impacts. Changes in transaminase (ALT and AST) and alkaline phosphatase activities as well as an increase in cholesterol and product of lipid peroxidation suggest a pronounced destruction of the liver. Altogether, social stress exacerbates many of the assayed blood parameters in the mice infected with the liver fluke.

Mitotic catastrophe and cancer drug resistance: A link that must to be broken.

An increased tendency of genomic alterations during the life cycle of cells leads to genomic instability, which is a major driving force for tumorigenesis. A considerable fraction of tumor cells are tetraploid or aneuploid, which renders them intrinsically susceptible to mitotic aberrations, and hence, are particularly sensitive to the induction of mitotic catastrophe. Resistance to cell death is also closely linked to genomic instability, as it enables malignant cells to expand even in a stressful environment. Currently it is known that cells can die via multiple mechanisms. Mitotic catastrophe represents a step preceding apoptosis or necrosis, depending on the expression and/or proper function of several proteins. Mitotic catastrophe was proposed to be an onco-suppressive mechanism and the evasion of mitotic catastrophe constitutes one of the gateways to cancer development. Thus, stimulation of mitotic catastrophe appears to be a promising strategy in cancer treatment. Indeed, several chemotherapeutic drugs are currently used at concentrations that induce apoptosis irrespective of the cell cycle phase, yet are very efficient at triggering mitotic catastrophe at lower doses, significantly limiting side effects. In the present review we summarize current data concerning the role of mitotic catastrophe in cancer drug resistance and discuss novel strategies to break this link.

Carrageenans-Sulfated Polysaccharides from Red Seaweeds as Matrices for the Inclusion of Echinochrome.

The possibility of using different types of carrageenans (CRG) as matrixes for incorporating of echinochrome A (Ech) was investigated. Ech interacts with carrageenans and is incorporated into the macromolecular structure of the polysaccharide. The inclusion of Ech in carrageenan matrices decreased its oxidative degradation and improved its solubility. The changing in the charge and morphology of CRGs during binding with Ech was observed. The rate of Ech release from CRG matrices depended on the structure of the used polysaccharide and the presence of specific ions. The gastroprotective effect of CRG/Ech complexes was investigated on the model of stomach ulcers induced by indomethacin in rats. Complexes of CRG/Ech exhibited significant gastroprotective activity that exceeded the activity of the reference drug Phosphalugel. The gastroprotective effect of the complexes can be associated with their protective layer on the surface of the mucous membrane of a stomach.

Coherent octave-spanning mid-infrared supercontinuum generated in As2S3-silica double-nanospike waveguide pumped by femtosecond Cr:ZnS laser.

A more than 1.5 octave-spanning mid-infrared supercontinuum (1.2 to 3.6 µm) is generated by pumping a As2S3-silica "double-nanospike" waveguide via a femtosecond Cr:ZnS laser at 2.35 µm. The combination of the optimized group velocity dispersion and extremely high nonlinearity provided by the As2S3-silica hybrid waveguide enables a ~100 pJ level pump pulse energy threshold for octave-spanning spectral broadening at a repetition rate of 90 MHz. Numerical simulations show that the generated supercontinuum is highly coherent over the entire spanning wavelength range. The results are important for realization of a high repetition rate octave-spanning frequency comb in the mid-infrared spectral region.

Graphene mode-locked Cr:ZnS chirped-pulse oscillator.

We report the first to our knowledge high-energy graphene mode-locked solid-state laser operating in the positive dispersion regime. Pulses with 15.5 nJ energy and 42 nm spectral bandwidth with 0.87 ps duration were obtained at 2.4 µm wavelength. The output can be compressed down to 189 fs. The graphene absorber damage threshold was established at fluence approaching 1 mJ/cm².

Graphene mode-locked Cr:ZnS laser with 41 fs pulse duration.

We report the ultrashort-pulse Cr:ZnS laser mode-locked by graphene-based saturable absorber mirror. Using the combination of bulk material and a chirped mirror, we demonstrate the shortest reported so far mid-IR pulses of only 5.1 optical cycles (41 fs) centered at 2.4 µm with 190 nm spectral bandwidth. The pulse spectrum almost completely fills the water-free atmospheric window. The output parameters reach 2.3 nJ pulse energy and 250 mW average output power at 108 MHz repetition rate.

Neural machine translation of clinical text: an empirical investigation into multilingual pre-trained language models and transfer-learning.

