The attenuation of activity-based anorexia by obese adipose tissue transplant is AgRP neuron-dependent.

Anorexia nervosa (AN) is an eating disorder observed primarily in girls and women, and is characterized by a low body mass index, hypophagia, and hyperactivity. The activity-based anorexia (ABA) paradigm models aspects of AN, and refers to the progressive weight loss, hypophagia, and hyperactivity developed by rodents exposed to time-restricted feeding and running wheel access. Recent studies identified white adipose tissue (WAT) as a primary location of the 'metabolic memory' of prior obesity, and implicated WAT-derived signals as drivers of recidivism to obesity following weight loss. Here, we tested whether an obese WAT transplant could attenuate ABA-induced weight loss in normal female mice. Recipient mice received a WAT transplant harvested from normal chow-fed, or HFD-fed obese mice; obese fat recipient (OFR) and control fat recipient (CFR) mice were then tested for ABA. During ABA, OFR mice survived longer than CFR mice, defined as maintaining 75% of their initial body weight. Next, we tested whether agouti-related peptide (AgRP) neurons, which regulate feeding behavior and metabolic sensing, mediate this effect of obese WAT transplant. CFR and OFR mice received either control or neonatal AgRP ablation, and were assessed for ABA. OFR intact mice maintained higher body weights longer than CFR intact mice, and this effect was abolished by neonatal AgRP ablation; further, ablation reduced survival in OFR, but not CFR mice. In summary, obese WAT transplant communicates with AgRP neurons to increase body weight maintenance during ABA. These findings encourage the examination of obese WAT-derived factors as potential treatments for AN.

Adipose tissue macrophages secrete small extracellular vesicles that mediate rosiglitazone-induced insulin sensitization.

The obesity epidemic continues to worsen worldwide, driving metabolic and chronic inflammatory diseases. Thiazolidinediones, such as rosiglitazone (Rosi), are PPARγ agonists that promote 'M2-like' adipose tissue macrophage (ATM) polarization and cause insulin sensitization. As ATM-derived small extracellular vesicles (ATM-sEVs) from lean mice are known to increase insulin sensitivity, we assessed the metabolic effects of ATM-sEVs from Rosi-treated obese male mice (Rosi-ATM-sEVs). Here we show that Rosi leads to improved glucose and insulin tolerance, transcriptional repolarization of ATMs and increased sEV secretion. Administration of Rosi-ATM-sEVs rescues obesity-induced glucose intolerance and insulin sensitivity in vivo without the known thiazolidinedione-induced adverse effects of weight gain or haemodilution. Rosi-ATM-sEVs directly increase insulin sensitivity in adipocytes, myotubes and primary mouse and human hepatocytes. Additionally, we demonstrate that the miRNAs within Rosi-ATM-sEVs, primarily miR-690, are responsible for these beneficial metabolic effects. Thus, using ATM-sEVs with specific miRNAs may provide a therapeutic path to induce insulin sensitization.

TM7SF3 controls TEAD1 splicing to prevent MASH-induced liver fibrosis.

The mechanisms of hepatic stellate cell (HSC) activation and the development of liver fibrosis are not fully understood. Here, we show that deletion of a nuclear seven transmembrane protein, TM7SF3, accelerates HSC activation in liver organoids, primary human HSCs, and in vivo in metabolic-dysfunction-associated steatohepatitis (MASH) mice, leading to activation of the fibrogenic program and HSC proliferation. Thus, TM7SF3 knockdown promotes alternative splicing of the Hippo pathway transcription factor, TEAD1, by inhibiting the splicing factor heterogeneous nuclear ribonucleoprotein U (hnRNPU). This results in the exclusion of the inhibitory exon 5, generating a more active form of TEAD1 and triggering HSC activation. Furthermore, inhibiting TEAD1 alternative splicing with a specific antisense oligomer (ASO) deactivates HSCs in vitro and reduces MASH diet-induced liver fibrosis. In conclusion, by inhibiting TEAD1 alternative splicing, TM7SF3 plays a pivotal role in mitigating HSC activation and the progression of MASH-related fibrosis.

Sex differences in risk-based decision-making and the modulation of risk preference by dopamine-2 like receptors in rats.

