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Objective: There is limited knowledge about the potential relationship between asthma and heart function. Aim of our present study was to examine if asthma may be associated with manifest or subclinical heart dysfunction. Methods: Seventy-two allergic mild-to-moderate and severe asthma patients and 20 matched controls were enrolled in the study. Depending on the anti-asthmatic therapy, four subgroups of asthma patients were created: patients under long-acting beta2-agonists (LABA) and inhaled cortisone without oral cortisone treatment with (1a) versus without (1b) additional omalizumab therapy; patients with LABA, inhaled cortisone and omalizumab treatment with (2a) versus without (2b) oral cortisone. Standard echocardiographic parameters as well as global longitudinal left and right ventricular strains as determined by ultrasound-based speckle-tracking method were evaluated. Furthermore, NT-pro-brain natriuretic peptide (NT-pro-BNP), immunoglobulin E (IgE), C-reactive protein (CRP), and blood count were assessed in asthma and control groups. Results: There were no relevant differences in standard echocardiographic measures between both asthma groups and the control collective. Longitudinal left ventricular strain values were reduced significantly in severe and mild-to-moderate asthma groups (−12.91 ± 0.84% and −13.92 ± 1.55%, respectively), whereas longitudinal right ventricular strain values were additionally relevantly decreased in severe asthma (−10.35 ± 1.04%) compared to the control (−16.55 ± 0.49% and −18.48 ± 1.90%, respectively). Cardiac strains were similar in subgroups 1a and 1b. In contrast, patients from subgroup 2a presented reduced heart strains and decreased lung function compared to those from 2b. CRP, IgE, and eosinophils were significantly increased in asthma versus control individuals. Conclusions: Allergic asthma, especially severe asthma is associated with subclinical impaired left and right ventricular function as determined by speckle-tracking analysis. [ABSTRACT FROM AUTHOR]

Solids with high ion mobility are of broad interest for energy storage applications. New systems featuring low-activated ion mobility are important to improve the performance in such systems. Herein we report on a model system dealing with such improved properties. Li0.2CdP2 was synthesized from the elements, lithium as structure stabilizer and CdI2 as reaction promoters in sealed silica ampoules at 823 K. It crystallizes tetragonal, in space group I4122 (α-CdAs2 structure type), with lattice parameters a = 7.6691(8) Å, c = 4.4467(4) Å and V = 261.53(4) Å3. After 24 h of storage in air lithium ions can be removed in a spontaneous delithiation reaction resulting in Li(OH)·H2O formation on the surface of the crystals. Formed α′-CdP2 adopts the α-CdAs2 structure type. Both compounds consist of isolated cadmium atoms and helical STACKABOVE1/ABOVEBELOW∞/BELOW/STACK[P−]-chains generating empty channels suitable to accommodate Li ions. The heavy atom structure was determined by X-ray diffraction methods while a full model including lithium was derived from a combined solid state NMR and quantum chemical calculation approach. An low activation barrier range in the order of 0.1 to 0.2 eV was determined by NMR spectroscopy pointing towards an extraordinary high Li mobility in Li0.2CdP2. Of course a Cd-based solid will have certain disadvantages like toxicity and mass for storage applications but substitution of Cd by suitable lighter elements can solve this issue. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate whether a combined human growth hormone (HGH) and human menopausal gonadotrophin (HMG) treatment can improve ovulation induction in poor ovarian responders. Ten patients aged 28–43 years and requiring > 25 ampoules of HMG for ovulation were admitted to the study. Pituitary growth hormone reserve was evaluated by clonidine stimulation and insulin tolerance tests before commencement of treatment. The patients underwent one treatment cycle with D-tryptophan-6-luteinizing hormone-releasing hormone (-Trp-LHRH) and HMG and another cycle with -Trp-LHRH, HMG and HGH. Serum HGH, insulin-like growth factor (IGF)-I and oestradiol were measured throughout the two treatment cycles and follicular maturation was assessed by ultrasonographic studies. All patients tested showed no elevation of their serum HGH concentration during a clonidine test, but showed an adequate response during insulin tolerance tests. No significant difference was found in the number of HMG ampoules, duration of treatment, number of leading follicles, and serum oestradiol concentration between the two treatment cycles. Co-treatment with HGH and HMG did not improve ovarian performance in poor ovarian responders. No correlation was found between the results of HGH pituitary function tests and the ovarian response to gonadotrophins. [ABSTRACT FROM PUBLISHER]

