LY3041658/ interleukin-8 complex structure as targets for IL-8 small molecule inhibitors discovery using a combination of in silico methods.

Since interleukin-8 (IL-8/CXCL8) and its receptor, CXCR1 and CXCR2, were known in the early 1990s, biological pathways related to these proteins were proven to have high clinical value in cancer and inflammatory/autoimmune conditions treatment. Recently, IL-8 has been identified as biomarker for severe COVID-19 patients and COVID-19 prognosis. Boyles et al. (mAbs 12 (2020), pp. 1831880) have published a high-resolution X-ray crystal structure of the LY3041658 Fab in a complex human CXCL8. They described the ability to bind to IL-8 and the blocking of IL-8/its receptors interaction by the LY3041658 monoclonal antibody. Therefore, the study has been designed to identify potential small molecules inhibiting interleukin-8 by targeting LY3041658/IL-8 complex structure using an in silico approach. A structure­based pharmacophore and molecular docking models of the protein active site cavity were generated to identify possible candidates, followed by virtual screening with the ZINC database. ADME analysis of hit compounds was also conducted. Molecular dynamics simulations were then performed to survey the behaviour and stability of the ligand-protein complexes. Furthermore, the MM/PBSA technique has been utilized to evaluate the free binding energy. The final data confirmed that one newly obtained compound, ZINC21882765, may serve as the best potential inhibitor for IL-8.

In-plane magnetic anisotropy and temperature dependence of switching field in (Ga, Mn) as ferromagnetic semiconductors.

We explore the magnetic anisotropy of GaMnAs ferromagnetic semiconductor by Planar Hall Effect (PHE) measurements. Using low magnitude of applied magnetic field (i.e., when the magnitude H is smaller than both cubic Hc and uniaxial Hu anisotropy field), we have observed various shapes of applied magnetic field direction dependence of Planar Hall Resistance (PHR). In particular, in two regions of temperature. At T < Tc/2, the "square-shape" signal and at T > Tc/2 the "zigzag-shape" signal of PHR. They reflect different magnetic anisotropy and provide information about magnetization reversal process in GaMnAs ferromagnetic semiconductor. The theoretical model calculation of PHR based on the free energy density reproduces well the experimental data. We report also the temperature dependence of anisotropy constants and magnetization orientations. The transition of easy axis from biaxial to uniaxiale axes has been observed and confirmed by SQUID measurements.

Intravenous butorphanol administration reduces intrathecal morphine-induced pruritus after cesarean delivery: a randomized, double-blind, placebo-controlled study.

PURPOSE: Pruritus associated with intrathecal opioid administration is a common side effect. There is evidence that κ-opioid receptor agonists have antipruritic activity. Butorphanol has agonist actions at both κ-opioid and µ-opioid receptors. This study was designed to evaluate the antipruritic efficacy of butorphanol after intrathecal morphine administration in the setting of a randomized, double-blind study of parturients undergoing cesarean section. METHODS: Ninety-one women who received combined spinal-epidural anesthesia with 1.2 ml 0.5 % isobaric bupivacaine and 0.1 mg preservative-free morphine were included in this study. After delivery of the baby, the parturients were randomly allocated to two groups: butorphanol group (n = 46) and physiological saline group (n = 45). In the butorphanol group, parturients received an intravenous loading dose of 1 mg butorphanol followed by infusion of 0.2 mg/h butorphanol. The physiological saline group received an infusion of the same volume of physiological saline. The presence of pruritus, visual analog scores for pain, sedation scores, and adverse effects were recorded 1, 2, 4, 6, 8, 10, 12, and 24 h after intrathecal morphine administration. RESULTS: The incidence of pruritus at 24 h was significantly more frequent in the physiological saline group than in the butorphanol group (48.9 vs. 13.0 %, P < 0.001). The severity of pruritus was significantly greater in the saline group than in the butorphanol group 2, 4, 6, 8 and 10 h after intrathecal morphine injection (P = 0.004, 0.001, 0.002, and 0.003, respectively). The visual analog scale scores at 24 h were significantly lower in the butorphanol group than in physiological saline group (P < 0.001). The Ramsay sedation score in the butorphanol group was significantly higher than that in the physiological saline group after 1, 2, 4, 6, 8, 10, 12, and 24 h (P < 0.05). There were no significant differences between the two groups in nausea/vomiting and other adverse effects. CONCLUSION: Administration of intravenous butorphanol after delivery of the baby can reduce pruritus that has been induced by intrathecal morphine administration in cesarean delivery with combined spinal-epidural anesthesia.

C4-dicarboxylate carriers and sensors in bacteria.

