Assessment of Stress and Well-Being of Japanese Employees Using Wearable Devices for Sleep Monitoring Combined With Ecological Momentary Assessment: Pilot Observational Study.

BACKGROUND: Poor sleep quality can elevate stress levels and diminish overall well-being. Japanese individuals often experience sleep deprivation, and workers have high levels of stress. Nevertheless, research examining the connection between objective sleep assessments and stress levels, as well as overall well-being, among Japanese workers is lacking. OBJECTIVE: This study aims to investigate the correlation between physiological data, including sleep duration and heart rate variability (HRV), objectively measured through wearable devices, and 3 states (sleepiness, mood, and energy) assessed through ecological momentary assessment (EMA) and use of rating scales for stress and well-being. METHODS: A total of 40 office workers (female, 20/40, 50%; mean age 40.4 years, SD 11.8 years) participated in the study. Participants were asked to wear a wearable wristband device for 8 consecutive weeks. EMA regarding sleepiness, mood, and energy levels was conducted via email messages sent by participants 4 times daily, with each session spaced 3 hours apart. This assessment occurred on 8 designated days within the 8-week timeframe. Participants' stress levels and perception of well-being were assessed using respective self-rating questionnaires. Subsequently, participants were categorized into quartiles based on their stress and well-being scores, and the sleep patterns and HRV indices recorded by the Fitbit Inspire 2 were compared among these groups. The Mann-Whitney U test was used to assess differences between the quartiles, with adjustments made for multiple comparisons using the Bonferroni correction. Furthermore, EMA results and the sleep and HRV indices were subjected to multilevel analysis for a comprehensive evaluation. RESULTS: The EMA achieved a total response rate of 87.3%, while the Fitbit Inspire 2 wear rate reached 88.0%. When participants were grouped based on quartiles of well-being and stress-related scores, significant differences emerged. Specifically, individuals in the lowest stress quartile or highest subjective satisfaction quartile retired to bed earlier (P<.001 and P=.01, respectively), whereas those in the highest stress quartile exhibited greater variation in the midpoint of sleep (P<.001). A multilevel analysis unveiled notable relationships: intraindividual variability analysis indicated that higher energy levels were associated with lower deviation of heart rate during sleep on the preceding day (ß=-.12, P<.001), and decreased sleepiness was observed on days following longer sleep durations (ß=-.10, P<.001). Furthermore, interindividual variability analysis revealed that individuals with earlier midpoints of sleep tended to exhibit higher energy levels (ß=-.26, P=.04). CONCLUSIONS: Increased sleep variabilities, characterized by unstable bedtime or midpoint of sleep, were correlated with elevated stress levels and diminished well-being. Conversely, improved sleep indices (eg, lower heart rate during sleep and earlier average bedtime) were associated with heightened daytime energy levels. Further research with a larger sample size using these methodologies, particularly focusing on specific phenomena such as social jet lag, has the potential to yield valuable insights. TRIAL REGISTRATION: UMIN-CTR UMIN000046858; https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000053392.

eIF4A1 enhances LARP1-mediated translational repression during mTORC1 inhibition.

Eukaryotic translation initiation factor (eIF)4A-a DEAD-box RNA-binding protein-plays an essential role in translation initiation. Recent reports have suggested helicase-dependent and helicase-independent functions for eIF4A, but the multifaceted roles of eIF4A have not been fully explored. Here we show that eIF4A1 enhances translational repression during the inhibition of mechanistic target of rapamycin complex 1 (mTORC1), an essential kinase complex controlling cell proliferation. RNA pulldown followed by sequencing revealed that eIF4A1 preferentially binds to mRNAs containing terminal oligopyrimidine (TOP) motifs, whose translation is rapidly repressed upon mTORC1 inhibition. This selective interaction depends on a La-related RNA-binding protein, LARP1. Ribosome profiling revealed that deletion of EIF4A1 attenuated the translational repression of TOP mRNAs upon mTORC1 inactivation. Moreover, eIF4A1 increases the interaction between TOP mRNAs and LARP1 and, thus, ensures stronger translational repression upon mTORC1 inhibition. Our data show the multimodality of eIF4A1 in modulating protein synthesis through an inhibitory binding partner and provide a unique example of the repressive role of a universal translational activator.