Abstract Two different types of adipose tissues can be found in humans enabling them to respond to starvation and cold: white adipose tissue (WAT) is generally known and stores excess energy in the form of triacylglycerol (TG), insulates against cold, and serves as a mechanical cushion. Brown adipose tissue (BAT) helps newborns to cope with cold. BAT has the capacity to uncouple the mitochondrial respiratory chain, thereby generating heat rather than adenosine triphosphate (ATP). The previously widely held view was that BAT disappears rapidly after birth and is no longer present in adult humans. Using positron emission tomography (PET), however, it was recently shown that metabolically active BAT occurs in defined regions and scattered in WAT of the adult and possibly has an influence on whole-body energy homeostasis. In obese individuals adipose tissue is at the center of metabolic syndrome. Targeting of WAT by thiazolidinediones (TZDs), activators of peroxisome proliferator-activated receptor γ (PPARγ) a ‘master’ regulator of fat cell biology, is a current therapy for the treatment of type 2 diabetes. Since its unique capacity to increase energy consumption of the body and to dissipate surplus energy as heat, BAT offers new perspectives as a therapeutic target for the treatment of obesity and associated diseases such as type 2 diabetes and metabolic syndrome. Recent discoveries of new signaling pathways of BAT development give rise to new therapeutic possibilities in order to influence BAT content and activity.

Abstract Breast and ovarian cancers are among the 10 leading cancer types in females with mortalities of 15% and 6%, respectively. Despite tremendous efforts to conquer malignant diseases, the war on cancer declared by Richard Nixon four decades ago seems to be lost. Approximately 21,800 women in the US will be diagnosed with ovarian cancer in 2011. Therefore, its incidence is relatively low compared to breast cancer with 207.090 prognosed cases in 2011. However, overall survival unmasks ovarian cancer as the most deadly gynecological neoplasia. Platinum-based chemotherapy is emerging as an upcoming treatment modality especially in triple negative breast cancer. However, in ovarian cancer Platinum-complexes for a long time are established as first line treatment. Emergence of a resistant phenotype is a major hurdle in curative cancer therapy approaches and many scientists around the world are focussing on this issue. This review covers new findings in this field during the past decade.

A human pregnancy exposed to a luteinizing-hormone-releasing hormone agonist (buserelin) in its early stages is reported. The possible mechanisms leading to conception under this mode of treatment and its consequences are discussed. [ABSTRACT FROM AUTHOR]

Connections between neurons can be mapped by acquiring and analysing electron microscopic brain images. In recent years, this approach has been applied to chunks of brains to reconstruct local connectivity maps that are highly informative 1-6 , but nevertheless inadequate for understanding brain function more globally. Here we present a neuronal wiring diagram of a whole brain containing 5 × 10 7 chemical synapses 7 between 139,255 neurons reconstructed from an adult female Drosophila melanogaster 8,9 . The resource also incorporates annotations of cell classes and types, nerves, hemilineages and predictions of neurotransmitter identities 10-12 . Data products are available for download, programmatic access and interactive browsing and have been made interoperable with other fly data resources. We derive a projectome-a map of projections between regions-from the connectome and report on tracing of synaptic pathways and the analysis of information flow from inputs (sensory and ascending neurons) to outputs (motor, endocrine and descending neurons) across both hemispheres and between the central brain and the optic lobes. Tracing from a subset of photoreceptors to descending motor pathways illustrates how structure can uncover putative circuit mechanisms underlying sensorimotor behaviours. The technologies and open ecosystem reported here set the stage for future large-scale connectome projects in other species., (© 2024. The Author(s).)

The recent assembly of the adult Drosophila melanogaster central brain connectome, containing more than 125,000 neurons and 50 million synaptic connections, provides a template for examining sensory processing throughout the brain 1,2 . Here we create a leaky integrate-and-fire computational model of the entire Drosophila brain, on the basis of neural connectivity and neurotransmitter identity 3 , to study circuit properties of feeding and grooming behaviours. We show that activation of sugar-sensing or water-sensing gustatory neurons in the computational model accurately predicts neurons that respond to tastes and are required for feeding initiation 4 . In addition, using the model to activate neurons in the feeding region of the Drosophila brain predicts those that elicit motor neuron firing 5 -a testable hypothesis that we validate by optogenetic activation and behavioural studies. Activating different classes of gustatory neurons in the model makes accurate predictions of how several taste modalities interact, providing circuit-level insight into aversive and appetitive taste processing. Additionally, we applied this model to mechanosensory circuits and found that computational activation of mechanosensory neurons predicts activation of a small set of neurons comprising the antennal grooming circuit, and accurately describes the circuit response upon activation of different mechanosensory subtypes 6-10 . Our results demonstrate that modelling brain circuits using only synapse-level connectivity and predicted neurotransmitter identity generates experimentally testable hypotheses and can describe complete sensorimotor transformations., (© 2024. The Author(s).)

