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Thermally activated ion channels are known to detect the entire thermal range from extreme heat (TRPV2), painful heat (TRPV1, TRPM3 and ANO1), non-painful warmth (TRPV3 and TRPV4) and non-painful coolness (TRPM8) through to painful cold (TRPA1) 1 , 2 , 3 , 4 , 5 , 6 , 7 . Genetic deletion of each of these ion channels, however, has only modest effects on thermal behaviour in mice 6 , 7 , 8 , 9 , 10 , 11 , 12 , with the exception of TRPM8, the deletion of which has marked effects on the perception of moderate coolness in the range 10–25 °C 13 . The molecular mechanism responsible for detecting non-painful warmth, in particular, is unresolved. Here we used calcium imaging to identify a population of thermally sensitive somatosensory neurons which do not express any of the known thermally activated TRP channels. We then used a combination of calcium imaging, electrophysiology and RNA sequencing to show that the ion channel generating heat sensitivity in these neurons is TRPM2. Autonomic neurons, usually thought of as exclusively motor, also express TRPM2 and respond directly to heat. Mice in which TRPM2 had been genetically deleted showed a striking deficit in their sensation of non-noxious warm temperatures, consistent with the idea that TRPM2 initiates a ‘warm’ signal which drives cool-seeking behaviour. The neuronal mechanism for the detection of non-painful warm stimuli has remained unclear; mammalian TRPM2 ion channel is shown to be required for warmth detection in the non-noxious range of 33–38 °C, and surprisingly to mediate responses to warmth in the autonomic nervous system. An ion channel responding to 'comfortable' warmth Despite the identification of several members of the TRP family of ion channels as heat-sensitive, the neuronal mechanism for the detection of non-painful warm stimuli has remained unclear, because genetic deletion of obvious candidates, such as TRPV3 and TRPV4, has had no effect on thermosensation. Rather than working with cloned channels, as is commonly done, Chun-Hsiang Tan and Peter McNaughton studied the responses of actual sensory neurons to thermal stimuli, then used an RNA-sequencing strategy to identify TRPM2 as genetically required for warmth detection in the non-noxious range of 33–38 °C, and, surprisingly, to mediate warm sensations in the autonomic nervous system.

Neutrophils must navigate accurately towards pathogens in order to destroy invaders and thus defend our bodies against infection. Here we show that hydrogen peroxide, a potent neutrophil chemoattractant, guides chemotaxis by activating calcium-permeable TRPM2 ion channels and generating an intracellular leading-edge calcium “pulse”. The thermal sensitivity of TRPM2 activation means that chemotaxis towards hydrogen peroxide is strongly promoted by small temperature elevations, suggesting that an important function of fever may be to enhance neutrophil chemotaxis by facilitating calcium influx through TRPM2. Chemotaxis towards conventional chemoattractants such as LPS, CXCL2 and C5a does not depend on TRPM2 but is driven in a similar way by leading-edge calcium pulses. Other proposed initiators of neutrophil movement, such as PI3K, Rac and lyn , influence chemotaxis by modulating the amplitude of calcium pulses. We propose that intracellular leading-edge calcium pulses are universal drivers of the motile machinery involved in neutrophil chemotaxis.

The abilities to detect warmth and heat are critical for the survival of all animals, both in order to be able to identify suitable thermal environments for the many different activities essential for life and to avoid damage caused by extremes of temperature. Several ion channels belonging to the TRP family are activated by non-noxious warmth or by heat and are therefore plausible candidates for thermal detectors, but identifying those that actually regulate warmth and heat detection in intact animals has proven problematic. TRPM2 has recently emerged as a likely candidate for the detector of non-noxious warmth, as it is expressed in sensory neurons, and mice show deficits in the detection of warmth when TRPM2 is genetically deleted. TRPM2 is a chanzyme, containing a thermally activated TRP ion channel domain attached to a C-terminal motif, derived from a mitochondrial ADP ribose pyrophosphatase, that confers on the channel sensitivity to ADP ribose and reactive oxygen species such as hydrogen peroxide. Several open questions remain. Male mammals prefer cooler environments than female, but the molecular basis of this sex difference is unknown. TRPM2 plays a role in regulating body temperature, but are other warmth-detecting mechanisms also involved? TRPM2 is expressed in autonomic neurons, but does it confer a sensory function in addition to the well-known motor functions of autonomic neurons? TRPM2 is thought to play important roles in the immune system, in pain and in insulin secretion, but the mechanisms are unclear. TRPM2 has to date received less attention than many other members of the TRP family but is rapidly assuming importance both in normal physiology and as a key target in disease pathology.

