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Kashmir valley is rich in flora and fauna that is mostly fragmented. Among various ornamental plants, Narcissus is considered exotic and poses threat to local biodiversity. Neutral molecular markers have been exploited for providing information on the diversity and population structure of various invasive and native populations. In the present investigation, 40 samples belonging to five different Narcissus species were genotyped using 13 random amplified microsatellite markers. Dendrogram and principal component analysis revealed high genetic diversity without congruence on geographical or species level. Analysis of molecular variance revealed maximum variability within (93.49%) the Narcissus populations. Fixation indices at the population level were low except for N. poeticusand N. tazetta, indicating slight genetic differentiation in them. Pairwise FSTcomparisons between five Narcissus populations were low to high. The high diversity observed in the present investigation indicates that the Narcissus species have not gone through any bottleneck due to either multiple introductions or the presence of these species from decades. To ascertain the exotic nature of Narcissus species, a thorough investigation into the species grown in the valley and Narcissus species grown in the centre of origin based on neutral markers is needed.

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Abstract: In the present study, SnS and Cr-doped SnS nanoparticles were synthesized by solvothermal method. The structural, functional, elemental, morphological, and electrochemical properties of the as-synthesized non-doped and Cr-doped SnS nanoparticles were examined using XRD, Raman, FTIR, SEM/EDX, and cyclic voltammetry analysis. The XRD results indicated a good crystallinity of the sample and confirmed the formation of the SnS nanoparticles in orthorhombic structure. The FTIR result also confirmed the functional groups present in the Cr-doped SnS nanoparticles. The well-formed SnS nanoparticles are observed as spherical shapes confirmed from the SEM analysis. EDX spectra confirmed the presence of Sn, Cr, and S elements in the Cr-doped SnS nanoparticles. The electrochemical performance of Cr-doped SnS nanoparticles shows higher specific capacitance of 375 F/g compared with 284 F/g of bare SnS nanoparticles, which confirms that Cr-doped SnS nanoparticles are promising candidate for supercapacitor applications.

A promising approach for the production of highly efficient and stable hybrid perovskite solar cells is employing mixed-ion materials. Remarkable performances have been reached by materials comprising a stabilized mixture of methylammonium (MA+) and formamidinium (FA+) as a monovalent cation. We compare and quantify the methods of stabilizing FA-based perovskites involving the additional blending of the smaller inorganic cations cesium (Cs+) and rubidium (Rb+), which can lead to an improvement in phase purity of black cubic perovskite modification. Even under excess lead iodide conditions, the presence of a separate PbI2phase as well as hexagonal phases, which are very common for formamidinium-containing perovskites, can be drastically reduced or even completely prevented. In this aspect, adding both Cs+and Rb+showed greater effectivity than only adding Cs+, enabling an increase in the percentage of the cubic phase within the material from 45% in the double-cation FA:MA mixture to 97.8% in the quadruple composition. The impact of admixing inorganic cations on the perovskite crystal structure resulted in enlarged homogeneous crystallite sizes and a less pronounced orientational order and indicated also minor modifications of unit cell sizes. Finally, we discuss the impact of the phase purity on charge-carrier recombination dynamics and solar cell performance.

In the ongoing intense quest to increase the performance of perovskite solar cells, optimizing the morphology of perovskite material has become imperative to achieve high power conversion efficiencies. Despite the fact that nucleation plays a key role in controlling the crystal morphology, very little is known about the nucleation and crystal growth processes. Here, we perform metadynamics simulations of nucleation of methylammonium lead triiodide (MAPI) in order to unravel the atomistic details of perovskite crystallization from a γ-butyrolactone solution. The metadynamics trajectories show that the nucleation process takes place in several stages. Initially, dense amorphous clusters mainly consisting of lead and iodide appear from the homogeneous solution. These clusters evolve into lead iodide (PbI2)-like structures. Subsequently, methylammonium (MA+) ions diffuse into these PbI2-like aggregates triggering the transformation into a perovskite crystal through a solid–solid transformation. These enticing results allowed us to design new experimental strategies to rationally control the dimensions of MAPI grains using the spin-coating technique and to engineer homogeneous nucleation and growth of MAPI single crystals. The experimental results amply support our unprecedented observations related to the critical role of monovalent cations in inducing the nucleation process in lead halide perovskites.

ABSTRACTObjective: To test the hypothesis that miltefosine (MTF)-polyphenol co-loaded second-generation nano-transfersomes (SGNTs) can be an effective approach for the topical treatment of cutaneous leishmaniasis (CL).Methods: The co-loaded SGNTs with various MTF-polyphenol combinations were developed, evaluated and compared for the entrapment efficiency, vesicle size, deformability index, ex-vivopermeation, cytotoxicity, and anti-leishmanial potential, using both in-vitroand in-vivomodels.Results: The co-loaded SGNTs were spherical in shape, with an average size of 119 ± 1.5 nm and a high entrapment efficiency of 73.7 ± 3.7%. The ex-vivostudy displayed a 3.2-fold higher permeation of MTF when entrapped in co-loaded SGNTs, whereas cytotoxicity potential of co-loaded SGNTs was 43.2% higher than the MTF solution. A synergistic interaction was observed between MTF and apigenin (APG) among all polyphenols and an 8.0-fold lower IC50was found against amastigotes of DsRed Leishmania mexicana, compared with the plain MTF solution. Moreover, the in-vivostudies displayed a 9.5-fold reduced parasitic burden in the L. mexicanainfected BALB/c mice treated with MTF-APG co-loaded SGNTs gel.Conclusions: The potential of MTF-APG co-loaded SGNTs topical formulation is established for the first time as an effective drug delivery strategy against CL.

