Wrist temperature and cortisol awakening response in humans with social jetlag in the North

The discrepancy between biological and social rhythms known as social jetlag (SJL) is common in modern society and has a range of negative consequences for cognitive functioning, well-being and health. Social jetlag is typical for people with late chronotypes. As shown earlier, the prevalence of individuals with a late chronotype is higher among the residents of high latitudes. Therefore, a higher rate of detection of people with SJL should be expected in the North. In this study we assessed the detection rate of SJL among 62 young inhabitants of the European North of Russia (the Komi Republic), and the relationship between SJL, the circadian rhythm of the wrist temperature, and the cortisol awakening response (CAR). The detection rate of SJL was 65% among the people examined. A significant decrease in the amplitude (A) of circadian rhythm of wrist temperature: (β = ?0.34 (CI 95%: ?0.66 to ?0.33); F_1,60 = 10.4; p < 0.0001; η² = 0.31), an increased incidence of depression: No-SJL = 4.5%; SJL = 17.5% (H = 4.84; p < 0.05), and a tendency for an increase in CAR was also observed in the SJL group. There were sex differences in sensitivity to SJL. Females with SJL but not males had higher global seasonality scores (β = 0.51 (CI 95%: 0.21 to 0.81); F_1,33 = 10.9; p < 0.002; η² =0.24), shorter sleep duration (β = ?0.52 (CI 95%: ?0.82 to ?0.22); F_1,33 = 12.9; p < 0.001; η² = 0.28), worse sleep quality (β = 0.39 (CI 95%: 0.07 to 0.72); F_1,33 = 6.31; p < 0.017; η² = 0.16) and lower A of circadian rhythm of wrist temperature (β = ?0.18 (CI 95%: ?0.55 to 0.18); F_1,33 = 4.48; p < 0.043; η² = 0.13) compared with females without SJL. Thus, our data indicate that 40 of 62 participants of investigation had social jetlag. A decrease of the amplitude of the circadian rhythm of the wrist temperature appears to be an objective marker of SJL. Social jetlag had a strong negative impact on females but not on males.     

Exploring a possibility of using Raman spectroscopy for detection of Lyme disease

Lyme disease (LD), one of the most prevalent tick-borne diseases in the United States (US), is caused by Borreliella burgdorferi sensu stricto (Bb). To date, in the US, LD diagnostics is primarily based on validated two-tiered serological testing, which overall exhibits low sensitivity among other drawbacks. In the present study, a potential of Raman spectroscopy (RS) to detect Bb infection in mice has been explored. For that, C3H mice were infected with wild-type Bb strains, 297, B31, or B31-derived mutant, ∆vlsE. Blood samples taken prior to and post Bb infection were subjected to RS. The data demonstrated that RS did not directly detect Bb spirochetes in blood, but rather sensed biochemical changes associated with Bb infection. Despite Bb infection-associated blood changes detectable by RS were very limited, the partial least square discriminant analysis showed that the average true positive rates were 86% for 297 and 89% for B31 and ∆vlsE.     

Cognitive disturbances in the cuprizone model of multiple sclerosis

Cognitive problems frequently accompany neurological manifestations of multiple sclerosis (MS). However, during screening of preclinical candidates, assessments of behaviour in mouse models of MS typically focus on locomotor activity. In the present study, we analysed cognitive behaviour of 9 to 10-week-old female C57Bl/6J mice orally administered with the toxin cuprizone that induces demyelination, a characteristic feature of MS. Animals received 400 mg/kg cuprizone daily for 2 or 4 weeks, and their performance was compared with that of vehicle-treated mice. Cuprizone-treated animals showed multiple deficits in short touchscreen-based operant tasks: they responded more slowly to visual stimuli, rewards and made more errors in a simple rule-learning task. In contextual/cued fear conditioning experiments, cuprizone-treated mice showed significantly lower levels of contextual freezing than vehicle-treated mice. Diffusion tensor imaging showed treatment-dependent changes in fractional anisotropy as well as in axial and mean diffusivities in different white matter areas. Lower values of fractional anisotropy and axial diffusivity in cuprizone-treated mice indicated developing demyelination and/or axonal damage. Several diffusion tensor imaging measurements correlated with learning parameters. Our results show that translational touchscreen operant tests and fear conditioning paradigms can reliably detect cognitive consequences of cuprizone treatment. The suggested experimental approach enables screening novel MS drug candidates in longitudinal experiments for their ability to improve pathological changes in brain structure and reverse cognitive deficits.     

