Transient Hysteresis in CDK4/6 Activity Underlies Passage of the Restriction Point in G1.

Cells escape the need for mitogens at a restriction point several hours before entering S phase. The restriction point has been proposed to result from CDK4/6 initiating partial Rb phosphorylation to trigger a bistable switch whereby cyclin E-CDK2 and Rb mutually reinforce each other to induce Rb hyperphosphorylation. Here, using single-cell analysis, we unexpectedly found that cyclin E/A-CDK activity can only maintain Rb hyperphosphorylation starting at the onset of S phase and that CDK4/6 activity, but not cyclin E/A-CDK activity, is required to hyperphosphorylate Rb throughout G1 phase. Mitogen removal in G1 results in a gradual loss of CDK4/6 activity with a high likelihood of cells sustaining Rb hyperphosphorylation until S phase, at which point cyclin E/A-CDK activity takes over. Thus, it is short-term memory, or transient hysteresis, in CDK4/6 activity following mitogen removal that sustains Rb hyperphosphorylation, demonstrating a probabilistic rather than an irreversible molecular mechanism underlying the restriction point.

Ninjurin 2 Modulates Tumorigenesis, Inflammation, and Metabolism via Pyroptosis.

The nerve injury-induced protein 2 (NINJ2) belongs to a family of homophilic adhesion molecules and was initially found to be involved in nerve regeneration. However, the role of NINJ2 in other cellular processes is not well studied. The Ninj2-deficient mice generated in the current study had a short lifespan and were prone to spontaneous tumors, systemic inflammation, and metabolic defects. Comprehensive carbohydrate and lipid metabolic analyses were performed to better understand the metabolic traits that contribute to these phenotypes. Carbohydrate metabolic analyses showed that NINJ2 deficiency led to defects in monosaccharide metabolism along with accumulation of multiple disaccharides and sugar alcohols. Lipidomic analyses showed that Ninj2 deficiency altered patterns of several lipids, including triglycerides, phospholipids, and ceramides. To identify a cellular process that associated with these metabolic defects, the role of NINJ2 in pyroptosis, a programmed cell death that links cancer, inflammation, and metabolic disorders, was examined. Loss of NINJ2 promoted pyroptosis by activating the NOD-like receptor protein 3 (NLRP3) inflammasome. Taken together, these data reveal a critical role of NINJ2 in tumorigenesis, inflammatory response, and metabolism via pyroptosis.

A multi-layered network model identifies Akt1 as a common modulator of neurodegeneration.

The accumulation of misfolded and aggregated proteins is a hallmark of neurodegenerative proteinopathies. Although multiple genetic loci have been associated with specific neurodegenerative diseases (NDs), molecular mechanisms that may have a broader relevance for most or all proteinopathies remain poorly resolved. In this study, we developed a multi-layered network expansion (MLnet) model to predict protein modifiers that are common to a group of diseases and, therefore, may have broader pathophysiological relevance for that group. When applied to the four NDs Alzheimer's disease (AD), Huntington's disease, and spinocerebellar ataxia types 1 and 3, we predicted multiple members of the insulin pathway, including PDK1, Akt1, InR, and sgg (GSK-3ß), as common modifiers. We validated these modifiers with the help of four Drosophila ND models. Further evaluation of Akt1 in human cell-based ND models revealed that activation of Akt1 signaling by the small molecule SC79 increased cell viability in all models. Moreover, treatment of AD model mice with SC79 enhanced their long-term memory and ameliorated dysregulated anxiety levels, which are commonly affected in AD patients. These findings validate MLnet as a valuable tool to uncover molecular pathways and proteins involved in the pathophysiology of entire disease groups and identify potential therapeutic targets that have relevance across disease boundaries. MLnet can be used for any group of diseases and is available as a web tool at http://ssbio.cau.ac.kr/software/mlnet.

Etiological distribution of isolated oculomotor nerve palsy: analysis of 633 patients and literature review.