We applied intensity-modulated photocurrent spectroscopy (IMPS) and intensity-modulated photovoltage spectroscopy (IMVS) techniques to explore the effect of rubidium (Rb) incorporation into lead halide perovskite films on the photovoltaic parameters of perovskite solar cells (PSC). IMPS responses revealed the transport mechanisms at the TiO2/perovskite interface and inside the perovskite absorber films. For recombination time constants, IMVS showed that the two perovskite solar cells differ in terms of trap densities that are responsible for recombination loss. Impedance spectroscopy carried out under illumination at open circuit for a range of intensities showed that the cell capacitance was dominated by the geometric capacitance of the perovskite layer. Our systematic studies revealed that Rb containing PSCs exhibit enhanced charge transport, slower charge recombination, faster photocurrent transient response, and lower capacitance than the Rb-free samples.

Two new donor–acceptor (D–A)-substituted S,N-heteroacene-based molecules were developed and investigated as hole-transporting material (HTM) for perovskite solar cells (PSCs). Optical and electrochemical characterization brought out that the energy levels of both HTMs are suitable for their use in PSCs. Consequently, a power-conversion efficiency of 17.7% and 16.1% was achieved from PSCs involving the HTM-1and HTM-2, respectively. The optoelectronic properties in terms of series resistance, conductivity, and charge carrier recombination were further examined to unfold the potential of these new HTMs. Time-resolved photoluminescence spectroscopy brought out that the hole injection from the valence band of perovskite into HTMs follows the trend, which is in accordance with the position of the highest occupied molecular orbital. Overall, our findings underline the potential of S,N-heteroacene co-oligomers as promising HTM candidates for PSCs.

Three-dimensional (3D) perovskite materials display remarkable potential in photovoltaics owing to their superior solar-to-electric power conversion efficiency, with current efforts focused on improving stability. Two-dimensional (2D) perovskite analogues feature greater stability toward environmental factors, such as moisture, owing to a hydrophobic organic cation that acts as a spacer between the inorganic layers, which offers a significant advantage over their comparatively less stable 3D analogues. Here, we demonstrate the first example of a formamidinium (FA) containing Dion–Jacobson 2D perovskite material characterized by the BFAn–1PbnI3n+1formulation through employing a novel bifunctional organic spacer (B), namely 1,4-phenylenedimethanammonium (PDMA). We achieve remarkable efficiencies exceeding 7% for (PDMA)FA2Pb3I10based 2D perovskite solar cells resisting degradation when exposed to humid ambient air, which opens up new avenues in the design of stable perovskite materials.

We report significant improvements in the optoelectronic properties of lead halide perovskites with the addition of monovalent ions with ionic radii close to Pb2+. We investigate the chemical distribution and electronic structure of solution processed CH3NH3PbI3perovskite structures containing Na+, Cu+, and Ag+, which are lower valence metal ions than Pb2+but have similar ionic radii. Synchrotron X-ray diffraction reveals a pronounced shift in the main perovskite peaks for the monovalent cation-based films, suggesting incorporation of these cations into the perovskite lattice as well as a preferential crystal growth in Ag+containing perovskite structures. Furthermore, the synchrotron X-ray photoelectron measurements show a significant change in the valence band position for Cu- and Ag-doped films, although the perovskite bandgap remains the same, indicating a shift in the Fermi level position toward the middle of the bandgap. Such a shift infers that incorporation of these monovalent cations dedope the n-type perovskite films when formed without added cations. This dedoping effect leads to cleaner bandgaps as reflected by the lower energetic disorder in the monovalent cation-doped perovskite thin films as compared to pristine films. We also find that in contrast to Ag+and Cu+, Na+locates mainly at the grain boundaries and surfaces. Our theoretical calculations confirm the observed shifts in X-ray diffraction peaks and Fermi level as well as absence of intrabandgap states upon energetically favorable doping of perovskite lattice by the monovalent cations. We also model a significant change in the local structure, chemical bonding of metal-halide, and the electronic structure in the doped perovskites. In summary, our work highlights the local chemistry and influence of monovalent cation dopants on crystallization and the electronic structure in the doped perovskite thin films.

A tailored optimization of perovskite solar cells requires a detailed understanding of the processes limiting the device efficiency. Here, we study the role of the hole transport layer (HTL) spiro-MeOTAD and its thickness in a mesoscopic TiO2-based solar cell architecture. We find that a sufficiently thick (200 nm) HTL not only increases the charge carrier collection efficiency but also the light harvesting efficiency. This is due to an enhanced reflection of a smooth HTL/Au–electrode interface. The rough CH3NH3PbI3perovskite surface requires an HTL thickness of >400 nm to avoid surface recombination and guarantee a high open-circuit voltage. Analyses of the electroluminescence efficiency and the diode ideality factor show that the open-circuit voltage becomes completely limited by trap-assisted recombination in the perovskite for a thick HTL. Thus, spiro-MeOTAD is a very good HTL choice from the device physics’ point of view. The fill factor analyzed by the Suns-Vocmethod is not transport limited, but trap-recombination limited as well. Consequently, a further optimization of the device has to focus on defects in the polycrystalline perovskite film.