Heightened risk-based decision-making is observed across several neuropsychiatric disorders including schizophrenia, bipolar disorder, and Parkinson's disease, yet no treatments exist that effectively normalize this aberrant behavior. Preclinical risk-based decision-making paradigms have identified the important modulatory roles of dopamine and sex in the performance of such tasks, though specific task parameters may alter such effects (e.g., punishment and reward values). Previous work has highlighted the role of dopamine 2-like receptors (D2R) during performance of the Risk Preference Task (RPT) in male rats, however sex was not considered as a factor in this study, nor were treatments identified that reduced risk preference. Here, we utilized the RPT to determine sex-dependent differences in baseline performance and impact of the D2R receptor agonist pramipexole (PPX), and antagonist sulpiride (SUL) on behavioral performance. Female rats exhibited heightened risk-preference during baseline testing. Consistent with human studies, PPX increased risk-preference across sex, though the effects of PPX were more pronounced in female animals. Importantly, SUL reduced risk-preference in these rats across sexes. Thus, under the task specifications of the RPT that does not include punishment, female rats were more risk-preferring and required higher PPX doses to promote risky choices compared to males. Furthermore, blockade of D2R receptors may reduce risk-preference of rats, though further studies are required.

Activity of Cerebellar Nuclei Neurons Correlates with ZebrinII Identity of Their Purkinje Cell Afferents.

Purkinje cells (PCs) in the cerebellar cortex can be divided into at least two main subpopulations: one subpopulation that prominently expresses ZebrinII (Z+), and shows a relatively low simple spike firing rate, and another that hardly expresses ZebrinII (Z-) and shows higher baseline firing rates. Likewise, the complex spike responses of PCs, which are evoked by climbing fiber inputs and thus reflect the activity of the inferior olive (IO), show the same dichotomy. However, it is not known whether the target neurons of PCs in the cerebellar nuclei (CN) maintain this bimodal distribution. Electrophysiological recordings in awake adult mice show that the rate of action potential firing of CN neurons that receive input from Z+ PCs was consistently lower than that of CN neurons innervated by Z- PCs. Similar in vivo recordings in juvenile and adolescent mice indicated that the firing frequency of CN neurons correlates to the ZebrinII identity of the PC afferents in adult, but not postnatal stages. Finally, the spontaneous action potential firing pattern of adult CN neurons recorded in vitro revealed no significant differences in intrinsic pacemaking activity between ZebrinII identities. Our findings indicate that all three main components of the olivocerebellar loop, i.e., PCs, IO neurons and CN neurons, operate at a higher rate in the Z- modules.

Association between social determinants of health and olfactory function: a scoping review.

BACKGROUND: Social determinants of health (SDoH) include the socioeconomic, demographic, and social conditions that influence differences in health status among individuals and groups. The impact of these conditions on olfactory function remains poorly understood. In this scoping review, we systematically review the available literature to synthesize the association between SDoH and olfactory function. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Review (PRISMA-ScR) guidelines, we performed systematic search queries in PubMed, Embase, and Ovid databases and categorized articles according to themes that emerged regarding SDoH. The primary outcomes included self-reported and objective measurements of smell. RESULTS: We identified 722 unique references that underwent title and abstract review by two independent reviewers, with 70 articles undergoing full-text review and 57 relevant for data extraction. Six themes emerged in our review, under which we categorized the studies and synthesized respective associations with olfactory function. These include studies exploring socioeconomic status (n = 19, 33%), education status (n = 27, 47%), occupational exposures (n = 26, 46%), racial/ethnic disparities (n = 12, 21%), and lifestyle/behavioral factors (n = 33, 58%). CONCLUSIONS: Within the context of this scoping review, olfactory dysfunction is significantly more prevalent in patients with lower socioeconomic status, exposure to environmental and occupational toxins, and of minority race/ethnicity, whereas the associations between olfactory dysfunction and education level and lifestyle factors such as smoking and drinking seem to be much more elusive. This review highlights the importance of accounting for SDoH in observational studies examining olfactory outcomes. Given the increased awareness of olfactory loss, special consideration should be given to understanding olfactory dysfunction in the context of these factors.

Corticotropin-releasing factor increases Purkinje neuron excitability by modulating sodium, potassium, and Ih currents.

Corticotropin-releasing factor (CRF) is a neuromodulator closely associated with stress responses. It is synthesized and released in the central nervous system by various neurons, including neurons of the inferior olive. The targets of inferior olivary neurons, the cerebellar Purkinje neurons (PNs), are endowed with CRF receptors. CRF increases the excitability of PNs in vivo, but the biophysical mechanism is not clear. Here we examine the effect of CRF on the firing properties of PNs using acute rat cerebellar slices. CRF increased the PN firing rate, regardless of whether they were firing tonically or switching between firing and quiescent periods. Current- and voltage-clamp experiments showed that the increase in firing rate was associated with a voltage shift of the activation curve of the persistent sodium current and hyperpolarizing-activated current, as well as activation of voltage-dependent potassium current. The multiple effects on various ionic currents, which are in agreement with the possibility that activation of CRF receptors triggers several intracellular pathways, are manifested as an increase excitability of PN.