Clinical text and documents contain very rich information and knowledge in healthcare, and their processing using state-of-the-art language technology becomes very important for building intelligent systems for supporting healthcare and social good. This processing includes creating language understanding models and translating resources into other natural languages to share domain-specific cross-lingual knowledge. In this work, we conduct investigations on clinical text machine translation by examining multilingual neural network models using deep learning such as Transformer based structures. Furthermore, to address the language resource imbalance issue, we also carry out experiments using a transfer learning methodology based on massive multilingual pre-trained language models (MMPLMs). The experimental results on three sub-tasks including (1) clinical case (CC), (2) clinical terminology (CT), and (3) ontological concept (OC) show that our models achieved top-level performances in the ClinSpEn-2022 shared task on English-Spanish clinical domain data. Furthermore, our expert-based human evaluations demonstrate that the small-sized pre-trained language model (PLM) outperformed the other two extra-large language models by a large margin in the clinical domain fine-tuning, which finding was never reported in the field. Finally, the transfer learning method works well in our experimental setting using the WMT21fb model to accommodate a new language space Spanish that was not seen at the pre-training stage within WMT21fb itself, which deserves more exploitation for clinical knowledge transformation, e.g. to investigate into more languages. These research findings can shed some light on domain-specific machine translation development, especially in clinical and healthcare fields. Further research projects can be carried out based on our work to improve healthcare text analytics and knowledge transformation. Our data is openly available for research purposes at: https://github.com/HECTA-UoM/ClinicalNMT.

A phase III study to access the safety and efficacy of prolgolimab 250 mg fixed dose administered every 3 weeks versus prolgolimab 1 mg/kg every 2 weeks in patients with metastatic melanoma (FLAT).

Background: Prolgolimab is the first Russian PD-1 inhibitor approved for the first-line treatment of unresectable or metastatic melanoma and advanced non-small cell lung cancer. It was approved in two weight-based regimens of 1 mg/kg Q2W and 3 mg/kg Q3W, but because of re-evaluation of weight-based dosing paradigm, studying of a fixed-dose regimen was considered perspective. Methods: We conducted a multicenter, single-arm, open-label efficacy, pharmacokinetics, and safety study to obtain data that would allow the approval of the new flat dosing regimen of prolgolimab in patients with previously untreated unresectable or metastatic melanoma (BCD-100-8/FLAT, NCT05783882). The primary objective was to prove the non-inferiority of prolgolimab 250 mg Q3W versus prolgolimab 1 mg/kg Q2W for the treatment of patients with unresectable or metastatic melanoma in terms of ORR according to RECIST 1.1. Patients from the MIRACULUM study (BCD-100-2/MIRACULUM, NCT03269565) comprised a historical control group. Results: One hundred fourteen patients received prolgolimab 250 mg Q3W, and 61 patients received prolgolimab (Prolgo) 1 mg/kg Q2W (historical control). Objective response was achieved by 33.3% [95% confidence interval (CI): 24.8, 42.8] of patients in the Prolgo 250 mg group compared with 32.8% (95% CI: 21.3, 46.0) of patients in the Prolgo 1 mg/kg group. Risk difference was 0.00, 95% CI (-0.12; NA), p = 0.0082. Both regimens were well tolerated, and safety profiles were comparable. The pharmacokinetic analysis (PK) showed that the regimen with the fixed dose of 250 mg Q3W was characterized by higher PK parameters. The immunogenicity study did not detect binding antibodies to prolgolimab in any of the subjects. Conclusion: The obtained results showed that the selected fixed dosing regimen of prolgolimab 250 mg Q3W is characterized by efficacy and safety parameters comparable to that observed for the 1 mg/kg Q2W regimen.

Role of twin Cys-Xaa9-Cys motif cysteines in mitochondrial import of the cytochrome C oxidase biogenesis factor Cmc1.

The Mia40 import pathway facilitates the import and oxidative folding of cysteine-rich protein substrates into the mitochondrial intermembrane space. Here we describe the in vitro and in organello oxidative folding of Cmc1, a twin CX(9)C-containing substrate, which contains an unpaired cysteine. In vitro, Cmc1 can be oxidized by the import receptor Mia40 alone when in excess or at a lower rate by only the sulfhydryl oxidase Erv1. However, physiological and efficient Cmc1 oxidation requires Erv1 and Mia40. Cmc1 forms a stable intermediate with Mia40 and is released from this interaction in the presence of Erv1. The three proteins are shown to form a ternary complex in mitochondria. Our results suggest that this mechanism facilitates efficient formation of multiple disulfides and prevents the formation of non-native disulfide bonds.

Chaotic chirped-pulse oscillators.

We present results of experimental investigation of the chaotic and quasi-periodic regime in the chirped-pulsed (dissipative soliton) Cr:ZnS and Cr:ZnSe mid-IR oscillators with significant third-order dispersion. The instability develops when the spectrum edge approaches resonance with a linear wave either due to power increase or by dispersion adjustment. In practice, this occurs when the spectrum edge reaches zero dispersion wavelength. The analysis suggests a three-oscillator chaos model, which is confirmed by numerical simulations. The regime is long-term stable and can be easily overlooked in similar systems. We show that chaotic regime is accompanied by a characteristic spectral shape and can be reliably recognized by using wavelength-skewed filters and by second-harmonic or two-photon absorption detectors.