Associations between glycemic variability, sleep quality, and daily steps in subjects without diabetes using wearable devices.

Background: Since there are limited studies on the associations between glycemic variability (GV) and sleep quality or physical activity in subjects without diabetes, we evaluated the associations between GV, as assessed by continuous glucose monitoring (CGM), and both sleep quality and daily steps using wearable devices in healthy individuals. Methods: Forty participants without diabetes were monitored by both an intermittently scanned CGM and a smartwatch-type activity tracker for 2 weeks. The standard deviation (SD) and coefficient of variation (CV) of glucose were evaluated as indices of GV. The activity tracker was used to calculate each participant's average step count per day. We also calculated sleep duration, sleep efficiency, and sleep latency based on data from the activity tracker. Spearman's correlation coefficient was used to assess the association between GV and sleep indices or daily steps. For each participant, periods were divided into quartiles according to step counts throughout the day. We compared mean parameter differences between the periods of lowest quartile and highest quartile (lower 25% and upper 25%). Results: SD glucose was significantly positively correlated with sleep latency (R = 0.23, P < 0.05). There were no significant correlations among other indices in GV and sleep quality (P > 0.05). SD glucose and CV glucose levels in the upper 25% period of daily steps were lower than those in the lower 25% period in each participant (both, P < 0.01). Conclusion: In subjects without diabetes, GV evaluated by intermittently scanned CGM was positively associated with the time to fall asleep. Furthermore, GV in the days of larger daily steps was decreased compared to the days of smaller daily steps in each participant.

Assessment of glycemic variability and lifestyle behaviors in healthy nondiabetic individuals according to the categories of body mass index.

BACKGROUND: There are limited data about the association between body mass index (BMI), glycemic variability (GV), and life-related factors in healthy nondiabetic adults. METHODS: This cross-sectional study was carried out within our ethics committee-approved study called "Exploring the impact of nutrition advice on blood sugar and psychological status using continuous glucose monitoring (CGM) and wearable devices". Prediabetes was defined by the HbA1c level of 5.7-6.4% and /or fasting glucose level of 100-125 mg/dL. Glucose levels and daily steps were measured for 40 participants using Free Style Libre and Fitbit Inspire 2 under normal conditions for 14 days. Dietary intakes and eating behaviors were assessed using a brief-type self-administered dietary history questionnaire and a modified questionnaire from the Obesity Guidelines. RESULTS: All indices of GV were higher in the prediabetes group than in the healthy group, but a significant difference was observed only in mean amplitude of glycemic excursions (MAGE). In the multivariate analysis, only the presence of prediabetes showed a significant association with the risk of higher than median MAGE (Odds, 6.786; 95% CI, 1.596-28.858; P = 0.010). Additionally, the underweight (BMI < 18.5) group had significantly higher value in standard deviation (23.7 ± 3.5 vs 19.8 ± 3.7 mg/dL, P = 0.038) and coefficient variability (22.6 ± 4.6 vs 18.4 ± 3.2%, P = 0.015), compared to the normal group. This GV can be partially attributed to irregularity of eating habits. On the contrary, the overweight (BMI ≥ 25) group had the longest time above the 140 or 180 mg/dL range, which may be due to eating style and taking fewer steps (6394 ± 2337 vs 9749 ± 2408 steps, P = 0.013). CONCLUSIONS: Concurrent CGM with diet and activity monitoring could reduce postprandial hyperglycemia through assessment of diet and daily activity, especially in non- normal weight individuals.

METTL18-mediated histidine methylation of RPL3 modulates translation elongation for proteostasis maintenance.