In and out of the loop: external and internal modulation of the olivo-cerebellar loop.

Cerebellar anatomy is known for its crystal like structure, where neurons and connections are precisely and repeatedly organized with minor variations across the Cerebellar Cortex. The olivo-cerebellar loop, denoting the connections between the Cerebellar cortex, Inferior Olive and Cerebellar Nuclei (CN), is also modularly organized to form what is known as the cerebellar module. In contrast to the relatively organized and static anatomy, the cerebellum is innervated by a wide variety of neuromodulator carrying axons that are heterogeneously distributed along the olivo-cerebellar loop, providing heterogeneity to the static structure. In this manuscript we review modulatory processes in the olivo-cerebellar loop. We start by discussing the relationship between neuromodulators and the animal behavioral states. This is followed with an overview of the cerebellar neuromodulatory signals and a short discussion of why and when the cerebellar activity should be modulated. We then devote a section for three types of neurons where we briefly review its properties and propose possible neuromodulation scenarios.

Ethnicity-related polymorphisms and haplotypes in the human ABCB1 gene.

INTRODUCTION: The human multidrug resistance gene ATP-binding cassette B1 (ABCB1) codes for P-glycoprotein (P-gp), an important membrane-bound efflux transporter known to confer anticancer drug resistance as well as affect the pharmacokinetics of many drugs and xenobiotics. A number of single nucleotide polymorphisms (SNPs) have been identified throughout the ABCB1 gene that may have an effect on P-gp expression levels and function. Haplotype as well as genotype analysis of SNPs is becoming increasingly important in identifying genetic variants underlying susceptibility to human disease. Three SNPs, 1236C-->T, 2677G-->T and 3435C-->T, have been repeatedly shown to predict changes in the function of P-gp. The frequencies with which these polymorphisms exist in a population have also been shown to be ethnically related. METHODS: In this study, 95 individuals representative of the entire ethnic make-up of the USA were compared with 101 individuals from an Ashkenazi-Jewish population. These individuals were analyzed by genomic sequencing and polymerase chain reaction, using restriction fragment length polymorphisms, to calculate their genotype frequencies. RESULTS: A total of 25 SNPs were located in the exons of the ABCB1 gene. All of the polymorphisms identified were in parts of the ABCB1 gene product predicted to be intracellular, and 16 appear to be novel as compared with those listed by the National Center for Biotechnological Information. Frequencies of the 1236C-->T and 2677G-->T/A/C SNPs were similar for the US and Ashkenazi populations (64.2 and 60.4%, respectively for 1236C-->T [chi2: 0.30; p < or = 1]; 55.8 and 64.4%, respectively for 2677G-->T/A/C [chi2: 1.49; p < or = 1]), but were different for 3435C-->T (24.2% for the US population and 69.3% for the Ashkenazi population [chi2: 39.927; p < or = 0.001]). The 1236T/ 2677T/3435T haplotype occurred in 23.6% (standard error: 0.013) of the Ashkenazi population. CONCLUSION: The SNP at location 3435C-->T plays a significant role in the ABCB1 gene. The haplotype and genotype analysis from these data may be used as a basis for studies on the relationship between ABCB1 genotypes and drug efficacy, drug toxicity, disease susceptibility or other phenotypes.

Cosmetic and reconstructive medical tattooing.

PURPOSE OF REVIEW: Cosmetic and reconstructive medical tattooing techniques are being used with a higher frequency than ever before. The volume of scientific research into its basics, however, is too small to prevent the present occurrence of complications. This review shows that most of the recent articles on the subject are in fact case reports and that many of the complications described result from the failure to conduct more research. RECENT FINDINGS: Recent findings include few and relatively unimportant new techniques, studies describing tattoo removal with laser, magnetic displacement and chemical irritants, more findings about infections and allergies, and complications with high field-strength magnetic resonance imaging scans. SUMMARY: Recent literature contains very few useful studies because generally they are not supported by sufficient scientific research.

Early-occurrence of manual motor blocks in Parkinson's disease: a quantitative assessment.

