Asymmetric neurons are necessary for olfactory learning in the Drosophila brain.

Animals have complementary parallel memory systems that process signals from various sensory modalities. In the brain of the fruit fly Drosophila melanogaster, mushroom body (MB) circuitry is the primary associative neuropil, critical for all stages of olfactory memory. Here, our findings suggest that active signaling from specific asymmetric body (AB) neurons is also crucial for this process. These AB neurons respond to odors and electric shock separately and exhibit timing-sensitive neuronal activity in response to paired stimulation while leaving a decreased memory trace during retrieval. Our experiments also show that rutabaga-encoded adenylate cyclase, which mediates coincidence detection, is required for learning and short-term memory in both AB and MB. We observed additive effects when manipulating rutabaga co-expression in both structures. Together, these results implicate the AB in playing a critical role in associative olfactory learning and short-term memory.

Therapeutic Potential of Green-Engineered ZnO Nanoparticles on Rotenone-Exposed D. melanogaster (Oregon R+): Unveiling Ameliorated Biochemical, Cellular, and Behavioral Parameters.

Nanotechnology holds significant ameliorative potential against neurodegenerative diseases, as it can protect the therapeutic substance and allow for its sustained release. In this study, the reducing and capping agents of Urtica dioica (UD), Matricaria chamomilla (MC), and Murraya koenigii (MK) extracts were used to synthesize bio-mediated zinc oxide nanoparticles (ZnO-NPs) against bacteria (Staphylococcus aureus and Escherichia coli) and against rotenone-induced toxicities in D. melanogaster for the first time. Their optical and structural properties were analyzed via FT-IR, DLS, XRD, EDS, SEM, UV-Vis, and zeta potential. The antioxidant and antimicrobial properties of the fabricated ZnO-NPs were evaluated employing cell-free models (DPPH and ABTS) and the well diffusion method, respectively. Rotenone (500 µM) was administered to Drosophila third instar larvae and freshly emerged flies for 24-120 h, either alone or in combination with plant extracts (UD, MC, an MK) and their biogenic ZnO-NPs. A comparative study on the protective effects of synthesized NPs was undertaken against rotenone-induced neurotoxic, cytotoxic, and behavioral alterations using an acetylcholinesterase inhibition assay, dye exclusion test, and locomotor parameters. The findings revealed that among the plant-derived ZnO-NPs, MK-ZnO NPs exhibit strong antimicrobial and antioxidant activities, followed by UD-ZnO NPs and MC-ZnO NPs. In this regard, ethno-nano medicinal therapeutic uses mimic similar effects in D. melanogaster by suppressing oxidative stress by restoring biochemical parameters (AchE and proteotoxicity activity) and lower cellular toxicity. These findings suggest that green-engineered ZnO-NPs have the potential to significantly enhance outcomes, with the promise of effective therapies for neurodegeneration, and could be used as a great alternative for clinical development.

Ecdysone signaling determines lateral polarity and remodels neurites to form Drosophila's left-right brain asymmetry.

Left-right (LR) asymmetry of the brain is fundamental to its higher-order functions. The Drosophila brain's asymmetrical body (AB) consists of a structural pair arborized from AB neurons and is larger on the right side than the left. We find that the AB initially forms LR symmetrically and then develops LR asymmetrically by neurite remodeling that is specific to the left AB and is dynamin dependent. Additionally, neuronal ecdysone signaling inhibition randomizes AB laterality, suggesting that ecdysone signaling determines AB's LR polarity. Given that AB's LR asymmetry relates to memory formation, our research establishes AB as a valuable model for studying LR asymmetry and higher-order brain function relationships.

Working Memory and Transcranial-Alternating Current Stimulation-State of the Art: Findings, Missing, and Challenges.

