Prevalence and Comorbidity of Insomnia and Effect on Functioning in Elderly Populations

A good night's sleep is often more elusive as we age, because the prevalence of insomnia in older people is high. Insufficient sleep can have important effects on daytime function by increasing the need to nap, reducing cognitive ability including attention and memory, slowing response time, adversely affecting relationships with friends and family, and contributing to a general sense of being unwell. However, rather than aging per se, circadian rhythm shifts, primary sleep disorders, comorbid medical/psychiatric illnesses, and medication use cause sleep difficulties in older people, which psychosocial factors may also affect. Clinicians should ask elderly patients about satisfaction with sleep. Any sleep complaints warrant careful evaluation of contributing factors and appropriate treatment.     

Early stage of adjuvant arthritis alters behavioral responses in male but not female rats

Anxiety and depression commonly occur in the pathology of rheumatic diseases. Little is known about how inflammatory disease in its early stage, before any clinical manifestation, may affect general activity. The aim of this study was to compare the anxiety-like behaviour in the early stage of adjuvant arthritis (AA), and the paw edema, and corticosterone (CORT) levels in the developed stage of AA among male and female Long Evans rats. The behavioural activity was evaluated by elevated plus maze tests. These revealed significantly reduced number of entries into the open arm of the maze in arthritic males compared to controls or to females 4 days after AA induction. Arthrihtic and control females did not differ. The number of entries into the closed arm of the maze was the same across the genders and studied intervals. Time spent in the open arm was significantly lower in arthritic males against controls or arthitic females. Time spent in the closed arm showed inverse picture to the time spent in the open arm. Hind paw swelling measured on day 23 of AA was the same in males and females, as was the elevation of CORT levels in plasma. Male rats showed anxiety-like behaviour on day 4 of AA, while female rats did not show any change, indicating different brain sensitivity to early inflammation among the genders.     

Neuronal metabotropic glutamate receptor 8 protects against neurodegeneration in CNS inflammation

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with continuous neuronal loss. Treatment of clinical progression remains challenging due to lack of insights into inflammation-induced neurodegenerative pathways. Here, we show that an imbalance in the neuronal receptor interactome is driving glutamate excitotoxicity in neurons of MS patients and identify the MS risk–associated metabotropic glutamate receptor 8 (GRM8) as a decisive modulator. Mechanistically, GRM8 activation counteracted neuronal cAMP accumulation, thereby directly desensitizing the inositol 1,4,5-trisphosphate receptor (IP3R). This profoundly limited glutamate-induced calcium release from the endoplasmic reticulum and subsequent cell death. Notably, we found Grm8-deficient neurons to be more prone to glutamate excitotoxicity, whereas pharmacological activation of GRM8 augmented neuroprotection in mouse and human neurons as well as in a preclinical mouse model of MS. Thus, we demonstrate that GRM8 conveys neuronal resilience to CNS inflammation and is a promising neuroprotective target with broad therapeutic implications.     

Broad and potent neutralizing human antibodies to tick-borne flaviviruses protect mice from disease

Tick-borne encephalitis virus (TBEV) is an emerging human pathogen that causes potentially fatal disease with no specific treatment. Mouse monoclonal antibodies are protective against TBEV, but little is known about the human antibody response to infection. Here, we report on the human neutralizing antibody response to TBEV in a cohort of infected and vaccinated individuals. Expanded clones of memory B cells expressed closely related anti-envelope domain III (EDIII) antibodies in both groups of volunteers. However, the most potent neutralizing antibodies, with IC₅₀s below 1 ng/ml, were found only in individuals who recovered from natural infection. These antibodies also neutralized other tick-borne flaviviruses, including Langat, louping ill, Omsk hemorrhagic fever, Kyasanur forest disease, and Powassan viruses. Structural analysis revealed a conserved epitope near the lateral ridge of EDIII adjoining the EDI–EDIII hinge region. Prophylactic or early therapeutic antibody administration was effective at low doses in mice that were lethally infected with TBEV.     