OBJECTIVES: Quantitative analysis of internally-cued, repetitive motor performance in patients with Parkinson's disease (PD). MATERIAL AND METHODS: Computerized quantitative measurements of the frequency, duration and temporal profile of manual motor blocks (MMBs) during performance of a manual tapping task, in 39 patients with PD, as compared to 17 age-matched healthy controls. RESULTS: Performance of PD patients was markedly abnormal both quantitatively and qualitatively, as reflected by an increase (7.0% vs. 4.6%) in MMBs, and by their occurrence from onset of movement. The phenomenon was already observed in the early stages of the disease, and was also correlated with the occurrence of freezing of gait. A standard levodopa-carbidopa (125-12.5 mg) dose only partially affected this phenomenon. CONCLUSIONS: Augmented motor blocks in internally-cued performance should be recognized as a frequent, distinct and generalized feature of PD. Whereas the gait disorder is regarded as characteristic of the advanced stage of PD, our findings suggest that the basic defect in internal rhythm formation can be detected by sensitive measurement tools from the early stages of the disease. In addition, the methodology developed in this study to quantitatively measure manual motor blocks may be a useful tool for future development of therapeutic regimens for this debilitating aspect of motor dysfunction in PD.

Enhanced fatigue during motor performance in patients with Parkinson's disease.

OBJECTIVE: To measure fatigue quantitatively during continuous motor performance in patients with PD. BACKGROUND: Enhanced fatigue on performance of motor tasks is a very frequent and disabling complaint of PD patients, and is poorly characterized and understood. Recent evidence suggests a role for mitochondrial dysfunction in the pathogenesis of PD. Reduced exercise capacity is one of the hallmarks of systemic mitochondrial impairment. METHODS: The authors used an automated system to measure muscle fatigue during a continuous (30-second), maximal, isometric forearm flexion in 17 PD patients and 10 age-matched control subjects. A fatigue index (FI) was then calculated. Peak force (PF) was measured as an internal standard of the examination. Measurements were performed before and 2 hours after an oral dose of levodopa/carbidopa (125 mg/12.5 mg). RESULTS: In PD patients there was a 50% increase in FI. The increased FI was often asymmetric and more pronounced on the side more affected by the disease. FI was significantly responsive to, and improved after, an oral dose of levodopa. The rate of improvement in FI induced by levodopa correlated with disease severity, as measured by the Unified Parkinson's Disease Rating Scale. No significant alterations in PF were observed. CONCLUSIONS: Enhanced muscle fatigue should be recognized as an integral part of the spectrum of motor impairment of PD. However, our data argue for its association with a central dopamine deficiency rather than with a muscle mitochondrial abnormality.

Diagnosis of "non-organic" limb paresis by a novel objective motor assessment: the quantitative Hoover's test.

The differentiation of "non-organic" limb weakness from genuine paralysis is sometimes difficult in neurological practice. To address this problem, we developed a computerized quantitative method, based on the Hoover's test principle, that determines the extent of involuntary limb activation when contralateral movement is performed. Measurements of hip or arm extension isometric force are performed during direct maximal voluntary effort and during contralateral hip flexion. Maximal involuntary/voluntary force ratio (IVVR) is calculated. IVVR of the lower limbs in ten healthy subjects was 0.614, 0.044 (mean, SEM). Similar results were obtained from seven patients with genuine weakness and in the non-affected limbs of nine patients with "non-organic" mono- or hemiparesis. In contrast, IVVR in the affected limbs in the "non-organic" group was markedly increased (2.48, 0.61; P < 0.001). The same pattern was elicited in the upper limbs (2.27, 0.46 vs 0.406, 0.06; P < 0,001). We conclude that Hoover's sign in "nonorganic" paralysis is a preservation or increase of a normal synkinetic phenomenon. Quantitative measurement of the IVVR can serve as a useful ancillary test in diagnosing non-organic weakness in either lower or upper limbs.

Muscle force and endurance in untreated and human growth hormone or insulin-like growth factor-I-treated patients with growth hormone deficiency or Laron syndrome.

Muscle force and endurance of four muscle groups (biceps, triceps, hamstrings and quadriceps) were measured by a computerized device in three groups: (A) 4 boys with isolated growth hormone deficiencies (IGHD) examined before at 10 and 24 months of hGH treatment; (B) 5 children (2 F, 3 M) with Laron syndrome were examined 3.5-4 years after initiation of insulin-like growth factor-I (IGF-I) treatment, and (C) comprised 8 untreated adults (5 F, 3 M) with Laron syndrome. For each patient, 2 matched controls, by age, sex, physical activity and height below the 50th percentile, were examined. GH- or IGF-I-deficient patients before treatment revealed reduced muscle force and endurance. GH treatment (0.6 U/kg/week) restored muscle force and endurance, progressively, mainly in the boys with puberty. Three to 4 years of IGF-I treatment (150 micrograms/kg/day) in patients with Laron syndrome proved to have a weaker effect than GH in restoring muscle force. The difference in effectiveness between hGH and IGF-I in restoring muscle force may be due to either the more marked muscle underdevelopment in Laron syndrome patients than in patients with IGHD or a difference in action potential between the two hormones.