Working memory (WM) is a cognitive process that involves maintaining and manipulating information for a short period of time. WM is central to many cognitive processes and declines rapidly with age. Deficits in WM are seen in older adults and in patients with dementia, schizophrenia, major depression, mild cognitive impairment, Alzheimer's disease, etc. The frontal, parietal, and occipital cortices are significantly involved in WM processing and all brain oscillations are implicated in tackling WM tasks, particularly theta and gamma bands. The theta/gamma neural code hypothesis assumes that retained memory items are recorded via theta-nested gamma cycles. Neuronal oscillations can be manipulated by sensory, invasive- and non-invasive brain stimulations. Transcranial alternating-current stimulation (tACS) and repetitive transcranial magnetic stimulation (rTMS) are frequency-tuned non-invasive brain stimulation (NIBS) techniques that have been used to entrain endogenous oscillations in a frequency-specific manner. Compared to rTMS, tACS demonstrates superior cost, tolerability, portability, and safety profile, making it an attractive potential tool for improving cognitive performance. Although cognitive research with tACS is still in its infancy compared to rTMS, a number of studies have shown a promising WM enhancement effect, especially in the elderly and patients with cognitive deficits. This review focuses on the various methods and outcomes of tACS on WM in healthy and unhealthy human adults and highlights the established findings, unknowns, challenges, and perspectives important for translating laboratory tACS into realistic clinical settings. This will allow researchers to identify gaps in the literature and develop frequency-tuned tACS protocols with promising safety and efficacy outcomes. Therefore, research efforts in this direction should help to consider frequency-tuned tACS as a non-pharmacological tool of cognitive rehabilitation in physiological aging and patients with cognitive deficits.

Phytochemical constituents and anti-tyrosinase activity of Macadamia integrifolia leaves extract.

Macadamia integrifolia Maiden & Betche is cultivated around the world for its highly valued nuts (macadamia nuts). Although the chemical composition of the edible macadamia oil has been repeatedly investigated, other plant organs have not been phytochemically or biologically assessed. In this study, ethanolic extract of M. integrifolia leaves was phytochemically investigated which led to the isolation of 6 compounds. Two functional galactolipids, i.e., monogalactosyl diacylglycrol 36:4 (MGDG 36:4), digalactosyl monoacylglycerol 18:2 (DGMG 18:2), gallic acid and protocatechuic acid were identified in the genus Macadamia for the first time, in addition to the cyanogenic glycoside dhurrin and ß-sitosterol. Additionally, anti-tyrosinase activity of the extract, its fractions and isolated compounds was investigated and a good tyrosinase inhibitory activity was observed for the extract, IC50=85 µg/mL and its polar fractions (ethyl acetate at 60 µg/mL and n-butanol at 75 µg/mL), with gallic acid showing strong anti-tyrosinase activity at IC50 56 µg/mL.

10 Minutes Frontal 40 Hz tACS-Effects on Working Memory Tested by Luck-Vogel Task.

Working memory is a cognitive process that involves short-term active maintenance, flexible updating, and processing of goal- or task-relevant information. All frequency bands are involved in working memory. The activities of the theta and gamma frequency bands in the frontoparietal network are highly involved in working memory processes; theta oscillations play a role in the temporal organization of working memory items, and gamma oscillations influence the maintenance of information in working memory. Transcranial alternating current stimulation (tACS) results in frequency-specific modulation of endogenous oscillations and has shown promising results in cognitive neuroscience. The electrophysiological and behavioral changes induced by the modulation of endogenous gamma frequency in the prefrontal cortex using tACS have not been extensively studied in the context of working memory. Therefore, we aimed to investigate the effects of frontal gamma-tACS on working memory outcomes. We hypothesized that a 10-min gamma tACS administered over the frontal cortex would significantly improve working memory outcomes. Young healthy participants performed Luck-Vogel cognitive behavioral tasks with simultaneous pre- and post-intervention EEG recording (Sham versus 40 Hz tACS). Data from forty-one participants: sham (15 participants) and tACS (26 participants), were used for the statistical and behavioral analysis. The relative changes in behavioral outcomes and EEG due to the intervention were analyzed. The results show that tACS caused an increase in the power spectral density in the high beta and low gamma EEG bands and a decrease in left-right coherence. On the other hand, tACS had no significant effect on success rates and response times. Conclusion: 10 min of frontal 40 Hz tACS was not sufficient to produce detectable behavioral effects on working memory, whereas electrophysiological changes were evident. The limitations of the current stimulation protocol and future directions are discussed in detail in the following sections.