Protein methylation occurs predominantly on lysine and arginine residues, but histidine also serves as a methylation substrate. However, a limited number of enzymes responsible for this modification have been reported. Moreover, the biological role of histidine methylation has remained poorly understood to date. Here, we report that human METTL18 is a histidine methyltransferase for the ribosomal protein RPL3 and that the modification specifically slows ribosome traversal on Tyr codons, allowing the proper folding of synthesized proteins. By performing an in vitro methylation assay with a methyl donor analog and quantitative mass spectrometry, we found that His245 of RPL3 is methylated at the τ-N position by METTL18. Structural comparison of the modified and unmodified ribosomes showed stoichiometric modification and suggested a role in translation reactions. Indeed, genome-wide ribosome profiling and an in vitro translation assay revealed that translation elongation at Tyr codons was suppressed by RPL3 methylation. Because the slower elongation provides enough time for nascent protein folding, RPL3 methylation protects cells from the cellular aggregation of Tyr-rich proteins. Our results reveal histidine methylation as an example of a ribosome modification that ensures proteome integrity in cells.

A significant risk of metabolic dysfunction-associated fatty liver disease plus diabetes on subclinical atherosclerosis.

BACKGROUND: This cross-sectional study aims to investigate the association between subclinical atherosclerosis and metabolic dysfunction-associated fatty liver disease (MAFLD) or non-alcoholic fatty liver disease (NAFLD), and a synergistic effect of diabetes mellitus (DM) and MAFLD on subclinical atherosclerosis. METHODS: Of 977 subjects who underwent health checkups with coronary artery calcification (CAC), carotid intima-media thickness, and brachial-ankle pulse wave velocity (ba-PWV), 890 were included in this study. They were classified as MAFLD, NAFLD, or Neither-FLD, and MAFLD was further categorized into three groups by three metabolic disorders (obesity, lean with metabolic dysregulation, DM), according to its new definition: Obesity-MAFLD, Lean-MAFLD and DM-MAFLD. RESULTS: In a multivariable analysis, MAFLD and NAFLD were significantly associated with subclinical atherosclerosis, except for an association between ba-PWV and NAFLD. MAFLD had higher odds for CAC than NAFLD (for CAC score > 100, odds ratio (OR) = 2.599, 95% confidence interval (CI) = 1.625-4.157; OR = 1.795, 95%CI = 1.145-2.814, respectively). In a sub-analysis, DM-MAFLD had higher odds for CAC (for CAC score > 100, OR = 5.833, 95%CI = 3.047-11.164) than the other groups of MAFLD, when compared to Neither FLD as a reference. Moreover, DM-MAFLD had a higher level of homeostasis model assessment of insulin resistance and high sensitive C-reactive protein, compared to the other groups of MAFLD. CONCLUSIONS: MAFLD was significantly associated with subclinical atherosclerosis in the general population. Additionally, DM-MAFLD could be a significant risk factor for cardiovascular disease through insulin resistance and low-grade inflammation and requires careful follow-up or appropriate intervention.

Conformational alterations in unidirectional ion transport of a light-driven chloride pump revealed using X-ray free electron lasers.

Light-driven chloride-pumping rhodopsins actively transport anions, including various halide ions, across cell membranes. Recent studies using time-resolved serial femtosecond crystallography (TR-SFX) have uncovered the structural changes and ion transfer mechanisms in light-driven cation-pumping rhodopsins. However, the mechanism by which the conformational changes pump an anion to achieve unidirectional ion transport, from the extracellular side to the cytoplasmic side, in anion-pumping rhodopsins remains enigmatic. We have collected TR-SFX data of Nonlabens marinus rhodopsin-3 (NM-R3), derived from a marine flavobacterium, at 10-µs and 1-ms time points after photoexcitation. Our structural analysis reveals the conformational alterations during ion transfer and after ion release. Movements of the retinal chromophore initially displace a conserved tryptophan to the cytoplasmic side of NM-R3, accompanied by a slight shift of the halide ion bound to the retinal. After ion release, the inward movements of helix C and helix G and the lateral displacements of the retinal block access to the extracellular side of NM-R3. Anomalous signal data have also been obtained from NM-R3 crystals containing iodide ions. The anomalous density maps provide insight into the halide binding site for ion transfer in NM-R3.

eIF2B-capturing viral protein NSs suppresses the integrated stress response.