Nano-crystalline Ni–Zn ferrites were synthesized by chemical co-precipitation and reverse micro-emulsion technique with an average crystallite size of 11 and 6 nm, respectively. The reverse micro-emulsion method has been found to be more appropriate for nano-ferrite synthesis as the produced particles are monodisperse and highly crystalline. Zero-field cooled and field cooled magnetization study under different magnetic fields and magnetic hysteresis loops at different temperatures have been performed. The non-saturated M–H loops, absence of hysteresis, and coercivity at room temperature are indicative of the presence of super paramagnetic and single-domain nano-particles for both the materials. In sample ‘a’, the blocking temperature (TB) has been observed to decrease from 255 to 120 K on increasing the magnetic field from 50 to 1,000 Oe, which can be attributed to the reduction of magneto crystalline anisotropy constant. The MSand coercivity were found to be higher for sample ‘a’ as compared with sample ‘b’ since surface effects are neglected on increasing the crystallite size.

Nanosized Mn0.5Zn0.5Fe2O4ferrite particles were synthesized by a reverse microemulsion reaction process. Core–shell nanocomposites composed of Mn0.5Zn0.5Fe2O4nanocrystals and conjugated polymer polyaniline were successfully synthesized from a simple and inexpensive process, and in situ chemical oxidative polymerization of aniline occurs. Mn0.5Zn0.5Fe2O4nanocrystals are in the micellar solution of dodecyl benzene sulfonic acid (DBSA). It acts as both a surfactant and a dopant. These nanocomposites were subsequently investigated for structural, morphological magnetic, and electromagnetic properties. Transmission electron microscopy (TEM) studies reveal the formation of core–shell type morphology with ferrite nanocrystals (∼9–11 nm) as the center, while the polymer (PANI) formulates the outer shell of the composite. A decrease in the blocking temperature of Mn0.5Zn0.5Fe2O4nanocrystals after coating with PANI has been recorded, attributing that the polymer matrix allows each ferrite nanoparticle to behave independently, indicating a decrease in the dipole–dipole interactions that will decrease the anisotropy energy barrier. Magnetic properties of the synthesized nanoferrite exhibit a very high magneto-crystalline anisotropy energy value of 31.3 × 105erg/cm3at a blocking temperature of 90 K. The complex permittivity, permeability, and microwave absorption properties of the composites were explored in the 8.2–12.2 GHz (X-band) frequency range. The nanocomposites are observed to show high shielding effectiveness (SEA= 31.2 dB) as compared to pure PANI, which strongly depends on dielectric loss, magnetic permeability, and volume fraction of Mn0.5Zn0.5Fe2O4nanocrystals. The high value of SEAsuggests that these composites can be used as a promising electromagnetic absorbing material.

In the central nervous system, adenosine and adenosine 5′‐triphosphate (ATP) play an important role in regulating neuronal activity as well as controlling other neurotransmitter systems, such as, GABA, glutamate, and dopamine. Ethanol increases extracellular adenosine levels that regulate the ataxic and hypnotic/sedative effects of ethanol. Interestingly, ethanol is known to increase adenosine levels by inhibiting an ethanol‐sensitive adenosine transporter, equilibrative nucleoside transporter type 1 (ENT1). Ethanol is also known to inhibit ATP‐specific P2X receptors, which might result in such similar effects as those caused by an increase in adenosine. Adenosine and ATP exert their functions through P1 (metabotropic) and P2 (P2X‐ionotropic and P2Y‐metabotropic) receptors, respectively. Purinergic signaling in cortex‐striatum‐ventral tegmental area (VTA) has been implicated in regulating cortical glutamate signaling as well as VTA dopaminergic signaling, which regulates the motivational effect of ethanol. Moreover, several nucleoside transporters and receptors have been identified in astrocytes, which regulate not only adenosine‐ATP neurotransmission, but also homeostasis of major inhibitory‐excitatory neurotransmission (i.e., GABA or glutamate) through neuron–glial interactions. This review will present novel findings on the implications of adenosine and ATP neurotransmission in alcohol use disorders.

Background: Many epidemiological studies report that alcoholics overwhelmingly smoke tobacco and vice versa, which suggests a possible functional interaction between ethanol and nicotine. Although nicotine–ethanol interaction is well documented within the central nervous system, the mechanism is not well understood. Therefore, it is important from a public health standpoint to understand the mechanisms involved in nicotine and ethanol functional interaction. The intracerebellar (ICB) administration of nicotine significantly attenuates ethanol ataxia through nicotinic acetylcholine receptor (nAChR) α4β2subtype. This study, an extension of earlier work, was intended to investigate the possible role of nAChR subtype α7in mitigating ethanol ataxia.

The incompetence of the current management of ulcerative colitis (UC) demands novel pharmaceutical techniques and advance therapeutic strategies to facilitate safe and efficacious treatment of the disease. In this quest, mesalazine, a 5-aminosalicylate with anti-inflammatory and potent antioxidant activities, along with curcumin, a natural anti-inflammatory and antioxidant polyphenol, were found to produce a synergistic efficacy to efficiently alleviate UC. In the current research, we have formulated pH-sensitive liposomes containing a low-dose combination of mesalazine and curcumin as a potential therapy for UC. It was hypothesized that the synergistic action of the two drugs, pH-dependent colon-specific delivery, and use of liposomes as a nano-technological drug carrier system would diminish drug-associated side effects, reduce the total administration dose, and provide efficacious and instant relief from UC. The hypothesis was validated using guinea pig model of mild-moderate UC, where pH-sensitive MZ-CM co-loaded liposomes were found to be more efficacious than single-drug liposomes or drug's solution form. Furthermore, both drugs exhibited high antioxidant activity and mitigated the oxidative stress present along UC; hence, prompted an instantaneous treatment of UC. We, therefore, validate that eudragit-S100 coated MZ-CM liposomes is a promising therapy that needs to be developed as a marketed product for the treatment of UC.

