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NP10679 is a context‐dependent and subunit‐selective negative allosteric modulator of N‐methyl‐d‐aspartate (NMDA) receptors. It is a more potent inhibitor of GluN2B‐containing NMDA receptors at the acidic levels of extracellular pH (eg, 6.9) found in the penumbral regions associated with cerebral ischemia than at physiological pH. This property allows NP10679 to act selectively in ischemic tissue while minimizing the nonselective blockade of NMDA receptors in healthy brain, thereby reducing on‐target adverse effects. We report the results of a first‐in‐human pharmacokinetic and safety phase 1 clinical trial in healthy volunteers receiving single or multiple doses of NP10679 (NCT04007263). We found that NP10679 was well‐tolerated and with a half‐life of 20 hours, which is amenable to once per day dosing. The only notable side effect in this clinical trial was modest somnolence at higher doses, atypical in that the subject could easily be aroused. The overall results suggest that NP10679 is a candidate for further development for use in acute brain injury, such as ischemic stroke or aneurysmal subarachnoid hemorrhage, as well as for use in neuropsychiatric indications.

This paper concentrates on the newly improved algorithm for solving the single-machine total weighted tardiness (SMTWT) problem, called Algorithm Inspired by Tree and Sorting (AIT-S). The algorithm is based on searching the solution space along with the tree and sorting rules. The properties of the algorithm are studied taking into account the results of experiments made using the designed and implemented experimentation system. This system allows in tuning the parameters of the algorithm as well as to compare the effects obtained by AIT-S algorithm with effects of AIT algorithm, and known meta-heuristic algorithms. The paper shows that the proposed algorithm still requires some improvements, however, it seems to be promising.

The Lofoten Basin in the eastern Nordic Seas plays a central role in modifying the warm Atlantic Water inflow toward the Arctic Ocean. Here, the Atlantic Water experiences increased residence times, cooling, and substantial transformation. In this study, we investigate the Atlantic Water inflow pathways to the Lofoten Basin and their vertical and seasonal variations using 2‐D and 3‐D Lagrangian simulations forced by a high‐resolution ocean model. Atlantic Water enters the basin from all directions, but we find two main inflow pathways at all vertical levels, one close to the Lofoten Escarpment in the southeast, associated with the Slope Current, and another close to the Helgeland Ridge in the southwest, associated with the Front Current. The surface inflow exhibits a stronger seasonal forcing than the inflow at depth as well as a stronger heat loss that is dominated by water masses entering the basin from the south. At deeper levels, the warm inflow from the east cools, while the relatively colder inflow from the west warms. The 2‐D and 3‐D synthetic trajectories show similar pathways. However, they are affected differently by the seasonal signal, giving different heat exchange patterns. Our results have implications for how results from Lagrangian observations in the region should be interpreted. The Lofoten Basin in the Nordic Seas is of fundamental importance for the modification of the warm northward flowing Atlantic Water. Much of the ocean heat is lost to the atmosphere in this region. This is maintained by warm water inflows from regions around. Here, we study these inflows, their vertical structure, seasonal variability, and contribution to the heat budget in the basin. We apply an ocean model to advect purposefully released particles in the Nordic Seas seeded at 15‐, 200‐, and 500‐m depth and study their pathways and fates. We analyze both a horizontal 2‐D (particles are fixed at depth) and a full 3‐D (particles can move in the vertical) simulation and compare the two. We find that the water masses mainly enter the Lofoten Basin in two regions, one in the southeast and one in the southwest. However, the vertical structure reveals that water that is cooled enter the basin via different routes at the surface than at deeper levels. The seasonal variations are also larger at surface than at depth. The 2‐D and 3‐D simulations show overall similar patterns, but the 3‐D simulation reveals larger seasonal variations than the 2‐D simulation. The Atlantic Water inflow to the Lofoten Basin is concentrated in two main regions, the Lofoten Slope Inflow and the Helgeland InflowThree‐dimensional Lagrangian simulations are crucial to detect seasonal variations in the vertical structure and temperature changes of the inflowsWater masses that are cooled in the Lofoten Basin mainly enter from the south at the surface and from the continental slope at depth

More and more premises suggest that maintaining positive trends in Polish economy won’t be possible without changing the philosophy of activity which many companies follow. Taking into consideration the growing demands of clients and the market, globalization, which is strengthening competition, as well as the growing complexity of tools and production-service methods, it is not enough to continue building market position based on limitation of costs and lower product prices. Rising to the growing challenges, in particular, the challenges ahead of production-service units, will require a broad application of the achievements of science and technology to the processes of development. Even the biggest companies more and more often take advantage of the help of various partners, who support them in the process of introducing new solutions raising the efficiency of activities.