Genetic Markers of a Munc13 Protein Family Member,BAIAP3, Are Gender Specifically Associated with Anxiety and Benzodiazepine Abuse in Mice and Humans

Anxiety disorders and substance abuse, including benzodiazepine use disorder, frequently occur together. Unfortunately, treatment of anxiety disorders still includes benzodiazepines, and patients with an existing comorbid benzodiazepine use disorder or a genetic susceptibility for benzodiazepine use disorder may be at risk of adverse treatment outcomes. The identification of genetic predictors for anxiety disorders, and especially for benzodiazepine use disorder, could aid the selection of the best treatment option and improve clinical outcomes. The brain-specific angiogenesis inhibitor I–associated protein 3 (Baiap3) is a member of the mammalian uncoordinated 13 (Munc13) protein family of synaptic regulators of neurotransmitter exocytosis, with a striking expression pattern in amygdalae, hypothalamus and periaqueductal gray. Deletion of Baiap3 in mice leads to enhanced seizure propensity and increased anxiety, with the latter being more pronounced in female than in male animals. We hypothesized that genetic variation in human BAIAP3 may also be associated with anxiety. By using a phenotype-based genetic association study, we identified two human BAIAP3 single-nucleotide polymorphism risk genotypes (AA for rs2235632, TT for rs1132358) that show a significant association with anxiety in women and, surprisingly, with benzodiazepine abuse in men. Returning to mice, we found that male, but not female, Baiap3 knockout (KO) mice develop tolerance to diazepam more quickly than control animals. Analysis of cultured Baiap3 KO hypothalamus slices revealed an increase in basal network activity and an altered response to diazepam withdrawal. Thus, Baiap3/BAIAP3 is gender specifically associated with anxiety and benzodiazepine use disorder, and the analysis of Baiap3/BAIAP3-related functions may help elucidate mechanisms underlying the development of both disorders.     

Early S-phase cell hypersensitivity to heat stress

Heat stress is one of the best-studied exogenous stress factors; however little is known about its delayed effects. Recently, we have shown that heat stress induces cellular senescence-like G2 arrest exclusively in early S-phase cells. The mechanism of this arrest includes the generation of heat stress-induced single-stranded DNA breaks, the collision of replication forks with these breaks and the formation of difficult-to-repair double-stranded DNA breaks. However, the early S phase-specific effects of heat stress are not limited to the induction of single-stranded DNA breaks. Here, we report that HS induces partial DNA re-replication and centrosome amplification. We suggest that HS-induced alterations in the expression levels of the genes encoding the replication licensing factors are the primary source of such perturbations. Notably, these processes do not contribute to acquisition of a senescence-like phenotype, although they do elicit postponed effects. Specifically, we found that the HeLa cells can escape from the heat stress-induced cellular senescence-like G2 arrest, and the mitosis they enter is multipolar due to the amplified centrosomes.     

Enhanced-contrast two-photon optogenetic pH sensing and pH-resolved brain imaging

We present experiments on cell cultures and brain slices that demonstrate two-photon optogenetic pH sensing and pH-resolved brain imaging using a laser driver whose spectrum is carefully tailored to provide the maximum contrast of a ratiometric two-photon fluorescence readout from a high-brightness genetically encoded yellow-fluorescent-protein-based sensor, SypHer3s. Two spectrally isolated components of this laser field are set to induce two-photon-excited fluorescence (2PEF) by driving SypHer3s through one of two excitation pathways—via either the protonated or deprotonated states of its chromophore. With the spectrum of the laser field accurately adjusted for a maximum contrast of these two 2PEF signals, the ratio of their intensities is shown to provide a remarkably broad dynamic range for pH measurements, enabling high-contrast optogenetic deep-brain pH sensing and pH-resolved 2PEF imaging within a vast class of biological systems, ranging from cell cultures to the living brain.