Can acclimation of thermal tolerance,in adults and across generations,act as a buffer against climate change in tropical marine ectotherms?

Thermal acclimation capacity was investigated in adults of three tropical marine invertebrates, the subtidal barnacle Striatobalanus amaryllis, the intertidal gastropod Volegalea cochlidium and the intertidal barnacle Amphibalanus amphitrite. To test the relative importance of transgenerational acclimation, the developmental acclimation capacity of A. amphitrite was investigated in F₁ and F₂ generations reared at a subset of the same incubation temperatures. The increase in CT_max (measured through loss of key behavioural metrics) of F₀ adults across the incubation temperature range 25.4–33.4 °C was low: 0.00 °C (V. cochlidium), 0.05 °C (S. amaryllis) and 0.06 °C (A. amphitrite) per 1 °C increase in incubation temperature (the acclimation response ratio; ARR). Although the effect of generation was not significant, across the incubation temperature range of 29.4–33.4 °C, the increase in CT_max in the F₁ (0.30 °C) and F₂ (0.15 °C) generations of A. amphitrite was greater than in the F₀ (0.10 °C). These correspond to ARR's of 0.03 °C (F₀), 0.08 °C (F₁) and 0.04 °C (F₂), respectively. The variability in CT_max between individuals in each treatment was maintained across generations, despite the high mortality of progeny. Further research is required to investigate the potential for transgenerational acclimation to provide an extra buffer for tropical marine species facing climate warming.     

New pentafluorophenyl complexes with phosphine-amide ligands

A series of nickel(II) and palladium(II) complexes containing one or two pentafluorophenyl ligands and the phosphino-amides o-Ph₂PC₆H₄CONHR [R = ⁱPr (a), Ph (b)] displaying different coordination modes have been synthesised. The chelating ability of these ligands and the influence of both coligands and the metal centre in their potential hemilabile behaviour have been explored. The crystal structure of (b) has been determined and reveals N–H⋯O intermolecular hydrogen bonding. Bis-pentafluorophenyl derivatives [M(C₆F₅)₂(o-Ph₂PC₆H₄CO-NHR)] [M = Ni; R = ⁱPr (1a); R = Ph (1b); M = Pd; R = ⁱPr (2a); R = Ph (2b)] in which (a) and (b) act as rigid P, O-chelating ligands were readily prepared from the labile precursors cis-[M(C₆F₅)₂(PhCN)₂]. X-ray structures of (1a), (1b) and (2a) have been established, allowing an interesting comparative structural discussion. Dinuclear [{Pd(C₆F₅)(tht)(μ-Cl)}₂] reacted with (a) and (b) yielding the monopentafluorophenyl complexes [Pd(C₆F₅)Cl{PPh₂(C₆H₄–CONH–R)}] (R = ⁱPr (3a), Ph (3b)) that showed a P, O-chelating behaviour of the ligands, confirmed by the crystal structure determination of (3a). New cationic palladium(II) complexes in which (a) and (b) behave as P-monodentate ligands have been synthesised by reacting them with [{Pd(C₆F₅)(tht)(μ-Cl)}₂], stoichiometric Ag(O₃SCF₃) and external chelating reagents such as cod [Pd(C₆F₅)(cod){PPh₂(C₆H₄-CONH-R)}](O₃SCF₃)(R = ⁱPr (4a), Ph (4b)) and 2,2′-bipy [Pd(C₆F₅)(bipy){PPh₂(C₆H₄-CONH-R)}](O₃SCF₃) (R = ⁱPr (5a), Ph (5b)). When chloride abstraction in [{Pd(C₆F₅)(tht)(μ-Cl)}₂] is promoted by means of a dithioanionic salt as dimethyl dithiophospate in the presence of (a) or (b), the corresponding neutral complexes [Pd(C₆F₅){S(S)P(OMe)₂}{PPh₂(C₆H₄-CONH-R)}] (R = ⁱPr (6a), Ph (6b)) were obtained.     