We have previously demonstrated that acute intracerebellar nicotine or N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), a selective alpha(4)beta(2) nicotinic acetylcholine receptor (nAChR) agonist, dose dependently attenuates Delta(9)-tetrahydrocannabinol (Delta(9)THC)-induced ataxia. Presently, we have shown that intracerebellar nicotine (1.25, 2.5, and 5 ng; once daily for 5 days) and RJR-2403 (250, 500, and 750 ng; once daily for 5 days) significantly attenuate cerebellar Delta(9)-THC-induced ataxia dose dependently, suggesting the development of cross-tolerance between nicotine or RJR-2403 with Delta(9)-THC in male CD-1 mice. Intracerebellar RJR-2403 (750 ng) microinfused for 1, 2, 3, 5, and 7 days (once daily) significantly attenuated Delta(9)-THC-induced ataxia in the 3-, 5-, and 7-day treatment groups; optimal cross-tolerance was evident at day 5 and persisted till 36 h after the last RJR-2403 microinfusion. Intracerebellar microinfusion of hexamethonium (nAChR antagonist; 1 mug) or dihydro-beta-erythroidine hydrobromide (alpha(4)beta(2) nAChR antagonist; 500 ng) for 5 days 10 min before daily intracerebellar nicotine or RJR-2403 microinfusion virtually abolished cross-tolerance between nicotine or RJR-2403 and Delta(9)-THC, indicating nAChR participation. In addition, microinfusion of antagonists 10 min after daily intracerebellar nicotine or RJR-2403 failed to alter the cross-tolerance, suggesting possible involvement of downstream cerebellar second-messenger mechanisms. Finally, the cerebellar concentration of nitric oxide products [total sum of nitrite + nitrate (NO(x))] was increased after 5 days of intracerebellar nicotine or RJR-2403 treatment, which was decreased by acute intracerebellar Delta(9)-THC treatment. The "nicotine or RJR-2403 + Delta(9)-THC" treatments significantly increased cerebellar NO(x) levels compared with treatment with Delta(9)-THC alone, supporting a functional correlation between cerebellar nitric oxide production and cerebellar Delta(9)-THC-induced ataxia and suggesting participation of nitric oxide in the observed cross-tolerance between nicotine/RJR-2403 and Delta(9)-THC.

Epidemiological studies show that people who drink alcoholic beverages also smoke cigarettes and vice versa. Furthermore, animal studies provide circumstantial evidence for ethanol and nicotine interaction. Previously, we demonstrated that intracerebellar nicotine attenuates ethanol ataxia. This study investigated the possible role of glutamate in modulating the interaction of nicotine and ethanol.

Background: Epidemiological studies show that people who drink alcoholic beverages also smoke cigarettes and vice versa. Furthermore, animal studies provide circumstantial evidence for ethanol and nicotine interaction. Previously, we demonstrated that intracerebellar nicotine attenuates ethanol ataxia. This study investigated the possible role of glutamate in modulating the interaction of nicotine and ethanol.

Background: We demonstrated previously that striatal adenosine modulates ethanol‐induced motor incoordination (EIMI) via adenosine A1receptors coupled to pertussis toxin (PT)‐sensitive G protein and adenylyl cyclase‐cyclic adenosine monophosphate (cAMP). Additionally, intrastriatal (IST) PT antagonizes EIMI and its potentiation by the adenosine A1agonist N6‐cyclohexyladenosine; it also inhibits cAMP concentration.

BackgroundIt was demonstrated previously that cerebellar adenosine modulates ethanol‐induced motor incoordination via A1subtype of adenosine receptors. Several reports suggest the involvement of brain glutamate mechanisms, in particular N‐methyl‐d‐aspartate (NMDA) receptor sites, in the central nervous system (CNS) actions of ethanol. Mutually antagonistic functional responses as a result of glutamate and adenosine within the brain regions have also been well documented.

We have recently demonstrated that Plasmodium falciparum, unlike its human host, has the type II fatty acid synthase, in which steps of fatty acid biosynthesis are catalyzed by independent enzymes. This difference could be successfully exploited in the design of drugs specifically targeted at the different enzymes of this pathway in P. falciparum, without affecting the corresponding enzymes in humans. The importance of enoyl-ACP reductase (FabI) in the fatty acid biosynthesis pathway makes it an important target in antimalarial therapy. We report here the initial characterization of Plasmodium FabI expressed in Escherichia coli. The Km values of the enzyme for crotonyl-CoA and NADH were derived as 165 and 33 μM, respectively. Triclosan shows competitive kinetics with respect to NADH but is uncompetitive with respect to NAD+, which shows that the binding of triclosan to the enzyme is facilitated in the presence of NAD+.

