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.

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.

Curcumin and Its Supramolecular Complex with Disodium Glycyrrhizinate as Potential Drugs for the Liver Fluke Infection Caused by Opisthorchis felineus.

Opisthorchiosis is a parasitic liver disease found in mammals that is widespread throughout the world and causes systemic inflammation. Praziquantel remains the drug of choice for the treatment of opisthorchiosis, despite its many adverse effects. An anthelmintic effect is attributed to the main curcuminoid of Curcuma longa L. roots-curcumin (Cur)-along with many other therapeutic properties. To overcome the poor solubility of curcumin in water, a micellar complex of curcumin with the disodium salt of glycyrrhizic acid (Cur:Na2GA, molar ratio 1:1) was prepared via solid-phase mechanical processing. In vitro experiments revealed a noticeable immobilizing effect of curcumin and of Cur:Na2GA on mature and juvenile Opisthorchis felineus individuals. In vivo experiments showed that curcumin (50 mg/kg) had an anthelmintic effect after 30 days of administration to O. felineus-infected hamsters, but the effect was weaker than that of a single administration of praziquantel (400 mg/kg). Cur:Na2GA (50 mg/kg, 30 days), which contains less free curcumin, did not exert this action. The complex, just as free curcumin or better, activated the expression of bile acid synthesis genes (Cyp7A1, Fxr, and Rxra), which was suppressed by O. felineus infection and by praziquantel. Curcumin reduced the rate of inflammatory infiltration, whereas Cur:Na2GA reduced periductal fibrosis. Immunohistochemically, a decrease in liver inflammation markers was found, which is determined by calculating the numbers of tumor-necrosis-factor-positive cells during the curcumin treatment and of kynurenine-3-monooxygenase-positive cells during the Cur:Na2GA treatment. A biochemical blood test revealed a normalizing effect of Cur:Na2GA (comparable to that of curcumin) on lipid metabolism. We believe that the further development and investigation of therapeutics based on curcuminoids in relation Opisthorchis felineus and other trematode infections will be useful for clinical practice and veterinary medicine.

Conjugates of Lupane Triterpenoids with Arylpyrimidines: Synthesis and Anti-inflammatory Activity.

Semisynthetic triterpenoid betulonic acid is of significant interest due to its biological activity and synthetic application. In this study, we report the synthesis of hybrid compounds, containing betulonic acid carboxamide and arylpyrimidine fragments. A total of 15 conjugates were prepared using the cyclocondensation reaction of new terpenoid alkynyl ketones with amidinium salts. The main synthetic approach to betulonic acid amide-derived alkynylketones was based on the cross-coupling reaction of N-(4-ethynylphenyl)- or N-(2-(4-ethynylphenyl)-1-(methoxycarbonyl)ethyl)- substituted betulonic acid carboxamide with aroylchlorides. Cyclocondensation of alkynones with amidine or guanidine hydrochlorides by reflux in MeCN in the presence of K2CO3 led to the formation of terpenoid pyrimidine hybrids in 52-89% isolated yield. Anti-inflammatory properties of new type of triterpenoid-pyrimidine conjugates were studied using the histamine- and concanavalin A- induced mouse paw edema models. In a model of acute inflammation betulonic acid amide-arylpyrimidines containing a 4-fluorophenyl substituent at the C-6 position of pyrimidine ring exhibited significant and selective anti-inflammatory activity. Compounds containing the 4-bromophenyl- substituent in the pyrimidine ring revealed selective anti-inflammatory activity in the model of immunogenic inflammation (concanavalin-A model). It should be noted that the methoxycarbonyl substituted ethane link between pharmacophore ligands (betulonic acid carboxamide and arylpyrimidine) has a significant effect on anti-inflammatory activity in both in vivo models of inflammation. It was shown by molecular docking that the new derivatives are incorporated into the binding site of the protein Keap1 Kelch-domain by their pyrimidine substituent with the formation of more non-covalent bonds.

