From green innovations in oligopeptide to oligonucleotide sustainable synthesis: differences and synergies in TIDES chemistry

The growing market for therapeutic peptides and oligonucleotides (TIDES) draws attention towards their manufacture, aiming at efficient and sustainable productive processes in view of the predicted massive application of these molecules in several therapeutic areas in the near future. A comparative assessment of the principal innovations in the synthesis of these molecules is described herein, with a major focus on solid-phase synthesis (SPS), describing particularly the less-explored field of solid-phase oligonucleotide synthesis (SPOS). A head-to-head analysis of SPS techniques applied to peptides and oligonucleotides was performed, highlighting the strengths and weaknesses of these iterative synthetic approaches. The green innovations introduced in solid-phase peptide synthesis (SPPS), namely reduction or replacement with greener alternatives of solvents and reagents, and implementations in purification techniques, were reviewed and projected to potential targets and sustainable practices in modern SPOS, including their application in P(v) chemistry for the synthesis of stereopure oligonucleotides. By a comparative analysis, the key elements for the development of overall green procedures for oligonucleotide manufacturing were emphasized. In addition, due to the intrinsically more sustainable profile of liquid-phase synthetic techniques (LPS), recent advancements in the field reported for both TIDES were analyzed to prove the industrial interest in the manufacturing of these classes of molecules, underlining the importance of investment and modernization in the development of stronger and greener synthetic pathways

Graded possibilistic clustering of non-stationary data streams

YesMultidimensional data streams are a major paradigm in data science. This work focuses on possibilistic clustering algorithms as means to perform clustering of multidimensional streaming data. The proposed approach exploits fuzzy outlier analysis to provide good learning and tracking abilities in both concept shift and concept drift

THE ANTAGONIST MUSCLE PATTERN IN ELBOW EXTENSION OFA THROWING TASK

INTRODUCTION The myoelectric activity in fast human movements is characterised by a phasic pattern with two fundamental events: the first agonist burst, responsible for the initial limb acceleration, and an antagonist impulse. The accurate definition of the antagonist burst role, and the relative participation of peripheral and central sources on its control, are not clearly defined in the literature (Angel, 1977; Marsden et al., 1983). The purpose of the present study was (1) to characterise the antagonistic pattern on the elbow extension when subjects had to throw a dart onto a target, and (2) to analyse the antagonist changes when subjects throw with different accuracy/speed demands. Experiments were performed on 13 subjects. Surface EMG were recorded from triceps and biceps brachii with active bipolar electrodes. Electrogoniometers wore used on shoulder and elbow joints. RESULTS The antagonist EMG contained a phasic burst (ANT) which began between the movement onset and the end of the agonist activation, with an usual co-contraction duration of less than 30 ms. The time interval between the movement onset and the beginning of ANT was normally higher than the EMG latency necessary for spindle influences, considered to be less than 20 ms (Tarkka, 1986). In our results, ANT always began during the acceleration phase and, in most cases, developed its maximum intensity around the moment of elbow peak velocity. So, the antagonist burst represents more than an impulse braking preventing full extension, and we must admit its participation in the control of the duration of the acceleration phase. Antagonist modifications with velocity indicated an amplitude increase, measured by the integrated EMG. without relevant temporal changes. Two subjects presented an alternative way of braking the movement, when the accuracy constraints were absent, based, on the increase of the joint stiffness through the co-contraction of agonist and antagonist muscles. This kind of movement braking resulted in a reduced timing accuracy demand when compared with the active braking, produced by the antagonist phasic burst (Ghez & Martin, 1 982). CONCLUSION The timing of the antagonist phasic burst invite us (1) to associate it with the control of the end of the acceleration phase and (2) to accept that it could be influenced by the muscular response to stretch, although modulated by higher central commands. (3) The general tendency was to maintain the temporal structure of antagonist EMG among conditions and to increase its intensity with the increase of the throwing velocity. (4) Two subjects presented an alternative way of braking the movement when the accuracy constraints wers absent. REFERENCES Angel, R. (1977). Antagonist muscle activity during rapid arm movements. Central versus proprioceptive influences. J. Neuroi, Neuros., Psychia t., 40: 683-686. Ghez, C., & Martin, J. (1 982). The control of rapid limb movement in the cat. Ill - Agonist- Antagonist coupling. Exp: Br. Res., 45: 1 15 - 125. Marsden, C., Obeso, J., & Rothwell, J. (1983). The function of the antagonist muscle during fast limb movements in man. J. Physiol., 335: 1 - 13. Tarkka, 1. (1986). Short and long latency reflexes in human muscles following electrical and mechanical stimulation. Acta Physiol. Scand., 128. Supplem. 557: 1-32