Ontogenetic and sexual differences of thermal biology and locomotor performance in a lacertid lizard,Eremias multiocellata

A viviparous lizard, Eremias multiocellata, was used to investigate the possible sexual and ontogenetic effects on selected body temperature, thermal tolerance range and the thermal dependence of locomotor performance. We show that adults are sexually dimorphic and males have larger bodies and heads than females. Adults selected higher body temperatures (34.5 vs. 32.4 °C) and could tolerate a broader range of body temperatures (8.1–46.8 vs. 9.1–43.1 °C) than juveniles. The sprint speed and maximum sprint distance increased with temperature from 21 °C to 33 °C, but decreased at 36 °C and 39 °C in both juveniles and adults. Adults ran faster and longer than juveniles at each tested temperature. Adult locomotor performance was not correlated with snout–vent length (SVL) or sex, and sprint speed was positively correlated with hindlimb length. Juvenile locomotor performance was positively correlated with both SVL and hindlimb length. The ontogenetic variation in selected body temperature, thermal tolerance and locomotor performance in E. multiocellata suggests that the effects of morphology on temperature selection and locomotor performance vary at different ontogenetic stages.     

Effects of postmortem carcass electrical stimulation on goat meat quality characteristics

Electrical stimulation (ES) has been reported to improve meat quality, but the effects of postmortem ES have not been fully characterized in goats. This experiment was conducted to determine the effects of postmortem ES on meat quality in two breeds of goats. Uncastrated Spanish and crossbreds (Boer × Spanish females × Kiko male) yearlings (n = 10/breed, body weight 31.2 ± 2.43 kg) were transported to the slaughter facility, held overnight in pens without feed, and slaughtered on two different days. Immediately after slaughter each carcass was split into two halves along the vertebral column. The left half was subjected to a high voltage ES (580 V) at 5 s intervals during 120 s (treatment) and the right half was kept as a non-stimulated control. After 24 h of cooler storage (2 °C), the carcasses were fabricated into 2.5 cm-thick loin/rib chops. Longissimus dorsi (LD) muscle pH and temperatures were recorded at 0, 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, and 24 h postmortem. The pH values of LD muscle were lower in stimulated sides than control sides (P < 0.01), and pH decreased quadratically (P < 0.01) with advancing time during the 24 h postmortem period. Treatment had no significant effect on the LD muscle temperature, and the temperature decline followed a cubic pattern (P < 0.01) during the 24 h postmortem period. Muscle glycogen concentrations immediately after electrical stimulation (0 h) were lower (P < 0.05) in the stimulated sides compared to control sides. Warner-Bratzler shear force (WBSF) values of loin chops were lower (P < 0.01) in stimulated sides (3.0 kg) compared to control sides (4.2 kg), and the chops from Spanish goats (3.9 kg) had higher (P < 0.05) WBSF values compared with crossbreds (3.3 kg). Color values (L*, a*, b*, chroma, and hue angle) and sarcomere length were not affected by ES or breed. Heated calpastatin activities were not influenced by ES, but the activities were lower at day 4 compared with day 1 of aging (P < 0.05). There were no significant effects (P > 0.05) of ES or aging time on selected myofibrillar protein concentrations (myosin heavy chain, myomesin, desmin, actin, troponin-T, and myosin light chain, P > 0.05). However, desmin concentration tended to decrease at day 4 of aging (P = 0.08). The results indicate that ES significantly accelerated postmortem glycolysis and improved tenderness of loin chops, as indicated by WBSF values.     

Acute effects of a dopamine/norepinephrine reuptake inhibitor on neuromuscular performance following self-paced exercise in cool and hot environments

Dopamine/norepinephrine (DA/NE) reuptake inhibitors have been used to manipulate the central mechanisms affecting arousal and motivation during exercise. Eight healthy, physically active males performed 30 min fixed-intensity cycling at 50% W_max followed by 30 min of self paced time trial (TT) with each section interspersed with a 30 s maximal sprint at 9, 19 and 29 min. The DA/NE re-uptake inhibitor administered was bupropion (BUP) versus a placebo (PLA) in either warm (32 °C, BUP32 or PLA32) or moderate (20 °C; BUP20, PLA20) ambient conditions. Core and skin temperature, heart rate and perceptual responses, neuromuscular and hormonal measures were assessed at multiple times throughout the trials and post exercise. Time trial performance remained unchanged across conditions (12.7–13.1 km) although core temperature was elevated in the fixed intensity section of the trials for BUP32 and BUP20 but continued to rise only in BUP32 during the time trial reaching 38.6 °C (P<0.05). NE increased in all conditions from pre-exercise with BUP32 values peaking at the end of TT to 1245.3±203.1 pg/mL (P<0.05) compared to the other conditions. Neuromuscular responses were similar among conditions although peak force was significantly reduced from pre (262±31 N) to post (202±31 N, P<0.05) exercise along with contraction duration (22%, P<0.05) in BUP20. We conclude that DA/NE re-uptake inhibitors influenced thermoregulation in the heat but not exercise performance. DA/NE re-uptake inhibitors are likely to act centrally to override the inhibitory signals for the cessation of exercise with these drugs acting peripherally to reduce the twitch characteristics of skeletal muscle in cooler conditions.     