Various stressors such as viral infection lead to the suppression of cap-dependent translation and the activation of the integrated stress response (ISR), since the stress-induced phosphorylated eukaryotic translation initiation factor 2 [eIF2(αP)] tightly binds to eIF2B to prevent it from exchanging guanine nucleotide molecules on its substrate, unphosphorylated eIF2. Sandfly fever Sicilian virus (SFSV) evades this cap-dependent translation suppression through the interaction between its nonstructural protein NSs and host eIF2B. However, its precise mechanism has remained unclear. Here, our cryo-electron microscopy (cryo-EM) analysis reveals that SFSV NSs binds to the α-subunit of eIF2B in a competitive manner with eIF2(αP). Together with SFSV NSs, eIF2B retains nucleotide exchange activity even in the presence of eIF2(αP), in line with the cryo-EM structures of the eIF2B•SFSV NSs•unphosphorylated eIF2 complex. A genome-wide ribosome profiling analysis clarified that SFSV NSs expressed in cultured human cells attenuates the ISR triggered by thapsigargin, an endoplasmic reticulum stress inducer. Furthermore, SFSV NSs introduced in rat hippocampal neurons and human induced-pluripotent stem (iPS) cell-derived motor neurons exhibits neuroprotective effects against the ISR-inducing stress. Since ISR inhibition is beneficial in various neurological disease models, SFSV NSs may be a promising therapeutic ISR inhibitor.

Unbiased, comprehensive analysis of Japanese health checkup data reveals a protective effect of light to moderate alcohol consumption on lung function.

The overall effect of lifestyle habits, such as alcohol consumption, on general health remains controversial and it is important to clarify how such habits affect aging-related health impairments. To discover novel impacts of lifestyle on general health, we employed a mathematical approach to perform a comprehensive, unbiased, cross-sectional analysis of data from 6036 subjects who participated in a Japanese health checkup. Notably, we found that moderate alcohol consumption was positively correlated with lung function, muscle mass, and strength. Health checkup data were collected periodically from the same subjects. These people were light to moderate drinkers who had high health awareness and were basically free of major underlying diseases. We next analyzed 5 years of data from 1765 of these subjects. We found that higher baseline alcohol consumption, as well as increased alcohol intake over 5 years attenuated time-related deterioration of forced vital capacity without affecting total lung volume. This effect was independent of smoking. Our study suggests a possible protective effect of moderate amounts of alcohol on lung function, due to increased muscle mass/strength and forced vital capacity.

New strategy for evaluating pancreatic tissue specimens from endoscopic ultrasound-guided fine needle aspiration and surgery.

BACKGROUND AND AIM: Preoperative histological evaluation of pancreatic neoplasms is important for guiding the resection strategy and preventing postoperative adverse events. However, conventional endoscopic methods have technical limitations that reduce the accuracy of the histopathological examination. Probe electrospray ionization mass spectrometry (PESI-MS) may be a useful technique for rapidly evaluating small specimens. METHODS: This single-center prospective study included patients with pancreatic neoplasms between October 2018 and December 2019. Pancreatic ductal adenocarcinoma (PDAC) specimens were obtained via endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and non-neoplastic tissue was obtained via surgery. Specimens were subjected to PESI-MS and the mass spectra were analyzed using partial least squares regression-discriminant analysis. RESULTS: The study included 40 patients with 20 nonneoplastic specimens and 19 PDAC specimens (1 case of neuroendocrine carcinoma was omitted). All nonneoplastic specimens were sufficient for PESI-MS analysis, although only 7 of 19 PDAC specimens were sufficient for PESI-MS analysis because of poor sample quality or insufficient quantity (<1 mg). Among the 27 analyzed cases, the mass spectra clearly differentiated between the PDAC and nonneoplastic specimens. CONCLUSIONS: This study revealed that PESI-MS could differentiate between PDAC and nonneoplastic specimens, even in cases where EUS-FNA produced very small specimens.

A significant association of non-obese non-alcoholic fatty liver disease with osteosarcopenic obesity in females 50 years and older.