Influence of Anthropometry, Age, Sex, and Activity Level on the Hand Reach Star Excursion Balance Test

The influence of anthropometric measurements, age, sex, and activity level have been found to influence tests of dynamic postural control such as the star excursion balance test (SEBT). The hand reach star excursion balance test (HSEBT) measures different aspects of dynamic postural control. The purpose of the present study was to explore the influence of these factors on the HSEBT. A convenience sample of 223 subjects performed four horizontal (L45, R45, L135, and R135) and two rotational (LROT and RROT) reaches. The influence of anthropometric measurements (height, arm length, leg length, and wingspan) on reach measurements were assessed using stepwise multiple linear regression. Influence of age (young: <20 years; adult: >20 years), sex (male; female) and activity level (athletes; recreational) on reach measurements were analyzed using independent samples t-test (p < 0.05) and interpreted using effect size (Cohens d) and established values of minimal detectable change (MDC). Wingspan explained a significant portion of the variance of only R45 (34.6%) and L45 (11.7%) reach measurements and normalized (percentage of wingspan). A medium effect of age, sex, and activity level was observed for normalized L45 and R45 reaches (d = 0.50–72). Group differences greater than MDC values and a medium effect for age (d = 0.55) and activity level (d = 0.75) were observed for the R135 reach. L45 and R45 reaches should be normalized to wingspan, but not the other reaches. Between individual or group comparisons should consider age, activity level and sex as potential covariates

Steps towards sustainable solid phase peptide synthesis: use and recovery ofN-octyl pyrrolidone

The investigation of new green biogenic pyrrolidinones as alternative solvents toN,N-dimethylformamide (DMF) for solid phase peptide synthesis (SPPS) led to the identification ofN-octyl pyrrolidone (NOP) as the best candidate. NOP showed good performances in terms of swelling, coupling efficiency and low isomerization generating peptides with very high purity. A mixture of NOP with 20% dimethyl carbonate (DMC) allowed a decrease in solvent viscosity, making the mixture suitable for the automated solid-phase protocol. Aib-enkephalin and linear octreotide were successfully used to test the methodologies. It is worth noting that NOP, DMC and the piperidine used in the deprotection step could be easily recovered by direct distillation from the process waste mixture. The process mass intensity (PMI), being reduced by 63-66%, achieved an outstanding value representing a clear step forward in achieving green SPPS

Sustainability in peptide chemistry: current synthesis and purification technologies and future challenges.

Developing greener synthesis processes is an inescapable necessity to transform the industrial landscape, mainly in the pharmaceutical sector, into a long-term, sustainable reality. In this context, the renaissance of peptides as medical treatments, and the enforcement of more stringent sustainability requirements by regulatory agencies, pushed chemists toward the introduction of sustainable processes to prepare highly pure, active pharmaceutical ingredients (APIs). Innovative upstream (synthesis) and downstream (purification) methodologies have been developed during the last 5 years with the introduction and optimization of several technologies in solid-phase peptide synthesis (SPPS), liquid-phase peptide synthesis (LPPS), chemoenzymatic peptide synthesis (CEPS), and chromatographic procedures. These innovations are also moving toward the introduction of continuous processes that represent one of the most important targets for iterative processes. This overview discusses the most recent efforts in making peptide chemistry greener. The extensive studies that were carried out on green solvents, reaction conditions, auxiliary reagents and purification technologies in the peptide segment can be useful to other fields of organic synthesi