BACKGROUND AND PURPOSE: The etiological distribution of oculomotor nerve palsy has varied amongst the studies. This study aimed to define the clinical features and underlying etiologies of isolated oculomotor nerve palsy by recruiting patients from all departments in a referral-based university hospital. METHODS: The medical records of 672 patients who had a confirmed diagnosis of isolated oculomotor nerve palsy at all departments of Seoul National University Bundang Hospital, Seongnam, South Korea, from 2003 to 2020 were reviewed. A proportion of the etiology of isolated oculomotor nerve palsy was also compared with that of patients pooled from the previous studies that were searched on PubMed in May 2022. RESULTS: The most common etiology was microvascular (n = 168, 26.5%), followed by vascular anomalies (n = 110, 17.4%), neoplastic (n = 86, 13.6%), inflammatory (n = 79, 12.5%), idiopathic (n = 60, 9.5%) and traumatic (n = 53, 8.4%). Neurologists were mainly involved in the management of microvascular and inflammatory oculomotor nerve palsies whilst ophthalmologists mainly participated in the care of idiopathic, neoplastic and traumatic palsies. Neurosurgeons mostly took care of oculomotor nerve palsy due to vascular anomalies. CONCLUSIONS: The proportion of etiologies of isolated oculomotor nerve palsy may differ according to the specialties involved in the management. The results of previous studies on the etiological distribution of isolated oculomotor nerve palsy should be interpreted with this consideration.

A rare case of secondary cutaneous lymphoplasmacytic lymphoma clinically presenting as acquired cutis laxa.

Lymphoplasmacytic lymphoma (LPL) is a rare variant of non-Hodgkin lymphoma, accounting for <1% of cases. Skin involvement in LPL is quite rare-accounting for approximately 5% of extramedullary disease-and includes a variety of clinical morphologies, such as erythematous-to-violaceous plaques, violaceous nodules or tumors, and ulceration at various anatomical sites. Herein, we report the case of a 45-year-old Korean woman who presented with generalized erythematous indurated plaques and pendulous skin growths, which were asymptomatic, with marked diffuse infiltration of lymphocytes and plasma cells in the dermis. Immunohistochemical studies revealed that the lymphoid cells expressed CD3, CD79a, and cytoplasmic IgG, but lacked CD10 and IgM. Moreover, kappa light chain restriction and monoclonal immunoglobulin heavy chain gene rearrangement were observed. Upon further workup, lymphoma involvement was reported in multiple lymph nodes, including those in the cervical and axillary regions. This case shows a unique form of cutaneous LPL clinically presenting as acquired cutis laxa, emphasizing the dermatologists' need to be vigilant for variant forms of this disease.

Fasudil alleviates the vascular endothelial dysfunction and several phenotypes of Fabry disease.

Fabry disease (FD), a lysosomal storage disorder, is caused by defective α-galactosidase (GLA) activity, which results in the accumulation of globotriaosylceramide (Gb3) in endothelial cells and leads to life-threatening complications such as left ventricular hypertrophy (LVH), renal failure, and stroke. Enzyme replacement therapy (ERT) results in Gb3 clearance; however, because of a short half-life in the body and the high immunogenicity of FD patients, ERT has a limited therapeutic effect, particularly in patients with late-onset disease or progressive complications. Because vascular endothelial cells (VECs) derived from FD-induced pluripotent stem cells display increased thrombospondin-1 (TSP1) expression and enhanced SMAD2 signaling, we screened for chemical compounds that could downregulate TSP1 and SMAD2 signaling. Fasudil reduced the levels of p-SMAD2 and TSP1 in FD-VECs and increased the expression of angiogenic factors. Furthermore, fasudil downregulated the endothelial-to-mesenchymal transition (EndMT) and mitochondrial function of FD-VECs. Oral administration of fasudil to FD mice alleviated several FD phenotypes, including LVH, renal fibrosis, anhidrosis, and heat insensitivity. Our findings demonstrate that fasudil is a novel candidate for FD therapy.

Risk of central nervous system demyelinating attack or optic neuritis recurrence after pediatric optic neuritis in Korea.