A novel and potent VLA-4 antagonist based on trans-4-substituted cyclohexanecarboxylic acid

During the course of our study, it was revealed that the poor pharmacokinetic properties of a series of benzoic acid derivatives such as 1 should be attributed to the diphenylurea moiety. Thus, we replaced the diphenylurea moiety in 1 with a 2-(2-methylphenylamino)benzoxazole moiety which mimics the diphenylurea structure. However, this modification resulted in a significant decrease (3, IC₅₀ = 19 nM) in VLA-4 inhibitory activity compared to 1 (IC₅₀ = 1.6 nM). To address this discrepancy, we worked on optimization of the carboxylic acid moiety in compound 3. As a result, our efforts have led to the discovery of trans-4-substituted cyclohexanecarboxylic acid derivative 11b (IC₅₀ = 2.8 nM) as a novel and potent VLA-4 antagonist. In addition, compound 11b exhibited favorable pharmacokinetic properties (CL = 3.3 ml/min/kg, F = 51%) in rats.     

Synthesis,crystal structure and magnetic properties of the spin crossover system [Fe(pq)3]2+

Three new compounds formulated (ClO₄)₂[Fe(pq)₃] (1), (BF₄)₂[Fe(pq)₃] · EtOH (2) and {(ClO₄)[MnCr(C₂O₄)₃][Fe(pq)₂(H₂O)₂]} (3), where pq is 2,2′-pyridylquinoline, have been synthesised and characterised. Despite the different crystal packing exhibited by 1 and 2, the cationic species [Fe(pq)₃]²⁺ are structurally quite similar. At 293 K, the Fe–N bond lengths are characteristic of the iron(II) in the high-spin state. In contrast to 1, 2 undergoes a continuous spin transition. Indeed, at 95 K its structure experiences a noticeable change in the Fe–N bonds and angles, i.e. the Fe–N bonds shorten by 0.194 Å on the average. The magnetic behaviour confirms that 1 is fully high-spin in the 4–300 K temperature range while 2 shows a spin transition centred at T_1/2 = 150 K. The corresponding enthalpy, entropy and interaction parameter are ΔH = 7.49 kJ mol^?1, ΔS = 50 J K^?1 mol^?1and Γ = 1.35 kJ mol^?1. Compound 3 has been obtained as a microcrystalline powder. The magnetic properties of 3 point at the occurrence of ferromagnetic coupling below 100 K and the onset of a ferromagnetic ordering below 10 K (Weiss constant equal to 6.8 K). The Mössbauer spectra of 3 show the occurrence of a magnetic order at T ? 4.2 K.     

Fingertip forces and completion time for index finger and thumb touchscreen gestures

Users actuate touchscreen computers by applying forces with their fingers to the touchscreen, although the amount and direction of the force is unknown. Our aim was to characterize the magnitude, direction and impulse of the force applied during single finger (tapping and sliding in four directions) and two finger gestures (stretch and pinch). Thirteen subjects performed repeated trials of each gesture. Mean(±SD) resultant force was 0.50(0.09) N for tap, 0.79(0.32) N to 1.18(0.47) N for sliding gestures, 1.47(0.63) N for pinch and 2.05(1.13) N for stretch. Mean resultant force was significantly less (p < 0.04) for tap than for all gestures except slide right. The direction of force application was more vertical for the two-finger gestures as compared to the single- finger gestures. Tap was the fastest gesture to complete at 133(83) ms, followed by slide right at 421(181) ms. On average, participants took the longest to complete the stretch gesture at 920(398) ms. Overall, there are differences in forces, force direction, and completion times among touchscreen gestures that could be used to estimate musculoskeletal exposure and help forge guidelines to reduce risk of musculoskeletal injury.     