Cold-formed steel (CFS) channels usually possess relatively narrower flanges, leading to a lesser radius of gyration. CFS built-up I-columns with wider flanges may perform better, but limited research outcomes are available on the same. CFS built-up columns constructed using wide-flanged edge-stiffened channels in the back-to-back alignment were investigated in the current study. This study comprises of three components. In the first component, fourteen specimens with warping restrained pinned end conditions were tested. Both material testing and geometric imperfections were determined before the specimens’ testing. Compressional resistance, load-axial shortening response and deformed shapes were studied and have been detailed in this paper. The second component deals with the formation of a nonlinear finite element model that considers nonlinearity in the material modelling and the geometric one and was solely developed for validating the strengths obtained from the test programme conducted. The tests and the numerical results comparisons indicated a good agreement with respect to ultimate compressional resistance, deformed shapes and load-axial shortening curves. The third component involved design strength quantification using the direct strength method (DSM) and effective width method for CFS sections to be compared against the test strengths. A conservative trend in the strength predictions was noted, and the design rules were also examined through reliability studies. Degradation in the axial strength, as well as axial stiffness, was noted as the overall slenderness of the column specimens increased. Also, interactive buckling comprising of local and distortional buckling; local, distortional and flexural buckling; and local and flexural buckling was the failure mode in all the specimens.

The favourable properties of stainless steel sections like high strength, corrosion resistance, fire resistance, ease of maintenance, reuse and recyclability make it very suitable for sustainable structural/architectural applications over a wide range. The results obtained from an experimental study on cold-formed ferritic stainless steel stub column are detailed in this paper. The specimens were fabricated from ferritic stainless steel 409 M grade. Six specimens consisting of square hollow section and rectangular hollow section with pined ends were tested under concentric compression. The structural response was noted in terms of axial shortening trend under the loading history, failure modes, peak load and axial stiffness variations. Tensile coupons were also tested to obtain mechanical properties of the selected material. The test results obtained were compared against the strengths determined using the design rules given in Australian/New Zealand standard, European code for designing stainless steel members, and also with the strengths obtained using direct strength method. The comparisons of the results helped in bringing out clear conclusions.

Human DNA polymerase and DNA ligase utilization for the repair of a major class of ionizing radiation-induced DNA lesion [DNA single-strand breaks containing 3'-phosphoglycolate (3'-PG)] was examined using a novel, chemically defined vector substrate containing a single, site-specific 3'-PG single-strand break lesion. In addition, the major human AP endonuclease, HAP1 (also known as APE1, APEX, Ref-1), was tested to determine if it was involved in initiating repair of 3'-PG-containing single-strand break lesions. DNA polymerase beta was found to be the primary polymerase responsible for nucleotide incorporation at the lesion site following excision of the 3'-PG blocking group. However, DNA polymerase delta/straightepsilon was also capable of nucleotide incorporation at the lesion site following 3'-PG excision. In addition, repair reactions catalyzed by DNA polymerase beta were found to be most effective in the presence of DNA ligase III, while those catalyzed by DNA polymerase delta/straightepsilon appeared to be more effective in the presence of DNA ligase I. Also, it was demonstrated that the repair initiating 3'-PG excision reaction was not dependent upon HAP1 activity, as judged by inhibition of HAP1 with neutralizing HAP1-specific polyclonal antibody.

The possible biphasic effect of caffeine on acute ethanol-induced motor incoordination by rotorod evaluation was investigated in mice. Caffeine in various doses was administered intracerebro-ventricularly (i.e.v.) to mice implanted with permanent indwelling stainless steel guide cannulae and intraperitoneally (i.p.) to non-cannulated animals. A motor incoordinating test dose of ethanol, 2 g kg−1, was given i.p. in both cases. Caffeine < 25 μg administered i.e.v., dose-dependently attenuated while 75 μg i.c.v. potentiated ethanol (i.p.)-induced motor incoordination. Similarly, caffeine < 20 mg kg−1given i.p., dose-dependently attenuated while 62.5 mg kg−1potentiated ethanol (i.p.)-induced motor incoordination. The data obtained demonstrated that caffeine given either i.c.v. or i.p. exerted biphasic effects on ethanol-induced motor incoordination. The data also suggested that caffeine antagonized ethanol-induced motor incoordination when administered in appropriately low concentrations. At these low concentrations (< 25 μg i.c.v.; < 20 mg kg−1i.p.) caffeine is well known to display high affinity for adenosine binding sites. Therefore, the present investigation lends further support to our earlier suggestion that adenosine may be involved in the motor impairing effect of ethanol.

The incidence, clinical disease and outcome of acute pancreatitis caused by ascariasis in an endemic area of Kashmir, India, was studied prospectively. Ascariasis was an aetiological factor in 59 of 256 patients (23.0 per cent) with acute pancreatitis. Worms had invaded the bile duct in 51 patients, the pancreatic duct in four and both ducts in four. Pancreatitis was mild in 46 patients and severe in 13. Associated pyogenic cholangitis was present in eight. Acute complications occurred in 11 patients. Endoscopic retrograde cholangiopancreatography (ERCP) was performed in all cases within 72 h of admission and delineated ascarides in the duodenum invading the ampullary orifice (44 patients), in the bile duct (55) and in the pancreatic duct (eight). At ERCP, worms were extracted from the ampullary orifice and removed via the mouth of 33 patients with intractable epigastric pain, leading to rapid relief of symptoms. The eight patients with pyogenic cholangitis underwent endoscopic nasobiliary drainage to decompress the bile ducts; worms were extracted from the bile duct of three of these patients using a Dormia basket. A total of 56 patients recovered from acute illness with a combination of conservative and endoscopic treatment; the other three required emergency surgery. At a mean(s.d.) follow-up of 19(7) months, ten patients showed symptomatic worm reinvasion of the biliary tree. The overall mortality rate was 3 per cent.