Neuropeptide F inhibits dopamine neuron interference of long-term memory consolidation in Drosophila.

Long-term memory (LTM) formation requires consolidation processes to overcome interfering signals that erode memory formation. Olfactory memory in Drosophila involves convergent projection neuron (PN; odor) and dopaminergic neuron (DAN; reinforcement) input to the mushroom body (MB). How post-training DAN activity in the posterior lateral protocerebrum (PPL1) continues to regulate memory consolidation remains unknown. Here we address this question using targeted transgenes in behavior and electrophysiology experiments to show that (1) persistent post-training activity of PPL1-α2α'2 and PPL1-α3 DANs interferes with aversive LTM formation; (2) neuropeptide F (NPF) signaling blocks this interference in PPL1-α2α'2 and PPL1-α3 DANs after spaced training to enable LTM formation; and (3) training-induced NPF release and neurotransmission from two upstream dorsal-anterior-lateral (DAL2) neurons are required to form LTM. Thus, NPF signals from DAL2 neurons to specific PPL1 DANs disinhibit the memory circuit, ensuring that periodic events are remembered as consolidated LTM.

Working Memory and Cross-Frequency Coupling of Neuronal Oscillations.

Working memory (WM) is the active retention and processing of information over a few seconds and is considered an essential component of cognitive function. The reduced WM capacity is a common feature in many diseases, such as schizophrenia, attention deficit hyperactivity disorder (ADHD), mild cognitive impairment (MCI), and Alzheimer's disease (AD). The theta-gamma neural code is an essential component of memory representations in the multi-item WM. A large body of studies have examined the association between cross-frequency coupling (CFC) across the cerebral cortices and WM performance; electrophysiological data together with the behavioral results showed the associations between CFC and WM performance. The oscillatory entrainment (sensory, non-invasive electrical/magnetic, and invasive electrical) remains the key method to investigate the causal relationship between CFC and WM. The frequency-tuned non-invasive brain stimulation is a promising way to improve WM performance in healthy and non-healthy patients with cognitive impairment. The WM performance is sensitive to the phase and rhythm of externally applied stimulations. CFC-transcranial-alternating current stimulation (CFC-tACS) is a recent approach in neuroscience that could alter cognitive outcomes. The studies that investigated (1) the association between CFC and WM and (2) the brain stimulation protocols that enhanced WM through modulating CFC by the means of the non-invasive brain stimulation techniques have been included in this review. In principle, this review can guide the researchers to identify the most prominent form of CFC associated with WM processing (e.g., theta/gamma phase-amplitude coupling), and to define the previously published studies that manipulate endogenous CFC externally to improve WM. This in turn will pave the path for future studies aimed at investigating the CFC-tACS effect on WM. The CFC-tACS protocols need to be thoroughly studied before they can be considered as therapeutic tools in patients with WM deficits.

Metabolic Analysis of Four Cultivars of Liriope platyphylla.

Liriope platyphylla (Liliaceae), a medical plant distributed mainly in China, Taiwan, and Korea, has been used traditionally for the treatment of cough, sputum, asthma, and neurodegenerative diseases. The present study involved the metabolic profiling of this plant and reports spicatoside A accumulation in four different varieties of L. platyphylla (Cheongyangjaerae, Seongsoo, Cheongsim, and Liriope Tuber No. 1) using HPLC and gas chromatography time-of-flight mass spectrometry (GC⁻TOFMS). A total of 47 metabolites were detected in the different cultivars using GC⁻TOFMS-based metabolic profiling. The resulting data were subjected to principal component analysis (PCA) for determining the whole experimental variation, and the different cultivars were separated by score plots. Furthermore, hierarchical clustering, Pearson's correlation, and partial least-squares discriminant analyses (PLS-DA) were subsequently performed to determine significant differences in the various metabolites of the cultivars. The HPLC data revealed that the presence of spicatoside A was detected in all four cultivars, with the amount of spicatoside A varying among them. Among the cultivars, Liriope Tuber No. 1 contained the highest amount of spicatoside A (1.83 ± 0.13 mg/g dry weight), followed by Cheongyangjaerae (1.25 ± 0.01 mg/g dry weight), Cheongsim (1.09 ± 0.04 mg/g dry weight), and Seongsoo (1.01 ± 0.02 mg/g dry weight). The identification of spicatoside A was confirmed by comparing the retention time of the sample with the retention time of the standard. Moreover, the Cheongsim cultivar contained higher levels of phenolic compounds-including vanillic acid, quinic acid, gallic acid, chlorogenic acid, caffeic acid, and benzoic acid-than those of the other two cultivars. On the other hand, the levels of amino acids were higher in the Seongsoo cultivar. Therefore, this study may help breeders produce new varieties with improved nutraceutical and nutritional qualities.