Glycopeptide dendrimer colchicine conjugates targeting cancer cells

Screening of a 65,536-member one-bead-one-compound (OBOC) combinatorial library of glycopeptide dendrimers of structure ((βGal)_n + 1X⁸X⁷X⁶X⁵)₂DapX⁴X³X²X¹(β-Gal)_m (βGal = β-galactosyl-thiopropionic acid, X^8–1 = variable amino acids, Dap = l-2,3-diaminopropionic acid, n, m = 0, or 1 if X⁸ = Lys resp. X¹ = Lys) for binding of Jurkat cells to the library beads in cell culture, resynthesis and testing lead to the identification of dendrimer J1 (βGal-Gly-Arg-His-Ala)₂Dap-Thr-Arg-His-Asp-CysNH₂ and related analogues as delivery vehicles. Cell targeting is evidenced by FACS with fluorescein conjugates such as J1F. The colchicine conjugate J1C is cytotoxic with LD₅₀ = 1.5 μM. The β-galactoside groups are necessary for activity, as evidenced by the absence of cell-binding and cytotoxicity in the non-galactosylated, acetylated analogue AcJ1F and AcJ1C, respectively. The pentagalactosylated dendrimer J4 βGal₄(Lys-Arg-His-Leu)₂Dap-Thr-Tyr-His-Lys(βGal)-Cys) selectively labels Jurkat cell as the fluorescein derivative J4F, but its colchicine conjugate J4C lacks cytotoxicity. Tubulin binding assays show that the colchicine dendrimer conjugates do not bind to tubulin, implying intracellular degradation of the dendrimers releasing the active drug.

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Magnetostructural correlations and catecholase-like activities of μ-alkoxo-μ-carboxylato double bridged dinuclear and tetranuclear copper(II) complexes

Two μ-alkoxo-μ-carboxylato bridged dinuclear copper(II) complexes, [Cu₂(L¹)(μ-HCO₂)] (1) ((H₃L¹ = 1,3-bis(5-bromosalicylideneamino)-2-propanol)), [Cu₂(L²)(μ-HCO₂)] · dmf (2) (H₃L² = 1,3-bis(3,5-chlorosalicylideneamino-2-propanol)), and two μ-alkoxo-μ-dicarboxylato doubly bridged tetranuclear copper(II) complexes, [{Cu₂(L³)}₂(μ-O₂C–C(CH₃)₂–CO₂)] · 5H₂O · 3CH₃OH (3) ((H₃L³ = 1,3-bis(salicylid-deneamino)-2-propanol)) and [{Cu₂(L³)}₂(μ- O₂CCH₂–C₆H₄–CH₂CO₂)] · 2H₂O (4) have been prepared and characterized. The single crystal X-ray analysis shows that the structures of complexes 1 and 2 are dimeric with two adjacent copper(II) atoms bridged by μ-alkoxo-μ-carboxylato ligands with the Cu⋯Cu distances and Cu–O(alkoxo)–Cu angles are 3.511 Å and 132.85° for 1, 3.517 Å and 131.7° for 2, respectively. Complexes 3 and 4 consist of μ-alkoxo-μ-dicarboxylato doubly bridged tetranuclear Cu(II) complexes with mean Cu–Cu distances and Cu–O–Cu angles of 3.158 Å and 108.05° for 3 and 3.081 Å and 104.76° for 4, respectively. Magnetic measurements reveal that 1 and 2 are strong antiferromagnetically coupled with 2J = −156 and −152 cm⁻¹, respectively, while 3 and 4 exhibit ferromagnetic coupling with 2J = 86 and 155.2 cm⁻¹, respectively. The 2J values of 1–4 are linearly correlated to the Cu–O–Cu angles. Dependence of the pH at 25 °C on the reaction rate of oxidation of 3,4-di-tert-butylcatechol (3,5-dtbc) to the corresponding quinone catalyzed by 1–4 was studied. Complexes 1–4 exhibit high catecholase-like activity at pH 9.0 and 25 °C for oxidation of 3,5-di-tert-butylcatechol.     

