Racemization-free synthesis of Nα-2-thiophenoyl-phenylalanine-2-morpholinoanilide enantiomers and their antimycobacterial activity

Nα-2-thiophenoyl-d-phenylalanine-2-morpholinoanilide (MMV688845, IUPAC: N-(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide) from the Pathogen Box® library (Medicines for Malaria Ventures, MMV) is a promising lead compound for antimycobacterial drug development. Two straightforward synthetic routes to the title compound starting from phenylalanine or its Boc-protected derivative are reported. Employing Boc-phenylalanine as starting material and the T3P® and PyBOP® amide coupling reagents enables racemization-free synthesis, avoiding the need for subsequent separation of the enantiomers. The crystal structure of the racemic counterpart gives insight into the molecular structure and hydrogen bonding interactions in the solid state. The R-enantiomer of the title compound (derived from d-phenylalanine) exhibits activity against non-pathogenic and pathogenic mycobacterial strains, whereas the S-enantiomer is inactive. Neither of the enantiomers and the racemate of the title compound shows cytotoxicity against various mammalian cells.

Preparation of Asymmetric Vesicles with Trapped CsCl Avoids Osmotic Imbalance, Non-Physiological External Solutions, and Minimizes Leakage

The natural asymmetry of cellular membranes influences their properties. In recent years, methodologies for preparing asymmetric vesicles have been developed that rely on the methyl-α-cyclodextrin catalyzed exchange of lipids between donor lipid multilamellar vesicles and acceptor lipid unilamellar vesicles, and the subsequent separation of the, now asymmetric, acceptor vesicles from the donors. Isolation is accomplished by pre-loading acceptor vesicles with a high concentration of sucrose, typically 25% (w/w), and separating from donor and cyclodextrin by sucrose gradient centrifugation. We found that when the asymmetric vesicles were dispersed under hypotonic conditions using physiological salt solutions, there was enhanced leakage of an entrapped probe, 6-carboxyfluorescein. Studies with symmetric vesicles showed this was due to osmotic pressure and was specific to hypotonic solutions. Inclusion of cholesterol partly reduced leakage but did not completely eliminate it. To avoid having to use hypotonic conditions or to suspend vesicles at non-physiological solute concentrations to minimize leakage, a method for preparing asymmetric vesicles using acceptor vesicle-entrapped CsCl at a physiological salt concentration (100 mM) was developed. Asymmetric vesicles prepared with the entrapped CsCl protocol were highly resistant to 6-carboxyfluorescein.

LATE MIOCENE-PLIOCENE TRANSFORM MARGIN OF KAMCHATKA

Testing of the geochemical compositions of the Late Cenozoic volcanites of Kamchatka on new discriminant diagrams confirmed the idea of the existence of different geodynamic regimes at this time. It is shown that the Late Miocene (~6 Ma)-Pliocene volcanites of Eastern Kamchatka and the Central Kamchatka Depression, as well as the Late Pliocene (~3.5 Ma)-Holocene alkaline, calcareous-alkaline, and adakite volcanites of the central part of the Middle Ridge are similar to the volcanites of the transform margins of the Pacific type. At the same time, the Miocene–Holocene volcanites of Southern Kamchatka, the Miocene-Early Pliocene volcanites of the Middle Ridge, and the Pleistocene–Holocene volcanites of Eastern Kamchatka are similar to the volcanites of the convergent margins. In the central part of Kamchatka (from the coast to the Middle Ridge), at the end of the Miocene-Pliocene, during the collision of the Kronotsky terrane of the island arc and the slip of the Pacific plate, magmatic complexes typical of the transform margin were formed in this area. The geochemistry of the transform margin volcanites is due to the upwelling of the subslab asthenosphere both into the collision zone and into the zone of the volcanic arc of the Middle Ridge, after the rupture and subsequent separation of the Komandor-Kronotsky microplate slab.