New gold(III) complexes involving substituted picolinic acids acting as bidentate ligands have been characterised: [AuCl2(LL′), and [Au(LL′)2]+ (H-LL′=hydroxy- or carboxy-substituted picolinic acid). The latter readily undergo deprotonation of the substituent on one ligand, to yield novel uncharged complexes which appear to be polymeric via hydrogen bonds between protonated and depronated substituents. A completely depronated anionic complex has also been obtained. The characterisation of these materials was considerably aided by197Au Mussbauer spectroscopy.

The effect of the methylxanthines caffeine, theophylline and isobutylmethylxanthine (IBMX) on ethanol-induced ataxia and loss of righting reflex was investigated in three strains of mice. A significant potentiation of ethanol-induced ataxia was produced in all strains of mice at 20, 45 and 75 min after ethanol in mice pretreated with 62.5 mg/kg caffeine and 12.5 mg/kg IBMX. In mice pretreated with 40 mg/kg caffeine potentiation of ethanol-induced ataxia was observed only at 20 min after ethanol. Theophylline pretreatment produced no alteration in ethanol-induced ataxia. The results of methylxanthine pretreatment on ethanol-induced ataxia were similar, regardless of a shorter (10 min) or longer (75 min) pretreatment time. The methylxanthines produced no effect on motor coordination or behavior when administered separately. Although ethanol-induced loss of righting reflex was shortened by theophylline, neither caffeine nor IBMX altered the duration of loss of righting reflex. It is possible that inhibition of adenosine uptake, a known effect of the methylxanthines, may be a more likely explanation for the modulation of the behavioral effects of ethanol.

The effects of estradiol (1 µg: E-1) treatment on uterine hyperemia and uterine sensitivity to various biogenic compounds were evaluated in ovariectomized (OVX) animals treated with either sesame oil or E-1 for 3 days. The E-1 treatments induced significant elevations in uterine weight, blood flow, and alpha- and beta-receptor numbers as compared with oil-treated controls. In contrast, uterine norepinephrine (NE) levels were reduced in E-1-treated, OVX guinea pigs as compared with oil-treated controls. Uterine sensitivity and responsivity to NE (10−6M) and acetylcholine (ACH: 10−8M) were either comparable to, or enhanced, in E-1-treated animals as compared with controls. In particular, combined ACH-NE treatment induced a dramatic increase in contraction force in E-1-treated uteri as compared with uteri from oil-treated animals. The use of specific adrenergic alpha- (phentolamine: 10−6M) or beta- (propranolol: 10−6M) receptor blocking agents indicated that the estrogenic response was mediated via the alpha-adrenergic receptor complex. Since atropine (10−8M) effectively blocked the cholinergic accentuation of this uterine response, it is suggested that a cholinergic priming, or beta-receptor block, is necessary for the full expression of the alpha-adrenergic-mediated, estrogenic response in the guinea pig. The estrogen-associated increase in available alpha- and beta-receptors and depressed tissue NE levels probably account for both the hyperemic response and enhanced tissue sensitivity to biogenic compounds in the guinea pig.

The effect of chronic ethanol administration on arterial baroreflexes was investigated in rats. Comparison of the results with those obtained from rats kept on an isocaloric control diet revealed that chronic ethanol had a differential action on baroreflex sensitivity (BS). The BS after evoked graded rises in arterial pressure was inhibited significantly whereas that tested after an evoked fall in arterial pressure was augmented significantly in chronic ethanol rats. These changes in BS were not secondary to changes in blood pressure as resting arterial pressure was similar in both groups. However, the heart rate was slightly, but significantly lower in the ethanol group. Challenging isocaloric control and chronic ethanol rats with an acute dose of 0.5 g/kg of ethanol produced nonsignificant changes in BS when evoked changes in blood pressure were both pressor and depressor. A dose of 3 g/kg of ethanol decreased the BS tested after phenylephrine-evoked rises in pressure in both groups; however, the percentage of inhibition of BS was greater in the isocaloric control group. The pressor responsiveness to phenylephrine was reduced slightly in chronic ethanol-treated rats, in contrast to that evoked by angiotensin II which was augmented slightly as compared to the control group. There was no significant difference in the depressor responsiveness to nitroprusside. After injection of acute doses of 0.5 and 3 g/kg of ethanol, the dose-response curves to phenylephrine were shifted to the right in a dose-related fashion in both groups, whereas the angiotensin II and nitroprusside dose-response curve remained unchanged after 0.5 g/kg of ethanol in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