Executive dysfunction is common in Parkinson's disease (PD) patients. The catechol-O-methyltransferase (COMT) Val158Met polymorphism has been proposed to affect executive functions (EFs) in the prefrontal cortex. The present study attempted to explore the influence of the COMT polymorphism on EFs in patients with PD. Fifty-four PD patients were recruited and underwent neuropsychological assessments for three core EFs. The COMT polymorphism was genotyped using the TaqMan SNP Genotyping Assay. Participants were divided into three study groups: Val homozygotes, heterozygotes, and Met homozygotes. The three COMT genotype groups had significantly different performances in set-shifting [χ2 (2, 54) = 9.717, p = 0.008] and working memory tasks [χ2 (2, 54) = 7.806, p = 0.020]. Post-hoc analyses revealed that PD Val homozygotes performed significantly poorer in the set-shifting task than did either the PD Met homozygotes (z = -2.628, p = 0.009) or PD heterozygotes (z = -2.212, p = 0.027). Our explorative results suggest that the putative level of prefrontal dopamine influenced set-shifting through a \"cane-shaped\" dopamine level-response relationship. Our results have clinical implications, which may influence PD treatment with dopamine in the future because the optimal dopamine level to maximize EFs may vary based on the clinical course and COMT polymorphism status. Further study recruiting a larger number of participants is needed to confirm our preliminary findings.

Abstract This study investigated the association between cognitive function and facial emotion recognition (FER) in patients with Parkinson’s disease (PD) and mild cognitive impairment (PD-MCI). We enrolled 126 participants from Taiwan, including 63 patients with idiopathic PD and 63 matched healthy controls. The PD group was divided into two groups: those with normal cognitive function (PD-NC) and those with MCI (PD-MCI). Participants underwent a modality emotion recognition test and comprehensive cognitive assessment. Our findings reveal that patients with PD-MCI exhibit significantly impaired FER, especially in recognizing “disgust,” compared with patients with PD-NC and healthy adults (P = .001). This deficit correlates with executive function, attention, memory, and visuospatial abilities. Attention mediates the relationship between executive function and “disgust” FER. The findings highlight how patients with PD-MCI are specifically challenged when recognizing “disgust” and suggest that cognitive training focusing on cognitive flexibility and attention may improve their FER abilities. This study contributes to our understanding of the nuanced relationship between cognitive dysfunction and FER in patients with PD-MCI, emphasizing the need for targeted interventions.

Monoamine neurotransmitters play essential roles in the regulation of arousal and sleep. Impaired metabolism of monoamine neurotransmitters could result in the accumulation of neurotoxic aldehyde metabolites and, hence, neuronal degeneration. Aldehyde dehydrogenases play an important role in the metabolism of the neurotoxic aldehyde metabolites, including the aldehyde metabolites of dopamine, serotonin, and noradrenaline. Deficient aldehyde dehydrogenase 2 (ALDH2) has been suggested to result in the accumulation of these biogenic aldehydes. An ALDH2 single nucleotide polymorphism (SNP), rs671 (A), results in significantly reduced ALDH2 enzyme activity. A total of 83 Parkinson’s disease (PD) patients were recruited in this study. In addition to the genotypes of rs671, the patients were assessed with the PD sleep scale-2nd version (PDSS-2) and the Epworth sleepiness scale (ESS) for symptoms of daytime and nocturnal sleep disturbances. The patients carrying rs671 (A) had more frequent dozing while lying down to rest in the afternoon (ESS item5) (F = 7.308, p = 0.008) than the rs671 (GG) patients. The patients with rs671 (A) reported a trend toward more frequent difficulty staying asleep than the patients with rs671 (GG). (F = 3.278, p = 0.074). The results indicate that patients carrying allele rs671 (A) are more likely to experience impairment in the regulation of arousal and sleep. The results also support the hypothesis that the accumulation of neurotoxic monoamine neurotransmitter aldehyde metabolites secondary to reduced ALDH2 enzyme activity may cause more severe monoaminergic neuronal loss and, hence, more severe symptoms in the regulation of wakefulness and sleep.

Elevated levels of interleukin 1β (IL‐1β) have been identified in patients with chronic viral hepatitis and have been associated with depressive symptoms. Given the high prevalence of depression in this patient population, this study sought to explore the potential influence of IL‐1β genetic variations on the severity of depressive symptoms. In a cohort of 181 Taiwanese patients with chronic viral hepatitis, we investigated the impact of five common IL‐1β single nucleotide polymorphisms (SNPs), including rs16944, rs1143627, rs1143630, rs1143643, and rs3136558, on depressive symptoms using the Beck's Depression Inventory‐II. Additionally, we analyzed the primary domains of IL‐1β‐related depressive symptoms according to Beck's six symptom categories of depression. Our analysis revealed significant associations between depressive symptoms and three intronic IL‐1β SNPs. After controlling for age, sex, marital status, and education level, patients with the rs1143630 GG, rs1143643 CC, and rs3136558 AA genotypes demonstrated higher severity of depressive symptoms in the domains of indecision (p = 0.004), agitation (p = 0.001), and feelings of punishment (p = 0.005), respectively, compared to rs1143630 GA+AA, rs1143643 CT, and rs3136558 AG+GG genotypes. According to Beck's categorization, these symptoms can be classified into three dimensions: disturbances in emotion regulation, energy, and cognition. Our findings demonstrate the association between IL‐1β polymorphisms and depressive symptoms and suggest a potential underlying mechanism for specific depressive symptoms within the chronic viral hepatitis population. These insights could improve our understanding and treatment of depressive symptoms in individuals with viral hepatitis.