PURPOSE: To investigate the rate of development of symptomatic central nervous system (CNS) demyelinating attacks or recurrent optic neuritis (ON) after the first episode of ON and its risk factors for Korean pediatric patients. METHODS: This multicenter retrospective cohort study included the patients under 18 years of age (n=132) diagnosed with ON without previous or simultaneous CNS demyelinating diseases. We obtained the clinical data including the results of neuro-ophthalmological examinations, magnetic resonance images (MRIs), antibody assays, and laboratory tests. We investigated the chronological course of demyelinating disease with respect to the occurrence of neurological symptoms and/or signs, and calculated the 5-year cumulative probability of CNS demyelinating disease or ON recurrence.  RESULTS: During the follow-up period (63.1±46.7 months), 18 patients had experienced other CNS demyelinating attacks, and the 5-year cumulative probability was 14.0±3.6%. Involvement of the extraorbital optic nerve or optic chiasm and asymptomatic lesions on the brain or spinal MRI at initial presentation were significant predictors for CNS demyelinating attack after the first ON. The 5-year cumulative probability of CNS demyelinating attack was 44.4 ± 24.8% in the AQP4-IgG group, 26.2±11.4% in the MOG-IgG group, and 8.7±5.9% in the double-negative group (P=0.416). Thirty-two patients had experienced a recurrence of ON, and the 5-year cumulative probability was 24.6±4.0%. In the AQP4-IgG group, the 5-year cumulative probability was 83.3±15.2%, which was significantly higher than in the other groups (P<0.001). CONCLUSIONS: A careful and multidisciplinary approach including brain/spinal imaging and antibody assay can help predict further demyelinating attacks in pediatric ON patients.

Toxicology and safety study of L-tryptophan and its impurities for use in broiler feed.

L-tryptophan has been utilized as a feed additive in animal nutrition to improve growth performance, as well as a dietary supplement to alleviate various emotional symptoms in humans. Despite its benefits, concerns regarding its safety arose following the outbreak of eosinophilia-myalgia syndrome (EMS) among individuals who consumed L-tryptophan. The causative material of EMS was determined to be not L-tryptophan itself, but rather L-tryptophan impurities resulting from a specific manufacturing process. To investigate the effect of L-tryptophan and its impurities on humans who consume meat products derived from animals that were fed L-tryptophan and its impurities, an animal study involving broiler chickens was conducted. The animals in test groups were fed diet containing 0.065%-0.073% of L-tryptophan for 27 days. This study aimed to observe the occurrence of toxicological or EMS-related symptoms and analyze the residues of L-tryptophan impurities in meat products. The results indicated that there was no evidence of adverse effects associated with the test substance in the investigated parameters. Furthermore, most of the consumed EMS-causing L-tryptophan impurities did not remain in the meat of broiler chickens. Thus, this study demonstrated the safety of L-tryptophan and some of its impurities as a feed additive.

Toxicology and safety study of L-tryptophan and its impurities for use in swine.

L-tryptophan, an essential amino acid for physiological processes, metabolism, development, and growth of organisms, is widely utilized in animal nutrition and human health as a feed additive and nutritional supplement, respectively. Despite its known benefits, safety concerns have arisen due to an eosinophilia-myalgia syndrome (EMS) outbreak linked to L-tryptophan consumed by humans. Extensive research has established that the EMS outbreak was caused by an L-tryptophan product that contained certain impurities. Therefore, safety validations are imperative to endorse the use of L-tryptophan as a supplement or a feed additive. This study was conducted in tertiary hybrid [(Landrace × Yorkshire) × Duroc] pigs to assess general toxicity and potential risks for EMS-related symptoms associated with L-tryptophan used as a feed additive. Our investigation elucidated the relationship between L-tryptophan and EMS in swine. No mortalities or clinical signs were observed in any animals during the administration period, and the test substance did not induce toxic effects. Hematological analysis and histopathological examination revealed no changes in EMS-related parameters, such as eosinophil counts, lung lesions, skin lesions, or muscle atrophy. Furthermore, no test substance-related changes occurred in other general toxicological parameters. Through analyzing the tissues and organs of swine, most of the L-tryptophan impurities that may cause EMS were not retained. Based on these findings, we concluded that incorporating L-tryptophan and its impurities into the diet does not induce EMS in swine. Consequently, L-tryptophan may be used as a feed additive throughout all growth stages of swine without safety concerns.