BACKGROUND & AIMS: Osteosarcopenic obesity (OSO) encompassing obesity, sarcopenia and osteopenia, is due to redistribution or infiltration of fat into muscle and bone. This cross-sectional study evaluated the association between OSO and non-alcoholic fatty liver disease (NAFLD). METHODS: Obesity, sarcopenia and osteopenia was defined using the percentage of body fat mass, reduced muscle mass, and the percentage of young adult mean < 80%, measured by dual-energy x-ray absorptiometry, respectively. Non-obese and obese NAFLD was diagnosed by ultrasound and body mass index cut-off point (25 kg/m2). A total of 619 subjects ≥ 50 years who completed health checkups were divided into obesity group including OSO and sarcopenic obesity (SO) alone phenotype, and non-obesity group that did not belong to any phenotype, including standard (St). RESULTS: Overall osteopenia and OSO were detected in only 10% and 1% in males, compared with 45% and 9% in females, respectively. Multivariate analysis for females demonstrated a significant association of OSO with non-obese NAFLD (odds ratio = 3.737, 95% confidence interval = 1.365-10.233, P = 0.010), while the association between SO alone and non-obese NAFLD was equivocal. The OSO phenotype had a significantly higher proportion of slower walking speed and weaker grip strength, compared to the St phenotype. The proportion of OSO increased with age in contrast to constant prevalence of non-obese NAFLD. CONCLUSION: Non-obese NAFLD had a significant association with OSO in females, independent of plausible confounders. These results suggest that non-obese NAFLD might be an independent risk factor for OSO.

ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B.

The small molecule ISRIB antagonizes the activation of the integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). ISRIB and eIF2(αP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange factor for eIF2. We have found that ISRIB-mediated acceleration of eIF2B's nucleotide exchange activity in vitro is observed preferentially in the presence of eIF2(αP) and is attenuated by mutations that desensitize eIF2B to the inhibitory effect of eIF2(αP). ISRIB's efficacy as an ISR inhibitor in cells also depends on presence of eIF2(αP). Cryoelectron microscopy (cryo-EM) showed that engagement of both eIF2B regulatory sites by two eIF2(αP) molecules remodels both the ISRIB-binding pocket and the pockets that would engage eIF2α during active nucleotide exchange, thereby discouraging both binding events. In vitro, eIF2(αP) and ISRIB reciprocally opposed each other's binding to eIF2B. These findings point to antagonistic allostery in ISRIB action on eIF2B, culminating in inhibition of the ISR.

Moderate alcohol consumption is not associated with subclinical cardiovascular damage but with hepatic fibrosis in non-alcoholic fatty liver disease.

BACKGROUND: Moderate alcohol consumption is believed to be associated with reduced mortality from cardiovascular disease (CVD) in the general population. This cross-sectional study aimed to comprehensively examine the association between alcohol consumption and subclinical cardiovascular damage or hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD). METHODS: Subjects with NAFLD without a history of heart disease were extracted from 977 consecutive examinees who completed health checkups and optional cardiovascular examinations. Subclinical cardiovascular damage was assessed by coronary artery calcification (CAC), carotid artery ultrasound, and brachial-ankle pulse wave velocity (ba-PWV). CAC scores were classified into three grades (0, ≤100, and >100) by Agatston's method. Alcohol consumption was divided into three groups [Non-drinking (G0); Light (G1), 0.1-6.9 drinks/week; Moderate (G2), 7-20.9 drinks/week for men and 7-13.9 drinks/week for women]. Noninvasive markers (FIB-4, Fibrosis-4; NFS, NAFLD fibrosis score) were calculated for assessment of hepatic fibrosis and classified into low and intermediate-high grade. RESULTS: The overall mean age was 60.2 years and males were 200 (74.6%) among 268 subjects with NAFLD. Number (%) of G0, G1, and G2 were 102 (38.1%), 103 (38.4%), and 63 (23.5%). Binary logistic regression analysis showed no significant difference between G0 and G1, or G0 and G2 in any of the above subclinical cardiovascular damages (CAC score >0, or CAC score >100, carotid plaque +, intima-media thickness ≥1.1 mm, and ba-PWV >1400 cm/s). However, only G2 had a significant association with intermediate-high grade of FIB-4 or NFS [odds ratio (95% confidence intervals), p value: 1.871 (1.209-2.893), p = 0.005; 2.910 (1.715-4.939), p = 0.000], compared to G0. CONCLUSIONS: Non-heavy drinking might not reduce the risk of CVD in NAFLD subjects. On the contrary, even moderate drinking could promote hepatic fibrosis. Thus, NAFLD drinkers should not be recommended for even a moderate amount of alcohol.