To clarify if the behavioral interaction between ethanol and adenosine reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. adenosine agonists, N6-(R-phenylisopropyl)adenosine (R-PIA), N6-(S-phenylisopropyl)adenosine, 5'-(N-cyclopropyl)-carboxamidoadenosine, antagonists, theophylline and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. Adenosine agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of adenosine modulation of this effect of ethanol and confirmed our previous reports in which adenosine agonists and antagonists were given i.p. Enprofylline, a weak adenosine antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain adenosine receptor mechanism(s) in ethanol-adenosine interactions. Results from R-PIA and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of adenosine A1 subtype. However, 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of adenosine A2. No effect of ethanol on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest adenosine receptor activation adequate to produce behavioral interaction with ethanol. There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Using rotorod performance as the test response, possible modulation and co‐modulation of ethanol‐induced motor incoordination by the cerebellar κ‐opioid and adenosine A1 receptors was studied. A dose‐related accentuation of ethanol‐induced motor incoordination was observed after direct cerebellar microinfusion of three κ‐opioid receptor agonists: U‐50488, U‐62066, and bremazocine. On the contrary, significant and dose‐related attenuation of ethanol's motor impairment was produced by intracerebellar nor‐binaltorphimine, a κ‐opioid receptor antagonist. Furthermore, the accentuation by κ‐agonists was virtually abolished by κ‐antagonist nor‐binaltorphimine. Therefore, the accentuation and attenuation by κ‐opioid receptor agonists/antagonist, respectively, was through specific κ‐opioid receptors. Pretreatment with the intracerebellar adenosine A1‐selective agonist, N6‐cyclohexyladenosine, further enhanced the ethanol‐induced motor incoordination and its accentuation by intracerebellar κ‐opioid receptor agonists. Ethanol‐induced motor incoordination was markedly attenuated by intracerebellar pertussis toxin (PTX) pretreatment, suggesting an involvement of PTX‐sensi‐tive G protein in the expression of motor incoordinating effect of ethanol. Additionally, the intracerebellar PTX also markedly attenuated the accentuation by κ‐opioid agonists of ethanol‐induced motor impairment, suggesting participation of PTX‐sensitive GTP‐binding G protein (Gi, Goin the κ‐opioid modulation of ethanol's motor impairment. It also confirms that κ‐opioid receptors are linked to PTX‐sensitive G protein. The functional similarity between κ‐opioid and adenosine A1 receptors in increasing ethanol's motor incoordination, together with their anatomical co‐localization primarily on the axons and axonal terminals of the cerebellar granule cells, suggests a possible common catalytic unit of adenylate cyclase as the basis of modulation of ethanol‐induced motor incoordination by both receptor mechanisms.

The regulation of uterine blood flow (UBF) in the guinea pig was investigated by determining the effects of steroid-catecholamine interaction on guinea pig UBF in cyclic (Day 0 = estrus) and ovariectomized (OVX)-steroid treated females. In cyclic guinea pigs, parallel elevations in uterine weight, UBF, beta and alpha receptor levels were observed during the estrus period, whereas uterine norepinephrine (NE) levels were low. In contrast, all parameters remained at low levels except NE levels during the luteal phase of the cycle which remained elevated in both normal and OVX-oil treated animals. Estrogen (E1)-treated females showed elevated uterine weights, UBF, beta, and alpha receptor levels but low uterine NE concentrations. Combined progesterone-estrogen (P2E1) treatment caused similar changes but maintained tissue NE at control levels. In the exposed uterine artery preparation, the sequential administration of acetylcholine followed by NE application induced a marked elevation in UBF in OVX, E-1-treated animals which was blocked by phentolamine (10(-6) M). This phenomena could not be demonstrated in either oil- or progesterone-treated OVX guinea pigs. In uterine membrane preparations from ovariectomized guinea pigs pretreated with either oil or progesterone, methacholine (cholinergic agonist; 10(-6) M) failed to alter the affinity of the alpha receptor for NE. However, in uterine preparations from OVX, estradiol-treated guinea pigs, methacholine significantly (P less than .05) increased the affinity of the alpha receptor for NE.(ABSTRACT TRUNCATED AT 250 WORDS)

Summary The effect of acute ethanol on the levels of NE, DA and its metabolites DOPAC and HVA, as well as on the levels of GABA, in the corpus striatum and hypothalamus were investigated in mice in the first two hours after acute ethanol administration. There was a marked increase in the concentration of DOPAC and HVA in the corpus striatum from 30 to 120 minutes after a dose of 3.5 g/kg of ethanol even though the concentration of DA was only elevated at 60 minutes after ethanol. A dose of 1.75 g/kg of ethanol did not increase DA levels 60 minutes after administration although it did increase the concentration of DOPAC and HVA at this time. In the hypothalamus a dose of 3.5 g/kg of ethanol did not change the concentration of NE or DA but did produce a marked increase in the levels of DOPAC and HVA at 60 and 120 minutes post ethanol. A lower dose of ethanol, 1.75 g/kg, produced the same effect 60 minutes after ethanol. Ethanol caused a dose-dependent accumulation of DOPA in the corpus striatum after inhibition of DOPA-decarboxylase suggesting an increased synthesis of DA. These data suggest that the increased concentrations of DA metabolites after ethanol is secondary to enhanced DA synthesis and turnover. The concentration of NE and GABA in the hypothalamus and the corpus striatum was unchanged at any time period after ethanol.