Cytosine Deaminase-Overexpressing hTERT-Immortalized Human Adipose Stem Cells Enhance the Inhibitory Effects of Fluorocytosine on Tumor Growth in Castration Resistant Prostate Cancer.

A promising de novo approach for the treatment of Castration-resistant prostate cancer (CRPC) exploits cell-mediated enzyme prodrug therapy comprising cytosine deaminase (CD) and fluorouracil (5-FC). The aim of this study was to determine the potential of bacterial CD-overexpressing hTERT-immortalized human adipose stem cells (hTERT-ADSC.CD) to suppress CRPC. A lentiviral vector encoding a bacterial CD gene was used to transfect and to generate the hTERT-ADSC.CD line. The ability of the cells to migrate selectively towards malignant cells was investigated in vitro. PC3 and hTERT-ADSC.CD cells were co-cultured. hTERT-ADSC.CD and 1 × 106 PC3 cells were administered to nude mice via intracardiac and subcutaneous injections, respectively, and 5-FC was given for 14 days. hTERT-ADSC.CD were successfully engineered. Enhanced in vitro hTERT-ADSC.CD cytotoxicity and suicide effect were evident following administration of 5 µM 5-FC. hTERT-ADSC.CD, together with 5-FC, augmented the numbers of PC3 cells undergoing apoptosis. In comparison to controls administered hTERT-ADSC.CD monotherapy, hTERT-ADSC.CD in combination with 5-FC demonstrated a greater suppressive effect on tumor. In CPRC-bearing mice, tumor suppression was enhanced by the combination of CD-overexpressing ADSC and the prodrug 5-FC. Stem cells exhibiting CD gene expression are a potential novel approach to treatment for CRPC.

Optimization of cultivar, germination time and extraction for radish sprout extract with high sulforaphene content.

BACKGROUND: Cruciferous vegetable sprout has been highlighted as a promising functional material rich in bioactive compounds called isothiocyanates (ITCs) and it can be grown in very short periods in controlled indoor farms. However, because ITCs content depends on multiple factors such as cultivar, germination time and myrosinase activity, those variables need to be controlled during germination or extraction to produce functional materials enriched in ITCs. Sulforaphene (SFEN), an ITC found primarily in radishes (Raphanus sativus L.), exerts beneficial effects on obesity. However, the optimal germination and extraction conditions for radish sprout (RSP) to increase SFEN content remain unascertained, and the extract's anti-obesity effect has yet to be evaluated. RESULTS: The present study found that the SFEN content was highest in purple radish sprout (PRSP) among the six cultivars investigated. Optimal SFEN content occurred after 2 days of PRSP germination (2 days PRSP). To maximize the dry matter yield, total ITCs and SFEN contents in RSP extract, we found the optimal conditions for extracting PRSP [27.5 °C, 60 min, 1:75.52 solute/solvent (w/v), no ascorbic acid] using response surface methodology. Consistent with high SFEN content, 2 days PRSP extract significantly outperformed 3 days or 4 days PRSP extract in inhibiting lipid accumulation in 3T3-L1 cells. Moreover, 2 days PRSP extract suppressed adipogenesis and lipogenesis-related protein expression. CONCLUSION: Regarding the cultivar, germination time and extraction conditions, optimally produced PRSP extract contains high SFEN content and exerts anti-obesity effects. Thus, we suggest PRSP extract as a potent functional material for obesity prevention. © 2024 Society of Chemical Industry.

What is the impact of one's chronic illness on his or her spouse's future chronic illness: a community-based prospective cohort study.