A significant association of non-obese non-alcoholic fatty liver disease with sarcopenic obesity.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is significantly related to sarcopenia as well as obesity and its associated comorbidities. This cross-sectional study aims to examine the association between four body composition phenotypes (standard, obesity alone, sarcopenia alone, sarcopenic obesity) and non-obese NAFLD, or obese NAFLD. METHODS: Reduced muscle mass and high percentage of body fat mass was measured by dual-energy x-ray absorptiometry, and body composition phenotypes were determined, according to Asian criteria for sarcopenia. Based on body mass index (BMI) cut-off point (25 kg/m2) and hepatic steatosis on ultrasound, 748 subjects who underwent a health checkup were enrolled and divided into three groups: non-obese NAFLD, obese NAFLD, and no steatosis. RESULTS: Of 563 subjects (64.1 ± 13.0 years) without secondary causes for steatosis, the overall prevalence of non-obese NAFLD and obese NAFLD were 17% and 16%, respectively. The former prevalence remained relatively constant at around 20% from the 50s to 80's, while the proportion of sarcopenic obesity in all subjects increased gradually with age, reaching 18% in the 80's. Multivariate analysis demonstrated a significant association between sarcopenic obesity and non-obese NAFLD after adjusting for confounders (odds ratio = 2.367, 95% confidence interval = 1.317-4.254, P = 0.004). On the other hand, no significant association was found between obesity alone and obese NAFLD, when BMI and visceral adipose tissue were added as confounders, although 91% of obese NAFLD was included in obesity alone phenotype. CONCLUSION: Non-obese NAFLD had a significant association with sarcopenic obesity, independent of metabolic confounders. Early treatment intervention for non-obese NAFLD could suppress the deterioration of sarcopenic obesity because non-obese NAFLD might be a risk factor for sarcopenic obesity.

Negative effect of fatty liver on visualization of pancreatic cystic lesions at screening transabdominal ultrasonography.

RATIONALE, AIMS, AND OBJECTIVES: The aim of this observational study is to identify factors by which some pancreatic cystic lesions (PCLs) were undetectable at transabdominal ultrasonography (TAUS), using magnetic resonance imaging (MRI) as reference standard. METHODS: The database for 781 consecutive subjects who underwent a health checkup including fat computed tomography and upper abdominal MRI as option was searched. The presence of fatty liver and fatty pancreas was diagnosed by TAUS, and atrophic pancreas was determined by reevaluating the image of the pancreas in the chest computed tomography for screening. Subjects with PCL detected and those undetected at TAUS were statistically compared in clinical characteristics. RESULTS: The prevalence of PCL detected at MRI was 17.8% in the general population. Multivariate logistic regression analysis showed that fatty liver, body mass index, and the size of PCL were significantly associated with the factors influencing the visualization of PCL at TAUS (odds ratio [OR]: 0.337, 95% confidence interval [CI]: 0.154-0.734, P = 0.006; OR: 0.852, 95% CI: 0.737-0.985, P = 0.030; OR:1.120, 95% CI: 1.045-1.200, P = .001). Thirty-six PCLs (64.3%) in a total of 56 PCLs were undermeasured by TAUS. Additionally, nine (56%) out of 16 PCLs (≥ 15 mm) were undermeasured by 5 mm or more by TAUS, although a significantly higher detection rate was observed for PCLs (≥ 15 mm) in comparison with that for PCLs (< 15 mm) (80% vs 33.6%, P = .000). CONCLUSIONS: It should be noted that coexisting fatty liver may lower the detection of PCL, and its size may be underestimated by TAUS.

Glial pathology in a novel spontaneous mutant mouse of the Eif2b5 gene: a vanishing white matter disease model.