Mechanical properties of the patellar tendon in adults and children

It is not currently known how the mechanical properties of human tendons change with maturation in the two sexes. To address this, the stiffness and Young's modulus of the patellar tendon were measured in men, women, boys and girls (each group, n=10). Patellar tendon force (F_pt) was calculated from the measured joint moment during a ramped voluntary isometric knee extension contraction, the antagonist knee extensor muscle co-activation quantified from its electromyographical activity, and the patellar tendon moment arm measured from magnetic resonance images. Tendon elongation was imaged using the sagittal-plane ultrasound scans throughout the contraction. Tendon cross-sectional area was measured at rest from ultrasound scans in the transverse plane. Maximal F_pt and tendon elongation were (mean±SE) 5453±307 N and 5±0.5 mm for men, 3877±307 N and 4.9±0.6 mm for women, 2017±170 N and 6.2±0.5 mm for boys and 2169±182 N and 5.9±0.7 mm for girls. In all groups, tendon stiffness and Young's modulus were examined at the level that corresponded to the maximal 30% of the weakest participant's F_pt and stress, respectively; these were 925–1321 N and 11.5–16.5 MPa, respectively. Stiffness was 94% greater in men than boys and 84% greater in women than girls (p<0.01), with no differences between men and women, or boys and girls (men 1076±87 N/mm; women 1030±139 N/mm; boys 555±71 N/mm and girls 561.5±57.4 N/mm). Young's modulus was 99% greater in men than boys (p<0.01), and 66% greater in women than girls (p<0.05). There were no differences in modulus between men and women, or boys and girls (men 597±49 MPa; women 549±70 MPa; boys 255±42 MPa and girls 302±33 MPa). These findings indicate that the mechanical stiffness of tendon increases with maturation due to an increased Young's modulus and, in females due to a greater increase in tendon cross-sectional area than tendon length.     

An oligothiophene compound neutralized influenza A viruses by interfering with hemagglutinin

Background and ObjectivesRecently influenza pandemic outbreaks were caused by emerging H5N1, H7N9 and H1N1 viruses. However, virucidal disinfectants are mainly unspecific and toxic. It is tactical to discover specific virucidal compounds.MethodsThe inhibitory potency was determined in H5N1 pseudovirus system; Interactions of compounds with hemagglutinin (HA) were detected with surface plasmon resonance (SPR) and further calculated with molecular docking. Virucidal effect was also estimated in influenza virus A/Puerto Rico/8/34(H1N1). Prevention efficacy was further estimated in mice model.ResultsOligothiophene compound 4sc was potently virucidal against H5N1 pseudovirus with selective index > 1169 (IC₅₀ = 0.17 ± 0.01 μM). Pseudovirus assay revealed 4sc may interact with HA. However, HA inhibition test indicated 4sc did not interact with receptor pocket in HA. SPR detection revealed 4sc interacted directly with HA and its HA2 subunits. Molecular docking analysis revealed that 4sc interacted with the cavity of HA2 stem region and HA1-HA2 interface which consist of 7 residues: L2₂, K26₂, G47₂ and F110₂ in HA2; M24₁, E25₁ and N27₁ in HA1. 4sc also potently and irreversibly neutralized PR8 (H1N1) virus, causing 10^{5.06 ± 0.26} fold decrease of virus titer after exposure for 10 min. 4sc blocked PR8 transmission to MDCK cells. Amazingly, virucidal effect of 4sc was not significantly reduced even at 4 °C. Furthermore, 4sc blocked viral transmission to mice.ConclusionOligothiophene compound 4sc is a novel selective virucide of influenza virus, which blocks entry by interfering viral hemagglutinin. Due to promising safety profile and stable virucidal effect at 4 °C, 4sc may be useful in disinfecting H5N1 and H1N1 influenza virus.     

Therapeutic and pharmacokinetic characterizations of an anti-amyloidogenic bis-styrylbenzene derivative for Alzheimer’s disease treatment

Alzheimer’s disease drug discovery regarding exploration into the molecules and processes has focused on the intrinsic causes of the brain disorder correlated with the accumulation of amyloid-β. An anti-amyloidogenic bis-styrylbenzene derivative, KMS80013, showed excellent oral bioavailability (F = 46.2%), facilitated brain penetration (26%, iv) in mouse and target specific in vivo efficacy in acute AD mouse model attenuating the cognitive deficiency in Y-maze test. Acute toxicity (LD₅₀ >2000 mg/kg) and hERG channel inhibition (14% at 10 μM) results indicated safety of KMS80013.     