Occasional stress is normal, but its bodily impact is huge. When choosing a tea, remember that some teas contain caffeine. If you want to drink tea to relax, cut out the caffeine with a decaf or herbal variety. [Extracted from the article]

The article presents views of computer/information science scholars regarding the most imaginative work in the field including Ken Birman, Greg Kearsley and Tiffany Koszalka. According to Birma, cloud computing is the most exciting and i8maginative technology in the areas of computing. It mentions Kearsley who reflected on security mechanisms for cloud-based databases and also presents views of Koszalka.

Tubuloglomerular feedback (TGF) describes a sequence of events linking salt concentrations in tubular fluid at the macula densa to the vascular tone of the afferent arteriole and thus to the glomerular filtration rate (GFR) of the same nephron. The signal transduction pathways of TGF remain incompletely understood, but both ATP release from macula densa cells and local formation of adenosine were suggested to be involved in the process. To test the role of extracellular formation of adenosine by ecto-5′-nucleotidase (cd73) in TGF, in regulation of GFR, and in tubular reabsorption, renal clearance and micropunture experiments were performed in cd73 wild-type (cd73+/+) and knockout mice (cd73−/−). The cd73−/−mice presented normal mean arterial blood pressure, but modestly lower whole kidney and single nephron GFR (SNGFR). Fractional reabsorption of Na+and K+up to the late proximal tubule, distal tubule, as well as urine were not significantly different between cd73−/−and cd73+/+mice. Lack of cd73 resulted in a diminished TGF response, as indicated by smaller changes of stop-flow pressure in response to increasing loop of Henle perfusion from 0 to 25 nl/min, smaller differences in SNGFR determined from paired proximal and distal tubular collections, and by smaller fractional changes of distal SNGFR in response to adding 6 nl/min of artificial tubular fluid to free-flowing proximal tubules. The TGF response in cd73+/+mice and the residual TGF response in cd73−/−mice were completely inhibited by adenosine A1-receptor blockade. The results suggest that extracellular formation of adenosine by ecto-5′-nucleotidase (cd73) is dispensable for normal fluid, Na+, or K+reabsorption along the nephron, but contributes to the regulation of GFR. Adenosine generated by both ecto-5′-nucleotidase (cd73)-dependent and -independent mechanisms participates in the mediation of TGF in vivo.

HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) are part of the combination therapy currently used to treat HIV infection. The features of a new NNRTI drug for HIV treatment must include selective potent activity against both wild-type virus as well as against mutant virus that have been selected by use of current antiretroviral treatment regimens. Based on analogy with known HIV-1 NNRTI inhibitors and modeling studies utilizing the X-ray crystal structure of inhibitors bound in the HIV-1 RT, a series of substituted 2-quinolones was synthesized and evaluated as HIV-1 inhibitors.

GW4511, GW4751, and GW3011 showed IC50 values ≤2 nM against wild type HIV-1 and <10 nM against 16 mutants. They were particularly potent against NNRTI-resistant viruses containing Y181C-, K103N-, and K103N-based double mutations, which account for a significant proportion of the clinical failure of the three currently marketed NNRTIs. The antiviral data together with the favorable pharmacokinetic data of GW4511 suggested that these benzophenones possess attributes of a new NNRTI drug candidate.