Brains comprise complex networks of neurons and connections, similar to the nodes and edges of artificial networks. Network analysis applied to the wiring diagrams of brains can offer insights into how they support computations and regulate the flow of information underlying perception and behaviour. The completion of the first whole-brain connectome of an adult fly, containing over 130,000 neurons and millions of synaptic connections 1-3 , offers an opportunity to analyse the statistical properties and topological features of a complete brain. Here we computed the prevalence of two- and three-node motifs, examined their strengths, related this information to both neurotransmitter composition and cell type annotations 4,5 , and compared these metrics with wiring diagrams of other animals. We found that the network of the fly brain displays rich-club organization, with a large population (30% of the connectome) of highly connected neurons. We identified subsets of rich-club neurons that may serve as integrators or broadcasters of signals. Finally, we examined subnetworks based on 78 anatomically defined brain regions or neuropils. These data products are shared within the FlyWire Codex ( https://codex.flywire.ai ) and should serve as a foundation for models and experiments exploring the relationship between neural activity and anatomical structure., (© 2024. The Author(s).)

With a rising demand of cocaine over the last years, it is likely that unregulated new psychoactive substances with similar effects such as indatraline ((1 R ,3 S )-3-(3,4-dichlorophenyl)- N -methyl-2,3-dihydro-1 H -inden-1-amine) and troparil (Methyl (1 R ,2 S ,3 S ,5 S )-8-methyl-3-phenyl-8-azabicyclo[3.2.1]octane-2-carboxylate) become popular as well. Both substances share a similar pharmacological profile as cocaine, while their potency is higher, and their duration of action is longer. This study investigated their metabolic fate in rat urine and incubations using pooled human liver S9 fraction (pHLS9). Indatraline formed two phase I and four phase II metabolites, with aromatic hydroxylation and glucuronidation being the main metabolic steps. All metabolites were detected in rat urine, while the parent compound was not detectable. Although low in abundance, indatraline metabolites were well identifiable due to their specific isotopic patterns caused by chlorine. Troparil formed four phase I and three phase II metabolites, with demethylation being the main metabolic step. Hydroxylation of the tropane ring, the phenyl ring, and combinations of these steps, as well as glucuronidation, were found. Phase I metabolites were detectable in rat urine and pHLS9, while phase II metabolites were only detectable in rat urine.

High-resolution electron microscopy of nervous systems has enabled the reconstruction of synaptic connectomes. However, we do not know the synaptic sign for each connection (i.e., whether a connection is excitatory or inhibitory), which is implied by the released transmitter. We demonstrate that artificial neural networks can predict transmitter types for presynapses from electron micrographs: a network trained to predict six transmitters (acetylcholine, glutamate, GABA, serotonin, dopamine, octopamine) achieves an accuracy of 87% for individual synapses, 94% for neurons, and 91% for known cell types across a D. melanogaster whole brain. We visualize the ultrastructural features used for prediction, discovering subtle but significant differences between transmitter phenotypes. We also analyze transmitter distributions across the brain and find that neurons that develop together largely express only one fast-acting transmitter (acetylcholine, glutamate, or GABA). We hope that our publicly available predictions act as an accelerant for neuroscientific hypothesis generation for the fly., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

New synthetic opioids are an increasing challenge for clinical and forensic toxicologists that developed over the recent years. Desmethylmoramide (DMM), a structural analogue of methadone, is one of the most recent appearances on the drug market. This study investigated its metabolic fate in rat and pooled human liver S9 fraction (pHLS9) to allow the identification of suitable urinary screening targets beyond the parent compound. The analysis of rat urine after the administration of DMM revealed five metabolites, which were the result of pyrrolidine ring or morpholine ring hydroxylation and combinations of them. Additionally, an N',N-bisdesalkyl metabolite was formed. Incubations of DMM using pHLS9 revealed a pyrrolidine hydroxy metabolite, as well as an N-oxide. No Phase II metabolites were detected in either rat urine or incubations using pHLS9. The metabolism of DMM did in part comply with that of its archetype dextromoramide (DXM). Although morpholine ring hydroxylation and N-oxidation were described for DXM and detected for DMM, phenyl ring hydroxylation was not found for DMM but described for DXM. An analysis of 24 h pooled rat urine samples after DMM administration identified the hydroxy and dihydroxy metabolite as the most abundant excretion products, and they may, thus, serve as screening targets, as the parent compound was barely detectable., (© 2023 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