BACKGROUND: Integrating a joint approach to chronic disease management within the context of a couple has immense potential as a valuable strategy for both prevention and treatment. Although spousal concordance has been reported in specific chronic illnesses, the impact they cumulatively exert on a spouse in a longitudinal setting has not been investigated. We aimed to determine whether one's cumulative illness burden has a longitudinal impact on that of their spouse. METHODS: Data was acquired from a community-based prospective cohort that included Koreans aged 60 years and over, randomly sampled from 13 districts nationwide. Data from the baseline assessment (conducted from November 2010 to October 2012) up to the 8-year follow-up assessment was analyzed from October 2021 to November 2022. At the last assessment, partners of the index participants were invited, and we included 814 couples in the analysis after excluding 51 with incomplete variables. Chronic illness burden of the participants was measured by the Cumulative Illness Rating Scale (CIRS). Multivariable linear regression and causal mediation analysis were used to examine the longitudinal effects of index chronic illness burden at baseline and its change during follow-up on future index and spouse CIRS scores. RESULTS: Index participants were divided based on baseline CIRS scores (CIRS < 6 points, n = 555, mean [SD] age 66.3 [4.79] years, 43% women; CIRS ≥ 6 points, n = 259, mean [SD] age 67.7 [4.76] years, 36% women). The baseline index CIRS scores and change in index CIRS scores during follow-up were associated with the spouse CIRS scores (ß = 0.154 [SE: 0.039], p < 0.001 for baseline index CIRS; ß = 0.126 [SE: 0.041], p = 0.002 for change in index CIRS) at the 8-year follow-up assessment. Subgroup analysis found similar results only in the high CIRS group. The baseline index CIRS scores and change in index CIRS scores during follow-up had both direct and indirect effects on the spouse CIRS scores at the 8-year follow-up assessment. CONCLUSIONS: The severity and course of one's chronic illnesses had a significant effect on their spouse's future chronic illness particularly when it was severe. Management strategies for chronic diseases that are centered on couples may be more effective.

Inhalable Nitric Oxide Delivery Systems for Pulmonary Arterial Hypertension Treatment.

Pulmonary arterial hypertension (PAH) is a severe medical condition characterized by elevated blood pressure in the pulmonary arteries. Nitric oxide (NO) is a gaseous signaling molecule with potent vasodilator effects; however, inhaled NO is limited in clinical practice because of the need for tracheal intubation and the toxicity of high NO concentrations. In this study, inhalable NO-releasing microspheres (NO inhalers) are fabricated to deliver nanomolar NO through a nebulizer. Two NO inhalers with distinct porous structures are prepared depending on the molecular weights of NO donors. It is confirmed that pore formation can be controlled by regulating the migration of water molecules from the external aqueous phase to the internal aqueous phase. Notably, open porous NO inhalers (OPNIs) can deliver NO deep into the lungs through a nebulizer. Furthermore, OPNIs exhibit vasodilatory and anti-inflammatory effects via sustained NO release. In conclusion, the findings suggest that OPNIs with highly porous structures have the potential to serve as tools for PAH treatment.

The impact of the COVID-19 pandemic on depression in community-dwelling older adults: a prospective cohort study.

BACKGROUND: There are growing concerns about the impact of the COVID-19 pandemic on the mental health of older adults. We examined the effect of the pandemic on the risk of depression in older adults. METHODS: We analyzed data from the prospective cohort study of Korean older adults, which has been followed every 2 years. Among the 2308 participants who completed both the third and the fourth follow-up assessments, 58.4% completed their fourth follow-up before the outbreak of COVID-19 and the rest completed it during the pandemic. We conducted face-to-face diagnostic interviews using Mini International Neuropsychiatric Interview and used Geriatric Depression Scale. We performed generalized estimating equations and logistic regression analyses. RESULTS: The COVID-19 pandemic was associated with increased depressive symptoms in older adults [b (standard error) = 0.42 (0.20), p = 0.040] and a doubling of the risk for incident depressive disorder even in euthymic older adults without a history of depression (odds ratio = 2.44, 95% confidence interval 1.18-5.02, p = 0.016). Less social activities, which was associated with the risk of depressive disorder before the pandemic, was not associated with the risk of depressive disorder during the pandemic. However, less family gatherings, which was not associated with the risk of depressive disorder before the pandemic, was associated with the doubled risk of depressive disorder during the pandemic. CONCLUSIONS: The COVID-19 pandemic significantly influences the risk of late-life depression in the community. Older adults with a lack of family gatherings may be particularly vulnerable.

Simultaneous determination of L-tryptophan impurities in meat products.