Deamination of 5-methylcytosine in DNA results in T/G mismatches. If unrepaired, these mismatches can lead to C-to-T transition mutations. The very short patch (VSP) repair process in Escherichia coli counteracts the mutagenic process by repairing the mismatches in favor of the G-containing strand. Previously we have shown that a plasmid containing an 11-kilobase fragment from the E. coli chromosome can complement a chromosomal mutation defective in both cytosine methylation and VSP repair. We have now mapped the regions essential for the two phenotypes. In the process, we have constructed plasmids that complement the chromosomal mutation for methylation, but not for repair, and vice versa. The genes responsible for these phenotypes have been identified by DNA sequence analysis. The gene essential for cytosine methylation, dcm, is predicted to code for a 473-amino-acid protein and is not required for VSP repair. It is similar to other DNA cytosine methylases and shares extensive sequence similarity with its isoschizomer, EcoRII methylase. The segment of DNA essential for VSP repair contains a gene that should code for a 156-amino-acid protein. This gene, named vsr, is not essential for DNA methylation. Remarkably, the 5' end of this gene appears to overlap the 3' end of dcm. The two genes appear to be transcribed from a common promoter but are in different translational registers. This gene arrangement may assure that Vsr is produced along with Dcm and may minimize the mutagenic effects of cytosine methylation.

To study the role of the striatum in modulating the effects of adenosine agonists and benzodiazepine inverse agonists on acute ethanol-induced motor impairment, we evaluated the effect of direct intrastriatal Ro15-4513 [0.625, 1.25 and 2.5 ng], a partial inverse agonist of benzodiazepine receptor, on ethanol-induced motor incoordination. A significant and nearly dose-dependent antagonism by Ro15-4513 was observed, which suggests involvement of the striatum in ethanol-induced motor incoordination. No effect of IST Ro15-4513 on motor incoordination induced by Na-pentobarbital (10 mg/kg, i.p.) was noted, indicating the selectivity of the antiethanol action of Ro15-4513. The IST adenosine agonist N6-cyclohexyladenosine (CHA) markedly accentuated ethanol-induced motor incoordination in a dose-related manner, suggesting a striatal adenosinergic modulation of ethanol-induced motor incoordination. The IST Ro15-4513 also significantly antagonized the accentuating effects of CHA on ethanol-induced motor incoordination. No change in normal motor coordination was observed after IST CHA or Ro15-4513 when followed by saline administration instead of ethanol. No accentuating effect by intrahippocampal CHA on ethanol-induced motor incoordination was seen, which suggests the selectivity of striatal adenosinergic modulation of ethanol-induced motor incoordination. There was no significant radioactivity present in the systemic circulation, in the CSF or in brain areas other than striatum after intrastriatal [3H]Ro15-4513 or [3H]CHA and ethanol injection. Data obtained so far support the involvement of striatum in ethanol's ataxia as well as striatal adenosinergic modulation of the central effect(s) of ethanol, possibly through Ro15-4513-sensitive mechanism(s).

As an extension of our previous work pertaining to brain adenosinergic modulation of ethanol-induced motor incoordination, the effect of direct intracerebellar administration of the A1-selective adenosine agonist, N6-cyclohexyladenosine (CHA) on ethanol-induced motor incoordination was evaluated. Marked accentuation of ethanol-induced motor impairment by CHA was observed. No change in the normal motor coordination was noted when CHA administration was followed by saline instead of ethanol. Intracerebellar cAMP or its analog, 8-(4-chlorophenylthio)-cAMP, significantly inhibited ethanol's motor impairment in a dose-related manner as well as abolished CHA's accentuating effect on ethanol-induced motor incoordination. These observations suggested a possible involvement of cAMP in the adenosinergic modulation and in the expression of ethanol-induced motor incoordination. Further support was provided by the observation of a marked accentuation and attenuation in a dose-related manner of ethanol-induced motor impairment as well as CHA's accentuation of ethanol's motor impairment by intracerebellar miconazole and forskolin, respectively. However, equimolar intracerebellar doses of miconazole and forskolin (inhibitor and stimulator of adenylyl cyclase, respectively) failed to significantly alter ethanol-induced motor incoordination probably due to their mutual functional antagonism. The expression of adenosinergic modulation and that of ethanol-induced motor impairment most likely involved Giprotein-coupled receptor(s) (such as adenosine receptors). The involvement of receptors linked to pertussis toxin-sensitive G-proteins was suggested because intracerebellar pertussis toxin pretreatment markedly inhibited ethanol-induced motor incoordination as well as CHA's accentuation of ethanol's motor impairment. Finally, cAMP, unlike its antagonism to CHA's accentuation, failed to antagonize the accentuation of ethanol-induced motor impairment by intracerebellar GABAAagonist (+)-muscimol. This indicated selectivity of cAMP participation in G protein coupled receptor (such as adenosine)-mediated response and not in ionic channel coupled receptor (such as GABAA)-mediated mechanism. Overall, the data suggested a possible involvement of cerebellar adenylyl cyclase-cAMP signalling pathway in the adenosinergic modulation of ethanol's ataxia.

Protection against the lethal effects of ethanol at 4.5 g/kg administered acutely was maximal when zinc was administered 60 min prior to ethanol. The timing of ethanol administration corresponded with elevated plasma levels of absorbed zinc. Protection was inversely related to the dose of zinc employed, as 0.5 μ.mol provided greater protection than 1.0 μmol, which provided greater protection than 2.0 μmol. Protection against ethanol lethality was greater if zinc was administered 60 min prior to each injection of ethanol. Acute zinc pretreatment did not alter the activity of liver alcohol dehydrogenase (ADH), nor did it alter the blood clearance of ethanol. Chronic zinc administration as ZnCl2, 100 μg/ml in the drinking water for 30 d, produced a 25% decrease in hepatic ADH activity, which was accompanied by a similar decrease in the intravascular clearance of ethanol.