Hexahydrocannabinol (HHC) is an emerging semi-synthetic cannabinoid, which is obtained from cyclization of cannabidiol and subsequent hydrogenation. As a potentially legal alternative of ∆9-tetrahydrocannabinol (∆9-THC), it is increasingly seized in the USA and Europe. The aims of this study were to investigate the metabolism of HHC in pooled human liver S9 fraction (pHLS9), rat and human samples. Additionally, a locally obtained low-THC cannabis product was investigated, which was advertised with an elevated concentration of HHC. Overall, HHC formed an 11-hydroxy (HO) metabolite, as well as a carboxy metabolite. While only the parent compound was detected in rat urine and feces, the hydroxy metabolite was additionally detected in pHLS9 and human plasma. The carboxy metabolite was only detectable in human plasma. The metabolism corresponded well to that of ∆9-THC, although glucuronidation and the formation of an 8-HO metabolite were not observed. Detectability of HHC and its carboxy metabolite in rat urine was investigated using gas chromatography-mass spectrometry, but neither the parent compound nor the metabolite were detectable. The investigated low-THC cannabis product appeared to be an actual cannabis product since, in addition to HHC, cannabinol, cannabidiol and ∆9-THC were detected after qualitative analysis. Estimation of its content revealed not only 30.6% of HHC but also 4% of ∆9-THC., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Animals communicate using sounds in a wide range of contexts, and auditory systems must encode behaviorally relevant acoustic features to drive appropriate reactions. How feature detection emerges along auditory pathways has been difficult to solve due to challenges in mapping the underlying circuits and characterizing responses to behaviorally relevant features. Here, we study auditory activity in the Drosophila melanogaster brain and investigate feature selectivity for the two main modes of fly courtship song, sinusoids and pulse trains. We identify 24 new cell types of the intermediate layers of the auditory pathway, and using a new connectomic resource, FlyWire, we map all synaptic connections between these cell types, in addition to connections to known early and higher-order auditory neurons-this represents the first circuit-level map of the auditory pathway. We additionally determine the sign (excitatory or inhibitory) of most synapses in this auditory connectome. We find that auditory neurons display a continuum of preferences for courtship song modes and that neurons with different song-mode preferences and response timescales are highly interconnected in a network that lacks hierarchical structure. Nonetheless, we find that the response properties of individual cell types within the connectome are predictable from their inputs. Our study thus provides new insights into the organization of auditory coding within the Drosophila brain., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Flubromazolam is widely known as highly potent designer benzodiazepine (DBZD). Recently, the two flubromazolam-derived new psychoactive substances (NPS) clobromazolam and bromazolam appeared on the drugs of abuse market. Since no information concerning their toxicokinetics in humans is available, the aims of the current study were to elucidate their metabolic profile and to identify the isozymes involved in their phase I and phase II metabolism. In vitro incubations with pooled human liver S9 fraction were performed and analyzed by liquid chromatography coupled to orbitrap-based high-resolution tandem mass spectrometry (LC-HRMS-MS). Biosamples after the ingestion of bromazolam allowed the identification of metabolites in human plasma and urine as well as the determination of bromazolam plasma concentrations by LC-HRMS-MS using the standard addition method. In total, eight clobromazolam metabolites were identified in vitro as well as eight bromazolam metabolites in vitro and in vivo. Predominant metabolic steps were hydroxylation, glucuronidation and combinations thereof. Alpha-hydroxy bromazolam glucuronide and bromazolam N-glucuronide are recommended as screening targets in urine. Bromazolam and its alpha-hydroxy metabolite are recommended if conjugate cleavage is part of the sample preparation procedure. The bromazolam plasma concentrations were determined to be 6 and 29 μg/L, respectively. Several cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) isozymes were shown to catalyze their metabolic transformations. CYP3A4 was involved in the formation of all phase I metabolites of both NPS, while UGT1A4 and UGT2B10 catalyzed their N-glucuronidation. Several UGT isoforms catalyzed the glucuronidation of the hydroxy metabolites. In conclusion, the determined bromazolam plasma concentrations in the low micrograms per liter range underlined the need for sensitive analytical methods and the importance of suitable urine screening procedures including DBZD metabolites as targets. Such an analytical strategy should be also applicable for clobromazolam., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)