Bacteria contain secondary carriers for the uptake, exchange or efflux of C4-dicarboxylates. In aerobic bacteria, dicarboxylate transport (Dct)A carriers catalyze uptake of C4-dicarboxylates in a H(+)- or Na(+)-C4-dicarboxylate symport. Carriers of the dicarboxylate uptake (Dcu)AB family are used for electroneutral fumarate:succinate antiport which is required in anaerobic fumarate respiration. The DcuC carriers apparently function in succinate efflux during fermentation. The tripartite ATP-independent periplasmic (TRAP) transporter carriers are secondary uptake carriers requiring a periplasmic solute binding protein. For heterologous exchange of C4-dicarboxylates with other carboxylic acids (such as citrate:succinate by CitT) further types of carriers are used. The different families of C4-dicarboxylate carriers, the biochemistry of the transport reactions, and their metabolic functions are described. Many bacteria contain membraneous C4-dicarboxylate sensors which control the synthesis of enzymes for C4-dicarboxylate metabolism. The C4-dicarboxylate sensors DcuS, DctB, and DctS are histidine protein kinases and belong to different families of two-component systems. They contain periplasmic domains presumably involved in C4-dicarboxylate sensing. In DcuS the periplasmic domain seems to be essential for direct interaction with the C4-dicarboxylates. In signal perception by DctB, interaction of the C4-dicarboxylates with DctB and the DctA carrier plays an important role.

Spinal anesthesia for a patient with type I sialidosis undergoing abdominal surgery.

Type I and II sialidosis are autosomal recessively inherited glycoprotein storage disorders. Until now, there has been no published reports of patients with these conditions requiring anesthesia. We present the case of a 31-year-old male afflicted with type I sialidosis who underwent a surgical jejunostomy. Regional (spinal) anesthesia was carried out uneventfully. We discuss the anesthetic challenges posed by patients with type I and II sialidosis. Airway assessment and management is particularly crucial.

Tacrolimus in dermatology.

BACKGROUND: Tacrolimus (FK 506), a metabolite of the fungus Streptomyces tsukubaensis, is an anti-T-cell drug. It acts by inhibiting the production of IL-2, IL-3, IL-4, TNFa, and GM-CSF. More potent and with slightly less secondary effects than cyclosporine, it has been the object of considerable interest, especially in conditions that could benefit from the latter. OBJECTIVE: In psoriasis, a placebo-controlled double-blind study has shown oral tacrolimus at 0.1 mg/kg/day to be effective in controlling recalcitrant lesions. In human, small studies have reported tacrolimus ointment to be effective in controlling acute contact dermatitis. Short-term trials of topical tacrolimus in the treatment of atopic dermatitis have recently shown excellent results in both adults and children. In animal studies of hair growth disorders, topical tacrolimus induces anagen and protects from chemotherapy-induced alopecia. Animal studies with the ointment for the prevention of skin graft rejection, lupus dermatoses, and skin papilloma formation have also shown to be promising. CONCLUSIONS: There are case reports of pyoderma gangrenosum, Sezary's syndrome, and Behcet's disease successfully treated with oral tacrolimus but, because of their small number, they remain anecdotal at this point.

Role of glutathione in the formation of the active form of the oxygen sensor FNR ([4Fe-4S].FNR) and in the control of FNR function.

The oxygen sensor regulator FNR (fumarate nitrate reductase regulator) of Escherichia coli is known to be inactivated by O2 as the result of conversion of a [4Fe-4S] cluster of the protein into a [2Fe-2S] cluster. Further incubation with O2 causes loss of the [2Fe-2S] cluster and production of apoFNR. The reactions involved in cluster assembly and reductive activation of apoFNR isolated under anaerobic or aerobic conditions were studied in vivo and in vitro. In a gshA mutant of E. coli that was completely devoid of glutathione, the O2 tension for the regulatory switch for FNR-dependent gene regulation was decreased by a factor of 4-5 compared with the wild-type, suggesting a role for glutathione in FNR function. In isolated apoFNR, glutathione could be used as the reducing agent for HS- formation required for [4Fe-4S] assembly by cysteine desulfurase (NifS), and for the reduction of cysteine ligands of the FeS cluster in FNR. Air-inactivated FNR (apoFNR without FeS) could be reconstituted to [4Fe-4S].FNR by the same reaction as used for apoFNR isolated under anaerobic conditions. The in vivo effects of glutathione on FNR function and the role of glutathione in the formation of active [4Fe-4S].FNR in vitro suggest an important role for glutathione in the de novo assembly of FNR and in the reductive activation of air-oxidized FNR under anaerobic conditions.

Co-ordination between localized wound-induced Ca2+ signals and pre-wound serum signals is required for proliferation after mechanical injury.