Phorbaketals L–N,cytotoxic sesterterpenoids isolated from the marine sponge of the genus Phorbas

Three new sesterterpenoids, phorbaketals L–N (1–3), were isolated from a marine sponge of the genus Phorbas and their complete structures were elucidated via analysis of HRFABMS and NMR spectroscopic data. Phorbaketal N (3) showed potent cytotoxicity against human pancreas cancer cells (IC₅₀ = 11.4 μM).     

Synthesis and antioxidant evaluation of (S,S)- and (R,R)-secoisolariciresinol diglucosides (SDGs)

Secoisolariciresinol diglucosides (SDGs) (S,S)-SDG-1 (major isomer in flaxseed) and (R,R)-SDG-2 (minor isomer in flaxseed) were synthesized from vanillin via secoisolariciresinol (6) and glucosyl donor 7 through a concise route that involved chromatographic separation of diastereomeric diglucoside derivatives (S,S)-8 and (R,R)-9. Synthetic (S,S)-SDG-1 and (R,R)-SDG-2 exhibited potent antioxidant properties (EC₅₀ = 292.17 ± 27.71 μM and 331.94 ± 21.21 μM, respectively), which compared well with that of natural (S,S)-SDG-1 (EC₅₀ = 275.24 ± 13.15 μM). These values are significantly lower than those of ascorbic acid (EC₅₀ = 1129.32 ± 88.79 μM) and α-tocopherol (EC₅₀ = 944.62 ± 148.00 μM). Compounds (S,S)-SDG-1 and (R,R)-SDG-2 also demonstrated powerful scavenging activities against hydroxyl [natural (S,S)-SDG-1: 3.68 ± 0.27; synthetic (S,S)-SDG-1: 2.09 ± 0.16; synthetic (R,R)-SDG-2: 1.96 ± 0.27], peroxyl [natural (S,S)-SDG-1: 2.55 ± 0.11; synthetic (S,S)-SDG-1: 2.20 ± 0.10; synthetic (R,R)-SDG-2: 3.03 ± 0.04] and DPPH [natural (S,S)-SDG-1: EC₅₀ = 83.94 ± 2.80 μM; synthetic (S,S)-SDG-1: EC₅₀ = 157.54 ± 21.30 μM; synthetic (R,R)-SDG-2: EC₅₀ = 123.63 ± 8.67 μM] radicals. These results confirm previous studies with naturally occurring (S,S)-SDG-1 and establish both (S,S)-SDG-1 and (R,R)-SDG-2 as potent antioxidants and free radical scavengers for potential in vivo use.     

Highly resolved proton matrix ENDOR of oriented photosystem II membranes in the S2 state

Proton matrix ENDOR was performed to investigate the protons close to the manganese cluster in oriented samples of photosystem II (PS II). Eight pairs of ENDOR signals were detected in oriented PS II membranes. At an angle of θ = 0° between the membrane normal vector n and the external field H₀, five pairs of ENDOR signals were exchangeable in D₂O medium and three pairs were not exchangeable in D₂O medium. The hyperfine splitting of 3.60 MHz at θ = 0° increased to 3.80 MHz at θ = 90°. The non-exchangeable signals with 1.73 MHz hyperfine splitting at θ = 0°, which were assigned to a proton in an amino acid residue, were not detected at θ = 90° in oriented PS II or in non-oriented PS II. Highly resolved spectra show that only limited numbers of protons were detected by CW-ENDOR spectra, although many protons were located near the CaMn₄O₅ cluster. The detected exchangeable protons were proposed to arise from the protons belonging to the water molecules, labeled W1-W4 in the 1.9 Å crystal structure, directly ligated to the CaMn₄O₅ cluster, and nearby amino-acid residue.     