ABSTRACT1263W94 is a novel benzimidazole compound being developed for treatment of human cytomegalovirus infection. No adverse pharmacological effects were demonstrated in safety pharmacology studies with 1263W94. The minimal-effect dose in a 1-month rat study was 100 mg/kg/day, and the no-effect dose in a 1-month monkey study was 180 mg/kg/day. Toxic effects were limited to increases in liver weights, neutrophils, and monocytes at higher doses in female rats. 1263W94 was not genotoxic in the Ames or micronucleus assays. In the mouse lymphoma assay, 1263W94 was mutagenic in the absence of the rat liver S-9 metabolic activation system, with equivocal results in the presence of the S-9 mix. Mean oral bioavailability of 1263W94 was >90% in rats and ∼50% in monkeys. Clearance in rats and monkeys was primarily by biliary secretion, with evidence of enterohepatic recirculation. In 1-month studies in rats and monkeys, mean peak concentrations and exposures to 1263W94 increased in near proportion to dose. Metabolism of 1263W94 to its primary metabolite, an N-dealkylated analog, appeared to be mediated via the isozyme CYP3A4 in humans. 1263W94 was primarily distributed in the gastrointestinal tract of rats but did not cross the blood-brain barrier. In monkeys, 1263W94 levels in the brain, cerebrospinal fluid, and vitreous humor ranged from 4 to 20%, 1 to 2%, and <1%, of corresponding concentrations in plasma, respectively. The high level of binding by 1263W94 to human plasma proteins (primarily albumin) was readily reversible, with less protein binding seen in the monkey, rat, and mouse. Results of these studies demonstrate a favorable safety profile for 1263W94.

ABSTRACTBenzimidazole nucleosides have been shown to be potent inhibitors of human cytomegalovirus (HCMV) replication in vitro. As part of the exploration of structure-activity relationships within this series, we synthesized the 2-isopropylamino derivative (3322W93) of 1H-β-d-ribofuranoside-2-bromo-5,6-dichlorobenzimidazole (BDCRB) and the biologically unnatural l-sugars corresponding to both compounds. One of the lderivatives, 1H-β-l-ribofuranoside-2-isopropylamino-5,6-dichlorobenzimidazole (1263W94), showed significant antiviral potency in vitro against both laboratory HCMV strains and clinical HCMV isolates, including those resistant to ganciclovir (GCV), foscarnet, and BDCRB. 1263W94 inhibited viral replication in a dose-dependent manner, with a mean 50% inhibitory concentration (IC50) of 0.12 ± 0.01 μM compared to a mean IC50for GCV of 0.53 ± 0.04 μM, as measured by a multicycle DNA hybridization assay. In a single replication cycle, 1263W94 treatment reduced viral DNA synthesis, as well as overall virus yield. HCMV mutants resistant to 1263W94 were isolated, establishing that the target of 1263W94 was a viral gene product. The resistance mutation was mapped to the UL97 open reading frame. The pUL97 protein kinase was strongly inhibited by 1263W94, with 50% inhibition occurring at 3 nM. Although HCMV DNA synthesis was inhibited by 1263W94, the inhibition was not mediated by the inhibition of viral DNA polymerase. The parent benzimidazole d-riboside BDCRB inhibits viral DNA maturation and processing, whereas 1263W94 does not. The mechanism of the antiviral effect of l-riboside 1263W94 is thus distinct from those of GCV and of BDCRB. In summary, 1263W94 inhibits viral replication by a novel mechanism that is not yet completely understood.

A series of 2-substituted benzimidazole d- and l-erythrofuranosyl nucleosides were synthesized and tested for activity against herpesviruses and for cytotoxicity. The d-nucleosides 2,5,6-trichloro-1-(β-d-erythrofuranosyl)benzimidazole (8a) and 2-bromo-5,6-dichloro-1-(β-d-erythrofuranosyl)benzimidazole (8b) were prepared by coupling 1,2,3-tri-O-acetyl-β-d-erythrofuranose (d-6) with the appropriate benzimidazole, followed by removal of the acetyl protecting groups. The 2-isopropylamino (9), 2-cyclopropylamino (10), and 2-mercaptobenzyl (11) derivatives were synthesized by nucleophilic displacements of the C-2 chlorine in the benzimidazole moiety of 8a. The d-nucleoside 4-bromo-5,6-dichloro-2-isopropylamino-1-(β-d-erythrofuranosyl)benzimidazole (17) was prepared by coupling d-6 with the appropriate benzimidazole. The l-erythrofuranosyl derivatives, 5,6-dichloro-2-isopropylamino-1-(β-l-erythrofuranosyl)benzimidazole (21a), its 2-cyclopropylamino analogue (21b), and the 2-isopropylamino analogue (25), were prepared by coupling l-6 with the appropriate benzimidazole. Several of these new derivatives had very good activity against HCMV in plaque and yield reduction assays (IC50 = 0.05−19 μM against the Towne strain of HCMV) and DNA hybridization assays. Very little activity was observed against other herpesviruses. This pattern is similar to the antiviral activity profile observed for the corresponding ribofuranosides 2,5,6-trichloro-1-(β-d-ribofuranosyl)benzimidazole (4a), its 2-bromo analogue (4b), and the 2-cyclopropylamino analogue (4c). In comparison, 8a was 15-fold more active against HCMV than 4a, and 8b was 4-fold more active against HCMV than 4b. The 5,6-dichloro-2-isopropylamino-1-(β-l-erythrofuranosyl)benzimidazole (21a) was less active than 4c, which is now in clinical trials for HCMV infection. Both 8a,b had comparable HCMV activity to 4c. Mode of action studies with the d-erythrose analogues established that 8b acted by inhibition of viral DNA processing whereas 9 and 10 may act via a different mechanism. The lack of a 5‘-hydroxymethyl group in all members of this series established that antiviral activity occurred without 5‘-phosphorylation, a feature required for the activity of most nucleoside analogues.