Teneligliptin in Management of Diabetic Kidney Disease: A Review of Place in Therapy.

Diabetes is a global health emergency of this century. Diabetic nephropathy is the most common microvascular complication associated with Type 2 Diabetes Mellitus (T2DM). T2DM has been reported as a major etiological factor in almost 45% of patients undergoing dialysis due to kidney failure. Lifestyle modifications; cessation of smoking, optimum control of blood glucose, blood pressure and lipids are required to reduce the progression of Diabetic Kidney Disease (DKD). Presently, Dipeptidyl peptidase-4 (DPP-4) inhibitors are preferred in the management of T2DM due to their established efficacy; favorable tolerability including, low risk of hypoglycaemia; weight neutrality and convenient once-a-day dosage. Present evidence suggests that linagliptin and teneligliptin can be used safely without dose adjustments in patients with T2DM with renal impairment, including End Stage Renal Disease (ESRD). There is a limited data about teneligliptin particularly in T2DM patients with renal impairment. The objective of this review is to evaluate efficacy and safety of teneligliptin in T2DM patients with renal impairment, in order to assess the current place in therapy and future prospects of teneligliptin. Reported evidence suggests that teneligliptin has consistent pharmacokinetic in mild, moderate, severe or ESRD, without any need for dose adjustments. Limited data from small sample studies of teneligliptin in DKD patients reported significant improvements in glycaemic parameters. Additionally, there is an improvement in kidney parameters like glycated albumin, urinary albumin and eGFR. There is an evidence of reduction in biomarkers of kidney impairment like P-selectin (sP-selectin), Platelet-Derived Microparticles (PDMPs) and Plasminogen Activator Inhibitor 1 (PAI-1). Clinical significance of these will be known in near future. Thus, teneligliptin has an important place of therapy in the management of T2DM with renal impairment.

Phenotypic and Genotypic Analysis of Multidrug-Resistant Mycobacterium tuberculosis Isolates from Sudanese Patients.

Background. Currently, mutations in rpoB, KatG, and rrs genes and inhA promoter were considered to be involved in conferring resistance to rifampicin, isoniazid, and streptomycin in Mycobacterium tuberculosis (MTB). Objective. The aims of this study were to detect the prevalence of first-line tuberculosis (TB) drug resistance among a group of previously treated and newly detected TB patients, to determine the association between prevalence of multidrug resistance (MDR) and demographic information (age and sex), to explain genes correlated with MDR Mycobacterium tuberculosis, and to characterize MTB via 16S ribosomal RNA (16S rRNA) analysis. Methods. A hundred MTB isolates from Sudanese pulmonary TB patients were included in the study. The proportional method of drug susceptibility test was carried out on Löwenstein-Jensen media. Multiplex PCR of rpoB and KatG genes and inhA promoter was conducted; then rrs genes were amplified by conventional PCR and were sequenced. The sequences of the PCR product were compared with known rrs gene sequences in the GenBank database by multiple sequence alignment tools. Result. The prevalence of MDR was 14.7% among old cases and 5.3% among newly diagnosed cases. Conclusion. Mutations in rrs could be considered as a diagnostic marker.

Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Andhra Pradesh cohort of the A1chieve study.

BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Andhra Pradesh, India. RESULTS: A total of 3077 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 2452), insulin detemir (n = 308), insulin aspart (n = 226), basal insulin plus insulin aspart (n = 21) and other insulin combinations (n = 68). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 8.9%) and insulin user (mean HbA1c: 9.2%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naïve: -1.2%, insulin users: -1.1%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.