History of pancreatic cancer surgery

The first mention of pancreatic cancer dates back to 1761, when the six-volume work of the famous Italian anatomist G. Morgagni On the location and causes of diseases discovered through dissection was published. However, the history of surgical treatment of malignant tumors of the pancreas dates back to the end of the 19th century. The accumulated experience of operational techniques and the introduction of aseptic rules created objective prerequisites for performing operations in complex anatomical zones during that period of time. On July 16, 1882, the famous German surgeon F. Trendelenburg, firstly, performed a successful resection of the tail of the pancreas for sarcoma, founding the development of surgery in this field. However, the success in this sphere could not be shifted to a tumor of the head of the gland due to the subsequent separation of the duct system from the duodenum. Over the following years, many outstanding surgeons tried to solve this problem, such as: A. Codivilla, W. Halsted, W. Kaush, until in the early 40s A. Whipple proposed a new method of pancreatoduodenal resection, that became the gold standard for head cancer treatment pancreas. Although it was not possible to achieve significant success in the treatment of cancer in the original method of operation, as a result at various stages of time this procedure wasnt used a lot and was almost forgotten. Today, surgery remains the leading method in the complex treatment of patients with pancreatic cancer. Minimally invasive technologies have been actively introduced into pancreatic surgery in the past two decades. The indications for surgery have been expanded, lymphadenectomy standards have been introduced, thereby increasing the chances of a successful cure.

Thermal stability of water fibers: effect of the alkaline treatment - aminopropyltrimetoxysilane [Estabilidad termica de fibras de aguaje: efecto del tratamiento alcalino – aminopropiltrimetoxysilano]

The present research evaluated the influence of the concentration of sodium hydroxide and aminopropyltrimethoxysilane on the thermal stability of the aguaje fibers. The fibers were extracted by manual immersion in water and subsequent separation by manual pressure. The NaOH concentrations were 5%, 10% and 15% w / v; while in the case of the silane coupling agent they were 1% and 1.5% v / v. The chemically treated fibers together with the control samples were subjected to thermogravimetric analysis evaluation, in addition, the variation of the humidity percentage, the chemical variation of the main functional groups of the fibers and the surface physical changes of the fibers were determined in a complementary way. The mercerization - silanization treatments increase the thermal degradation temperature of the aguaje fibers, in the conditions tested this increase was 3.89% in the best of cases (5% NaOH + 1.0 Silane). Regarding untreated fibers, mercerization - silanization treatments decrease the percentage of lost mass or degradation, in the best of cases this decrease in mass percentage was 26.85% (15% NaOH + 1.5 Silane), compared to fibers without treatment. Finally, mercerization-silanization treatments increase the percentages of cellulose present in the aguaje fibers evaluated, while the amount of extractives and lignin decrease, under the chemical treatment conditions carried out in the present research.

COVID-19 Challenge: What Has Been Done and What Must Be Done?

The sequence of systemic measures to combat the COVID-19 pandemic in Russia is described. Some other countries experience of providing the specialized trauma care in a pandemic has been summarized. Almost everywhere, strict measures of infection prevention and treatment were introduced in stages. To date, there are the following generally accepted measures: discontinuation of planned surgeries, screening of emergency patients on COVID-19 with the subsequent separation of patient flows, the maximum reduction of hospital stay length. The special attention should be paid to personal protective equipment. The organizational and medical measures necessary for prevention of such pandemics in the future are described, namely equipping sanitary triage posts, creating a stock of personal protective equipment and disinfectants, developing a plan for transforming general hospitals into hospitals for infectious patients with the allocation of a primary patient reception post and their subsequent distribution into the green or red zones. The importance of pre-operative bed day reduction, telemedicine technologies and the need of healthcare financing increase to solve the tasks are substantiated.

Breaking Point

GWTW restored Steiner to the top rank of film composers; and in 1940, Jack Warner assigned him to a series of A-pictures that remain jewels in that studio’s crown. In assessing scores for such movies as The Letter and Sergeant York, this chapter details the instrumental experimentation Steiner used to create fresh sounds (an aspect of his work often neglected). Max also was overjoyed to become a father: son Ronald, he hoped, would continue the Steiner musical dynasty. But years of nonstop work, worsening financial problems, and failing eyesight led the composer to suffer a breakdown in 1941. According to Louise, Steiner—usually a kind and generous man—exploded in a rage, striking his wife with a glass ashtray and hitting her in an apparent mental breakdown. Their subsequent separation initiated years of personal unhappiness, amid one of the most creative periods of Steiner’s life.

Roi de guerre ou Roi de paix? Louis XV and the French monarchy, 1740–1748

This article examines debate about the nature of the French monarchy during the early years of Louis XV’s personal rule. It argues that the king, his ministers and advisers as well as the wider French public were torn between traditional models of monarchy based upon the concept of a ‘roi de guerre’ and the diplomatic and human consequences of military conflict that had caused many to urge a more restrained, pacific projection of French power. In 1748, Louis XV offered a peace that reflected the desire to avoid a repetition of his predecessor’s errors, but France lacked the strength needed to impose a Pax Francia. The subsequent separation between the Bourbon dynasty and active military service did much to undermine the monarchy in the eyes of an increasingly patriotic public opinion.