The signals which initiate proliferation of endothelial cells after injury are important for selective blood vessel growth during wound healing or tumour growth. Upon mechanically wounding quiescent cells, a transient [Ca2+]i increase was induced in cells at the wound edge. These same cells proliferated 18-24 h post wounding, as measured by bromodeoxyuridine incorporation. The localized Ca2+ signal was required specifically during wounding since blocking Ca2+ influx reduced proliferation by 40-50%. Proliferation also required serum since starvation reduced proliferation by 80%. Serum-starved cells proliferated if briefly primed with serum prior to wounding. The signals derived from serum and [Ca2+]i combined at least additively to induce proliferation. Therefore, serum priming followed by a single, transient Ca2+ signal induced by mechanical injury must occur in a temporally and spatially regulated manner for normal proliferation. Co-ordination between signalling cascades induced by growth factors and release from contact inhibition might be obligatory for localized re-endothelialization after injury.

Changes in the proton potential and the cellular energetics of Escherichia coli during growth by aerobic and anaerobic respiration or by fermentation.

The energetic parameters of Escherichia coli were analyzed for the aerobic/anaerobic transition. The electrochemical proton potential (delta p) across the cytoplasmic membrane was determined in the steady state of respiration with O2, nitrate, fumarate, dimethylsulfoxide (Me2SO), and for fermentation. With O2, a proton potential of -160 mV was obtained. For anaerobic respiration with nitrate, fumarate or Me2SO, delta p decreased only slightly by about 20 mV in contrast to earlier assumptions, whereas delta p dropped by approximately 40 mV during fermentation. Under all conditions, the membrane potential (delta psi) contributed the major portion to delta p. The cellular ATP levels were highest for aerobic growth (about 13 micromol/g dry cells) and decreased to 3-6 micromol/g in anaerobic metabolism. Delta G'Phos, however, was constant due to equivalent changes of the ADP contents. Transition to the stationary growth phase caused a massive drop in the ATP content. It is concluded that, during anaerobic respiration, the energetic situation for the bacteria is very similar to that for aerobic growth with respect to delta G'Phos and delta p whereas, for fermentation, a significant decrease in delta p was observed. The consequences for the cellular energetics and for the regulation of the aerobic/anaerobic transition are discussed.

Requirement for the proton-pumping NADH dehydrogenase I of Escherichia coli in respiration of NADH to fumarate and its bioenergetic implications.

In Escherichia coli the expression of the nuo genes encoding the proton pumping NADH dehydrogenase I is stimulated by the presence of fumarate during anaerobic respiration. The regulatory sites required for the induction by fumarate, nitrate and O2 are located at positions around -309, -277, and downstream of -231 bp, respectively, relative to the transcriptional-start site. The fumarate regulator has to be different from the O2 and nitrate regulators ArcA and NarL. For growth by fumarate respiration, the presence of NADH dehydrogenase I was essential, in contrast to aerobic or nitrate respiration which used preferentially NADH dehydrogenase II. The electron transport from NADH to fumarate strongly decreased in a mutant lacking NADH dehydrogenase I. The mutant used acetyl-CoA instead of fumarate to an increased extent as an electron acceptor for NADH, and excreted ethanol. Therefore, NADH dehydrogenase I is essential for NADH-->fumarate respiration, and is able to use menaquinone as an electron acceptor. NADH-->dimethylsulfoxide respiration is also dependent on NADH dehydrogenase I. The consequences for energy conservation by anaerobic respiration with NADH as a donor are discussed.

Enhancement of proliferation in cultures of Chinook salmon embryo cells by interactions between inosine and bovine sera.

The influence of inosine on DNA synthesis by Chinook salmon embryo cells (CHSE-214) was investigated because previously cell number was shown to increase from six- to thirtyfold if inosine was added to the basal medium (L-15) supplemented with either dialyzed fetal bovine serum (dFBS), calf serum (CS), or dCS. Relative to L-15, 3H-thymidine incorporation was inhibited by these sera alone but elevated in nondialyzed (intact) FBS. Inosine at 10 microM stimulated 3H-thymidine incorporation from ten- to seventyfold in dFBS, CS, and dCS but was only slightly stimulatory in FBS and in L-15 alone. As well as inosine, hypoxanthine, cIMP, IMP, IDP, and ITP were just as stimulatory, but the nonsalvageable purines (xanthine, xanthosine, and XMP) were not. The stimulatory action of inosine was highest in low density cultures. Dipyridamole and S-(p-nitrobenzyl)-6-thioinosine (NBTI), inhibitors of facilitated nonconcentrative nucleoside transport, did not completely block the enhancement of cell number by inosine and by themselves increased proliferation in CS and dCS. Overall, these results suggest that exogenous inosine promoted CHSE-214 proliferation by overcoming factors in the nondialyzable fraction of sera that led to purine loss and by raising intracellular purine nucleotides to levels necessary for cells to respond to growth factors in the nondialyzable fraction of sera.