Dimethyl carbonate as a green alternative to acetonitrile in reversed-phase liquid chromatography. Part I: Separation of small molecules

: Nowadays, environmental problems are drawing the attention of governments and international organisations, which are therefore encouraging the transition to green industrial processes and approaches. In this context, chemists can help indicate a suitable direction. Beside the efforts focused on greening synthetic approaches, currently also analytical techniques and separations are under observation, especially those employing large volumes of organic solvents, such as reversed-phase liquid chromatography (RPLC). Acetonitrile has always been considered the best performing organic modifier for RPLC applications, due to its chemical features (complete miscibility in water, UV transparency, low viscosity etc); nevertheless, it suffers of severe shortcomings, and most importantly, it does not fully comply with Environmental, Health and Safety (EHS) requirements. For these reasons, alternative greener solvents are being investigated, especially easily available alcohols. In this work, chromatographic performance of the most common solvents used in reversed-phase chromatography, i.e., acetonitrile, ethanol and isopropanol, have been compared to a scarcely used solvent, dimethyl carbonate (DMC). The analytes of interest were two small molecules, caffeine and paracetamol, whose kinetics and retention behaviour obtained with the four solvents have been compared, and all contributions to band broadening have been assessed. Results about kinetic performance are very promising, indicating that a small amount (7 % v/v) of DMC is able to produce the same efficiency as a 2.5-times larger ACN volume (18 % v/v), and larger efficiency than alcohols. This paper reports, for the first time, fundamental studies concerning the mass transfer phenomena when DMC is used as an organic solvent in RPLC, and, together with the companion paper, represents the results of a research whose final aim was to discover whether DMC is suitable for chromatographic applications both in linear and preparative conditions

Isolation and characterization of two newly established thymoma PDXs from two relapses of the same patient: a new tool to investigate thymic malignancies

BackgroundThymic malignancies are a heterogeneous group of rare cancers for which systemic chemotherapy is the standard treatment in the setting of advanced, recurrent or refractory diseases. Both environmental and genetic risk factors have not been fully clarified and few target-specific drugs have been developed for thymic epithelial tumors. A major challenge in studying thymic epithelial tumors is the lack of preclinical models for translational studies.Main bodyStarting from bioptic material of two consecutive recurrences of the same patient, we generated two patient-derived xenografts. The patient-derived xenografts models were characterized for histology by immunohistochemistry and mutations using next-generation sequencing. When compared to the original tumors resected from the patient, the two patient-derived xenografts had preserved morphology after the stain with hematoxylin and eosin, although there was a moderate degree of de-differentiation. From a molecular point of view, the two patient-derived xenografts maintained 74.3 and 61.8% of the mutations present in the human tumor of origin.Short conclusionThe newly generated patient-derived xenografts recapitulate both the molecular characteristics and the evolution of the thymoma it derives from well, allowing to address open questions for this rare cancer

Active Coordination in Ad Hoc Networks

Abstract. The increasing ubiquity of communicating mobile devices and vastly different mobile application needs have led to the emergence of middleware models for ad hoc networks that simplify application pro-gramming. One such system, EgoSpaces, addresses specific needs of indi-vidual applications, allowing them to define what data is included in their operating context using declarative specifications constraining properties of data, agents that own the data, hosts on which those agents are run-ning, and attributes of the ad hoc network. In the resulting coordination model, application agents interact with a dynamically changing environ-ment through a set of views, or custom defined projections of the set of data present in the surrounding ad hoc network. This paper builds on EgoSpaces by allowing agents to assign behaviors to their personal-ized views. Behaviors consist of actions that are automatically performed in response to specified changes in a view. Behaviors discussed in this paper encompass reactive programming, transparent data migration, au-tomatic data duplication, and event capture. Formal semantic definitions and programming examples are given for each behavior.