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.

Energy-dependent protein folding: modeling how a protein folding machine may work.

Background: Proteins fold robustly and reproducibly in vivo, but many cannot fold in vitro in isolation from cellular components. Despite the remarkable progress that has been achieved by the artificial intelligence approaches in predicting the protein native conformations, the pathways that lead to such conformations, either in vitro or in vivo, remain largely unknown. The slow progress in recapitulating protein folding pathways in silico may be an indication of the fundamental deficiencies in our understanding of folding as it occurs in nature. Here we consider the possibility that protein folding in living cells may not be driven solely by the decrease in Gibbs free energy and propose that protein folding in vivo should be modeled as an active energy-dependent process. The mechanism of action of such a protein folding machine might include direct manipulation of the peptide backbone. Methods: To show the feasibility of a protein folding machine, we conducted molecular dynamics simulations that were augmented by the application of mechanical force to rotate the C-terminal amino acid while simultaneously limiting the N-terminal amino acid movements. Results: Remarkably, the addition of this simple manipulation of peptide backbones to the standard molecular dynamics simulation indeed facilitated the formation of native structures in five diverse alpha-helical peptides. Steric clashes that arise in the peptides due to the forced directional rotation resulted in the behavior of the peptide backbone no longer resembling a freely jointed chain. Conclusions: These simulations show the feasibility of a protein folding machine operating under the conditions when the movements of the polypeptide backbone are restricted by applying external forces and constraints. Further investigation is needed to see whether such an effect may play a role during co-translational protein folding in vivo and how it can be utilized to facilitate folding of proteins in artificial environments.

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.

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.

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.

Lupane-type conjugates with aminoacids, 1,3,4- oxadiazole and 1,2,5-oxadiazole-2-oxide derivatives: Synthesis, anti-inflammatory activity and in silico evaluation of target affinity.

With the purpose to improve anti-inflammatory activity, the impact of introduction of 1,2,5- and 1,3,4-oxadiazole fragments to betulonic acid core as well as hybrids tethered with short ω-amino acids has been studied. The anti-inflammatory activity of synthesized compounds was tested in vivo using models of inflammation induced by concanavalin A and histamine. The majority of new compounds demonstrated higher anti-inflammatory activity compared with starting betulonic acid. To confirm the molecular targets of new derivatives in NRf2 and NFκB pathways the docking at Kelch and BTB active sites of Keap1 as well as IKK was done. The novelty of the present work is the development of new class of low toxic anti-inflammatory substances consisting of amino acid-linked betulonic acid - oxadiazole conjugates. These compounds can be considered as prospective chemopreventive agents.

Effects of supramolecular complexation of praziquantel with disodium glycyrrhizinate on the liver fluke Opisthorchis felineus: An in vitro and in vivo study.

Millions of people worldwide have a chronic infection with the liver fluke Opisthorchis felineus, which causes opisthorchiasis in humans and animals. The only known effective drug for this disease is praziquantel (PrzQ); however, its efficacy is below 100%, and it has some adverse effects. In this study, a water-soluble complex of PrzQ with a disodium salt of glycyrrhizic acid (disodium glycyrrhizinate; Na2GA) in a 1:10 ratio (PrzQ:GA) allowed the PrzQ dose to be decreased 11-fold for effective killing of O. felineus. An in vitro experiment showed a sufficient anthelmintic efficiency of PrzQ:GA against both adult and juvenile O. felineus individuals. A Syrian golden hamster model of opisthorchiasis revealed a considerable anthelmintic effect at all tested PrzQ:GA doses (50, 100, 200, 400, and 1100 mg/kg) with the best performance at 400 and 1100 mg/kg. Further comparison of the effects of PrzQ (400 mg/kg) and PrzQ:GA (400 mg/kg) regarding the state of the host indicated significant advantages of the latter. Histological examination showed that PrzQ:GA was better at decreasing the O. felineus-induced inflammatory infiltration (as compared with PrzQ alone) as well as interfered with the development of epithelial dysplasia and metaplasia in large bile ducts and cholangiofibrosis. Both PrzQ and PrzQ:GA decreased the number of myeloid (CFU-GM) and erythroid (BFU-E + CFU-E) colonies induced by O. felineus infection. The drugs had no negative effect on the animal behavior in an open field test 2-4 h after administration. Thus, PrzQ:GA proved to be a good anthelmintic agent having no evident adverse effects on the host, thereby suggesting that further preclinical and clinical trials would be warranted.