AbstractStereoselective glycosylation of 2,5,6-trichlorobenzimidazole (1b), 2-bromo-5,6-dichlorobenzimidazole (1c), 5,6-dichlorobenzimidazole (1d), 5,6-dichlorobenzimidazole-2-thione (1e), 5,6-dichloro-2-(methylthio)benzimidazole (1f), 2-(benzylthio)-5,6-dichlorobenzimidazole (1g), and 2-chloro-5,6-dimethylbenzimidazole (1h) with 2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl chloride was achieved to give the desired β nucleosides 2b-h.Subsequent deprotection afforded the corresponding free β-D-2-deoxyribosides 3b-h.The 2-methoxy derivative 3iwas synthesized by the treatment of 2bwith methanolic sodium methoxide. Displacement of the 2-chloro group of 2bwith lithium azide followed by a removal of the protective groups gave the 2-azido-5,6-dichlorobenzimidazole derivative (5). The 2-amino derivative (6) was obtained by hydrogenolysis of 5over Raney nickel. 5,6-Dichloro-2-isopropylamino-1-(2-deoxy-β-D-erythro-pentofuranosyl)benzimidazole (10) was prepared using 2′-deoxyuridine (7), N-deoxyribofuranosyl transferase and 1dfollowed by functionalization of the C2 position. Antiviral evaluation of target compounds established that compounds 3band 3cwere active against human cytomegalovirus (HCMV) at non-cytotoxic concentrations. The activity of these 2-deoxy ribosides, however, was less than the activity of the parent riboside, 2,5,6-trichloro-1-β-D-ribofuranosylbenzimidazole (TCRB). Compared to TCRB, 3band 3cwere somewhat more cytotoxic and active against herpes simplex virus type 1. Compounds 3d-iwith other substituents in the 2-position were inactive against both viruses and non-cytotoxic. In contrast, compounds with amine substituents in the 2-position (5, 6, 10) were active against HCMV albeit less so than TCRB. These results establish that 2-deoxy-D-ribosyl benzimidazoles are less active against the DNA virus HCMV than are the corresponding D-ribosides.

AbstractA series of 2′-deoxy analogues of the antiviral agent 5,6-dichloro-2-isopropylamino-1-(β-L-ribofuranosyl)-1H-benzimidazole (1263W94) were synthesized and evaluated for activity against human cytomegalovirus (HCMV) and for cytotoxicity. The 2-substituents in the benzimidazole moiety correspond to those that were used in the 1263W94 series. In general, as was found in the 1263W94 series, cyclic and branched alkylamino groups were needed for potent activity against HCMV. Three analogues 3a, 3band 3dwere as potent as 1263W94. Further evaluation of two analogues, 3aand 3b, suggested that these 2′-deoxy analogues may act via a novel mechanism of action similar to that of 1263W94. These 2′-deoxy analogues generally lacked cytotoxicity in vitro. Pharmacokinetic parameters in mice and protein binding properties of 3awere quite similar to 1263W94. However, the oral bioavailability of 3awas only half of that observed for 1263W94.