E6-AP association promotes SOD1 aggresomes degradation and suppresses toxicity

Protein aggregation and ordered fibrillar amyloid deposition inside and outside of the central nervous system cells is the common pathologic hallmark of most aging-related neurodegenerative disorders. Dominant mutations in the gene encoding superoxide dismutase 1 (SOD1) protein are linked to familial amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive degeneration of motor neurons, leading to muscle paralysis and death. The major histochemical hallmark in the remaining motor neurons of ALS is the intracellular accumulation of ubiquitinated inclusions consisting of insoluble aberrant protein aggregates. However, the molecular pathomechanisms underlying the process have been elusive. Here for the first time, we report that E6-AP, a homologous to E6-AP C terminus-type E3 ubiquitin ligase depleted in ALS mouse models before neurodegeneration. E6-AP coimmunoprecipitates with the SOD1 protein and is predominantly mislocalized in mutant SOD1-containing inclusion bodies. Overexpression of E6-AP increases the ubiquitination and facilitates degradation of SOD1 proteins. Finally, we show that the overexpression of E6-AP suppresses the aggregation and cell death mediated by mutated SOD1 proteins and cellular protective effect is more prominent when E6-AP is overexpressed along with Hsp70. These data suggest that enhancing the activity of E6-AP ubiquitin ligase might be a viable therapeutic strategy to eliminate mutant SOD1-mediated toxicity in ALS.     

Adult trkB Signaling in Parvalbumin Interneurons is Essential to Prefrontal Network Dynamics

Inhibitory interneurons expressing parvalbumin (PV) are central to cortical network dynamics, generation of γ oscillations, and cognition. Dysfunction of PV interneurons disrupts cortical information processing and cognitive behavior. Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling regulates the maturation of cortical PV interneurons but is also implicated in their adult multidimensional functions. Using a novel viral strategy for cell-type-specific and spatially restricted expression of a dominant-negative trkB (trkB.DN), we show that BDNF/trkB signaling is essential to the integrity and maintenance of prefrontal PV interneurons in adult male and female mice. Reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) resulted in deficient PV inhibition and increased baseline local field potential (LFP) activity in a broad frequency band. The altered network activity was particularly pronounced during increased activation of the prefrontal network and was associated with changed dynamics of local excitatory neurons, as well as decreased modulation of the LFP, abnormalities that appeared to generalize across stimuli and brain states. In addition, our findings link reduced BDNF/trkB signaling in prefrontal PV interneurons to increased aggression. Together our investigations demonstrate that BDNF/trkB signaling in PV interneurons in the adult mPFC is essential to local network dynamics and cognitive behavior. Our data provide direct support for the suggested association between decreased trkB signaling, deficient PV inhibition, and altered prefrontal circuitry.SIGNIFICANCE STATEMENT Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling promotes the maturation of inhibitory parvalbumin (PV) interneurons, neurons central to local cortical dynamics, γ rhythms, and cognition. Here, we used a novel viral approach for reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) to establish the role of BDNF/trkB signaling in adult prefrontal network activities. Reduced BDNF/trkB signaling caused pronounced morphologic alterations, reduced PV inhibition, and deficient prefrontal network dynamics. The altered network activity appeared to manifest across stimuli and brain states and was associated with aberrant local field potential (LFP) activities and increased aggression. The results demonstrate that adult BDNF/trkB signaling is essential to PV inhibition and prefrontal circuit function and directly links BDNF/trkB signaling to network integrity in the adult brain.     

Genetic diversity of porcine sapoviruses, kobuviruses, and astroviruses in asymptomatic pigs: an emerging new sapovirus GIII genotype

Small, non-enveloped RNA viruses belonging to the genera Sapovirus, Kobuvirus, and Mamastrovirus are usually associated with gastroenteritis in humans and animals. These enteric pathogens are considered potential zoonotic agents. In this study, the prevalence and genetic diversity of sapoviruses (SaVs), kobuviruses (KoVs), and astroviruses (AstVs) in asymptomatic pigs were investigated using a PCR approach. KoV was found to be the most prevalent virus (87.3 %), followed by AstV (34.2 %) and SaV (10.2 %). Interestingly, the intra- and inter-cluster distances between porcine SaV capsid sequences revealed one strain (P38/11/CZ) that formed a new genotype within genogroup III of porcine SaVs, and it is tentatively called “P38/11-like” genotype. Moreover, this is the first report of porcine kobuvirus detection on Czech pig farms. The high prevalence rate of gastroenteritis-producing viruses in clinically healthy pigs represents a continuous source of infection of pigs, and possibly to humans.