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.

Modeling protein folding in vivo.

A half century of studying protein folding in vitro and modeling it in silico has not provided us with a reliable computational method to predict the native conformations of proteins de novo, let alone identify the intermediates on their folding pathways. In this Opinion article, we suggest that the reason for this impasse is the over-reliance on current physical models of protein folding that are based on the assumption that proteins are able to fold spontaneously without assistance. These models arose from studies conducted in vitro on a biased sample of smaller, easier-to-isolate proteins, whose native structures appear to be thermodynamically stable. Meanwhile, the vast empirical data on the majority of larger proteins suggests that once these proteins are completely denatured in vitro, they cannot fold into native conformations without assistance. Moreover, they tend to lose their native conformations spontaneously and irreversibly in vitro, and therefore such conformations must be metastable. We propose a model of protein folding that is based on the notion that the folding of all proteins in the cell is mediated by the actions of the "protein folding machine" that includes the ribosome, various chaperones, and other components involved in co-translational or post-translational formation, maintenance and repair of protein native conformations in vivo. The most important and universal component of the protein folding machine consists of the ribosome in complex with the welcoming committee chaperones. The concerted actions of molecular machinery in the ribosome peptidyl transferase center, in the exit tunnel, and at the surface of the ribosome result in the application of mechanical and other forces to the nascent peptide, reducing its conformational entropy and possibly creating strain in the peptide backbone. The resulting high-energy conformation of the nascent peptide allows it to fold very fast and to overcome high kinetic barriers along the folding pathway. The early folding intermediates in vivo are stabilized by interactions with the ribosome and welcoming committee chaperones and would not be able to exist in vitro in the absence of such cellular components. In vitro experiments that unfold proteins by heat or chemical treatment produce denaturation ensembles that are very different from folding intermediates in vivo and therefore have very limited use in reconstructing the in vivo folding pathways. We conclude that computational modeling of protein folding should deemphasize the notion of unassisted thermodynamically controlled folding, and should focus instead on the step-by-step reverse engineering of the folding process as it actually occurs in vivo. REVIEWERS: This article was reviewed by Eugene Koonin and Frank Eisenhaber.

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.

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.

Involvement of autophagy in the outcome of mitotic catastrophe.

Evading cell death is a major driving force for tumor progression that is one of the main problems in current cancer research. Mitotic catastrophe (MC) represents attractive platform compromising tumor resistance to current therapeutic modalities. MC appeared as onco-suppressive mechanism and is defined as a stage driving the cell to an irreversible destiny, i.e. cell death via apoptosis or necrosis. Our study highlights that MC induction in colorectal carcinoma cell lines ultimately leads to the autophagy followed by apoptosis. We show that autophagy suppression in Atg 13 knockout non-small cell lung carcinoma cells lead to the dramatic decrease of MC rate. Furthermore, mitochondria-linked anti-apoptotic proteins Mcl-1 and Bcl-xL play a crucial role in the duration of MC and a cross-talk between autophagy and apoptosis. Thus, the suppression of apoptosis by overexpression of Mcl-1 or Bcl-xL affected MC and lead to a significant induction of autophagy in HCT116 wt and HCT116 14-3-3σ-/- cells. Our data demonstrate that MC induction is a critical stage, in which a cell decides how to die, while mitochondria are responsible for the maintaining the balance between MC - autophagy - apoptosis.