The direct impact of chronic hepatitis B and hepatitis C on neurocognition remains elusive due to the frequent comorbidities, and the domains of the neurocognitive functions affected have rarely been investigated comprehensively. We cross-sectionally assessed the neurocognitive functions of the individuals with chronic hepatitis B, chronic hepatitis C, treated chronic hepatitis C with a sustained virologic response, and their healthy control counterparts. Laboratory examinations were used to investigate the impact of inflammation on neurocognition, exclude the medical conditions that could interfere with neurocognition assessment, and assess liver function and fibrotic severity of the liver of the participants. This study found the detrimental impact of chronic hepatitis B on language and executive functions. In contrast, individuals with chronic hepatitis C showed deficits in executive functions, psychomotor speed, memory, and attention. Successful elimination of hepatitis C resulted in improved liver function, but not neuropsychological test performance. Moreover, erythrocyte sedimentation rate level was found to mediate the deficits in the attention of individuals with chronic hepatitis C. These results demonstrate the neurocognitive deficits and the difference in the profiles of neurocognitive deficits in individuals with chronic hepatitis B and chronic hepatitis C. Our study also provided results suggesting the mediation by systemic inflammation on the attention deficit in individuals with chronic hepatitis C.

Recent studies have identified a correlation between chronic viral hepatitis and cognitive impairment, yet the underlying mechanisms remain unclear. This study investigated the influence of TGFB1 genetic polymorphisms on cognitive function in individuals with and without hepatitis infections, hypothesizing that these polymorphisms and the viral hepatitis‐induced inflammatory environment interact to affect cognitive abilities. Participants (173 with viral hepatitis and 258 healthy controls) were recruited. Genotyping of TGFB1 SNPs was performed using the C2‐58 Axiom Genome‐Wide TWB 2.0 Array Plate. Cognitive function was assessed using the MMSE and MoCA tests. Our results showed that healthy individuals carrying the C allele of rs2241715 displayed better performance in sentence writing (p = 0.020) and language tasks (p = 0.022). Notably, viral hepatitis was found to moderate the impact of the rs2241715 genotype on language function (p = 0.002). Similarly, those carrying the T allele of rs10417924 demonstrated superior orientation to time (p = 0.002), with viral hepatitis modifying the influence of the SNP on this particular cognitive function (p = 0.010). Our findings underscore the significant role of TGFβ1 in cognitive function and the moderating impact of viral hepatitis on TGFB1 SNP effects. These findings illuminate the potential of TGFB1 as a therapeutic target for cognitive impairment induced by viral hepatitis, thus broadening our understanding of TGFβ1 functionality in the pathogenesis of neurodegeneration.

BackgroundSocial functioning is crucial for daily living and is an essential indicator of dementia in patients with Parkinson's disease. The pattern of social functioning in patients with Parkinson's disease without dementia (i.e. those who are cognitively intact or have mild cognitive impairment (PD-MCI)) and its determinants are unclear.AimsIn exploring the heterogeneity of social functioning among patients with Parkinson's disease-associated dementia, we determined the optimal cut-off score of the Parkinson's Disease Social Functioning Scale (PDSFS) for patients with PD-MCI, and the variables influencing patients’ social functioning.MethodA total of 302 participants underwent the Mini-Mental State Examination (MMSE) and PDSFS; 120 patients with Parkinson's disease completed the measurements (MMSE, Activities of Daily Living Scale and Neuropsychiatric Inventory). Group comparisons, receiver operating characteristic curves, Spearman correlation and multiple and hierarchical regression analyses were conducted.ResultsThe PD-MCI group scored the lowest on the PDSFS (F = 10.10, P < 0.001). The PDSFS cut-off score was 53 (area under the curve 0.700, sensitivity 0.800, specificity 0.534). The MMSE (β = 0.293, P = 0.002), Activities of Daily Living Scale (β = 0.189, P = 0.028) and Neuropsychiatric Inventory (β = −0.216, P = 0.005) scores predicted the PDSFS score. Further, there was an interaction effect between the Activities of Daily Living Scale and Neuropsychiatric Inventory scores on the PDSFS score (β = 0.305, P < 0.001).ConclusionsWe determined a PDSFS cut-off score for detecting PD-MCI and found that patients with PD-MCI have social dysfunction. Future research should focus on the effects of neuropsychiatry symptoms and activities of daily living on social functioning, and tailor the intervention programme for patients with Parkinson's disease.