Vanishing white matter disease (VWM) is an autosomal recessive neurological disorder caused by mutation(s) in any subunit of eukaryotic translation initiation factor 2B (eIF2B), an activator of translation initiation factor eIF2. VWM occurs with mutation of the genes encoding eIF2B subunits (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5). However, little is known regarding the underlying pathogenetic mechanisms or how to treat patients with VWM. Here we describe the identification and detailed analysis of a new spontaneous mutant mouse harboring a point mutation in the Eif2b5 gene (p.Ile98Met). Homozygous Eif2b5I98M mutant mice exhibited a small body, abnormal gait, male and female infertility, epileptic seizures, and a shortened lifespan. Biochemical analyses indicated that the mutant eIF2B protein with the Eif2b5I98M mutation decreased guanine nucleotide exchange activity on eIF2, and the level of the endoplasmic reticulum stress marker activating transcription factor 4 was elevated in the 1-month-old Eif2b5I98M brain. Histological analyses indicated up-regulated glial fibrillary acidic protein immunoreactivity in the astrocytes of the Eif2b5I98M forebrain and translocation of Bergmann glia in the Eif2b5I98M cerebellum, as well as increased mRNA expression of an endoplasmic reticulum stress marker, C/EBP homologous protein. Disruption of myelin and clustering of oligodendrocyte progenitor cells were also indicated in the white matter of the Eif2b5I98M spinal cord at 8 months old. Our data show that Eif2b5I98M mutants are a good model for understanding VWM pathogenesis and therapy development. Cover Image for this issue: doi: 10.1111/jnc.14751.

Pancreatic fat content may increase the risk of imaging progression in low-risk branch duct intraductal papillary mucinous neoplasm.

OBJECTIVE: To identify risk factors of imaging progression (increase in cyst size or main pancreatic duct size, or a new mural nodule) in low-risk branch duct intraductal papillary mucinous neoplasm (BD-IPMN), including obesity-related factors such as pancreatic fat content. METHODS: Our hospital databases were searched for patients who had completed health checkup, including upper abdominal magnetic resonance imaging (MRI) over 48 months (August 2012 to July 2016). Individuals with BD-IPMN without worrisome features and high-risk stigmata who underwent surveillance with at least one follow-up MRI, irrespective of the follow-up period, were included. Pancreatic computed tomography attenuation indexes were defined as the difference between the pancreas and spleen attenuation (P - S) and the pancreas to spleen attenuation ratio (P/S). RESULTS: Among 75 patients diagnosed as having low-risk BD-IPMN, during a median follow-up of 36 months, 11 (15%) had imaging progression in cyst size, including two with worrisome features. A multivariate logistic analysis showed that the initial cyst size and both indexes (P - S, or P/S) were significantly associated with imaging progression in IPMN, respectively (Model 1: odds ratio [OR] 1.188, 95% confidence interval [CI] 1.060-1.331, P = 0.003; OR 0.871, 95% CI 0.776-0.977, P = 0.019; Model 2: OR 1.186, 95% CI 1.064-1.322, P = 0.002; OR 0.002, 95% CI 0.000-0.970, P = 0.049). CONCLUSIONS: Pancreatic fat content and initial cyst size were significantly associated with imaging progression in low-risk BD-IPMN. Revisions of international consensus Fukuoka guidelines might be customized based on initial cyst size and pancreatic fat content.

Structural basis for eIF2B inhibition in integrated stress response.

A core event in the integrated stress response, an adaptive pathway common to all eukaryotic cells in response to various stress stimuli, is the phosphorylation of eukaryotic translation initiation factor 2 (eIF2). Normally, unphosphorylated eIF2 transfers the methionylated initiator tRNA to the ribosome in a guanosine 5'-triphosphate-dependent manner. By contrast, phosphorylated eIF2 inhibits its specific guanine nucleotide exchange factor, eIF2B. To elucidate how the eIF2 phosphorylation status regulates the eIF2B activity, we determined cryo-electron microscopic and crystallographic structures of eIF2B in complex with unphosphorylated or phosphorylated eIF2. The unphosphorylated and phosphorylated forms of eIF2 bind to eIF2B in completely different manners: the nucleotide exchange-active and -inactive modes, respectively. These structures explain how phosphorylated eIF2 dominantly inhibits the nucleotide exchange activity of eIF2B.