The mechanics of activated semitendinosus are not representative of the pathological knee joint condition of children with cerebral palsy

Characteristic cerebral palsy effects in the knee include a restricted joint range of motion and forcefully kept joint in a flexed position. To show whether the mechanics of activated spastic semitendinosus muscle are contributing to these effects, we tested the hypothesis that the muscle’s joint range of force exertion is narrow and force production capacity in flexed positions is high. The isometric semitendinosus forces of children with cerebral palsy (n = 7, mean (SD) = 7 years (8 months), GMFCS levels III–IV, 12 limbs tested) were measured intra-operatively as a function of knee angle, from flexion (120°) to full extension (0°). Peak force measured in the most flexed position was considered as the benchmark. However, peak force (mean (SD) = 112.4 N (54.3 N)) was measured either at intermediate or even full knee extension (three limbs) indicating no narrow joint range of force exertion. Lack of high force production capacity in flexed knee positions (e.g., at 120° negligible or below 22% of the peak force) was shown except for one limb. Therefore, our hypothesis was rejected for a vast majority of the limbs. These findings and those reported for spastic gracilis agree, indicating that the patients’ pathological joint condition must rely on a more complex mechanism than the mechanics of individual spastic muscles.     

(R)-3-Amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives as potent inhibitors of dipeptidyl peptidase-4: Design,synthesis, biological evaluation,and molecular modeling

A series of (R)-3-amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives was designed, synthesized, and evaluated as novel inhibitors of dipeptidyl peptidase-4 (DPP-4) for the treatment of type 2 diabetes. Most of the synthesized compounds demonstrated good inhibition activities against DPP-4. Among these, compounds 3e, 4c, 4l, and 4n exhibited prominent inhibition activities against DPP-4, with IC₅₀s of 0.07, 0.07, 0.14, and 0.17 μM, respectively. The possible binding modes of compounds 3e and 4n with dipeptidyl peptidase-4 were also explored by molecular docking simulation. These potent DPP-4 inhibitors were optimized for the absorption, distribution, metabolism, and excretion (ADME) properties, and compound 4n displayed an attractive pharmacokinetic profile (F = 96.3%, t_1/2 = 10.5 h).     

Effect of the timing of ice slurry ingestion for precooling on endurance exercise capacity in a warm environment

It has been demonstrated that precooling with ice slurry ingestion enhances endurance exercise capacity in the heat. However, no studies have yet evaluated the optimal timing of ice slurry ingestion for precooling. This study aimed to investigate the effects of varying the timing of ice slurry ingestion for precooling on endurance exercise capacity in a warm environment. Ten active male participants completed 3 experimental cycling trials to exhaustion at 55% peak power output (PPO) after 15 min of warm-up at 30% PPO at 30 °C and 80% relative humidity. Three experimental conditions were set: no ice slurry ingestion (CON), pre-warm-up ice slurry ingestion (−1 °C; 7.5 g kg⁻¹) (PRE), and post-warm-up ice slurry ingestion (POST). Rectal and mean skin temperatures at the beginning of exercise in the POST condition (37.1±0.2 °C, 33.8±0.9 °C, respectively) were lower than those in the CON (37.5±0.3 °C; P<0.001, 34.8±0.8 °C; P<0.01, respectively) and PRE (37.4±0.2 °C; P<0.01, 34.6±0.7 °C; P<0.01, respectively) conditions. These reductions increased heat storage capacity and resulted in improved exercise capacity in the POST condition (60.2±8.7 min) compared to that in the CON (52.0±11.9 min; effect size [ES]=0.78) and PRE (56.9±10.4 min; ES=0.34) conditions. Ice slurry ingestion after warm-up effectively reduced both rectal and skin temperatures and increased cycling time to exhaustion in a warm environment. Timing ice slurry ingestion to occur after warm-up may be effective for precooling in a warm environment.     

Chiral porphyrin complexes of cobalt(II) and ruthenium(II) in catalytic cyclopropanation and amination reactions

We report here the syntheses of two new metal complexes (M = Co, 2; M = Ru, 3) of the chiral porphyrin TmyrtP (1) (TmyrtP = dianion of the meso-tetrakis[(1R)-apopinen-2-yl]porphyrin). Both complexes exist as a mixture of atropisomers. Complexes 2 and 3 activate aromatic azides for the amination under mild conditions of unsaturated hydrocarbons. Even though the observed ee values are low, this is the first asymmetric transfer of the nitrene residue of aryl azides to a prochiral olefin catalyzed by a transition metal complex to be reported in the literature. Complex 3 also showed a good catalytic activity in cyclopropanation reactions with ethyldiazoacetate even at low temperatures (−30 °C) but a poor diastereo- and enantioselectivity were observed.