L-tryptophan has been used as a feed additive for swine and poultry and as a nutrient supplement for humans. However, some impurities in L-tryptophan have been reported as causative components of eosinophilia-myalgia syndrome. Therefore, from a safety perspective, it is important to analyze meat samples for these impurities. This study aims to develop an analytical method for the simultaneous detection of L-tryptophan impurities in meat products using LC-MS/MS. Among the various impurities, detection methods for (S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanoic acid (5-hydroxytryptophan) (HTP), 1-methyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid (MTCA), 3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo-[2,3-b]-indole-2-carboxylic acid (PIC), and 1,1'-ethylidenebistryptophan (EBT) and 2-(3-indoylmethyl)-L-tryptophan (IMT) were developed. The developed method allowed simultaneous determination of these four impurities in 5 min. No interferences from the matrix were observed, and the method showed good sensitivity to each analyte. The method detection limit and limit of quantification in meat matrices were below 11.2 and 35.7 µg/kg, respectively.

Etiologic distribution of isolated abducens nerve palsy: Analysis of 807 patients and literature review.

BACKGROUND AND PURPOSE: The etiologies of abducens nerve palsy have shown a large variability among studies. This study aimed to establish the clinical features and underlying etiologies of isolated abducens nerve palsy by recruiting patients from all departments in a referral-based university hospital. METHODS: We reviewed the medical records of 807 patients with a confirmed diagnosis of isolated abducens nerve palsy at all departments of Seoul National University Bundang Hospital, Seongnam, Republic of Korea, from 2003 to 2020. We also compared the proportion of etiology with that of the patients pooled from the previous studies. RESULTS: The most common etiology was microvascular (n = 296, 36.7%), followed by idiopathic (n = 143, 17.7%), neoplastic (n = 115, 14.3%), vascular anomalies (n = 82, 10.2%), inflammatory (n = 76, 9.4%), and traumatic (n = 35, 4.3%). Patients were mostly managed by ophthalmologists (n = 576, 71.4%), followed by neurologists (n = 479, 59.4%), emergency physicians (n = 278, 34.4%), neurosurgeons (n = 191, 23.7%), and others (n = 72, 8.9%). The proportion of etiology significantly differed according to the age and sex of the patients and the specialties involved in the management (p < 0.001). Compared to the pooled data from the previous reports, the current study showed a higher prevalence of microvascular cause but a lower occurrence of traumatic and neoplastic causes. CONCLUSIONS: The results of previous studies on etiologic distribution of isolated abducens nerve palsy should be interpreted with consideration of the demographic features of patients recruited and the specialties involved.

Competing memories of mitogen and p53 signalling control cell-cycle entry.

Regulation of cell proliferation is necessary for immune responses, tissue repair, and upkeep of organ function to maintain human health. When proliferating cells complete mitosis, a fraction of newly born daughter cells immediately enter the next cell cycle, while the remaining cells in the same population exit to a transient or persistent quiescent state. Whether this choice between two cell-cycle pathways is due to natural variability in mitogen signalling or other underlying causes is unknown. Here we show that human cells make this fundamental cell-cycle entry or exit decision based on competing memories of variable mitogen and stress signals. Rather than erasing their signalling history at cell-cycle checkpoints before mitosis, mother cells transmit DNA damage-induced p53 protein and mitogen-induced cyclin D1 (CCND1) mRNA to newly born daughter cells. After mitosis, the transferred CCND1 mRNA and p53 protein induce variable expression of cyclin D1 and the CDK inhibitor p21 that almost exclusively determines cell-cycle commitment in daughter cells. We find that stoichiometric inhibition of cyclin D1-CDK4 activity by p21 controls the retinoblastoma (Rb) and E2F transcription program in an ultrasensitive manner. Thus, daughter cells control the proliferation-quiescence decision by converting the memories of variable mitogen and stress signals into a competition between cyclin D1 and p21 expression. We propose a cell-cycle control principle based on natural variation, memory and competition that maximizes the health of growing cell populations.

Clinicoprognostic Study of Hydroa Vacciniforme-like Lymphoproliferative Diseases: A Systematic Review.

BACKGROUND: Limited clinicopathological and prognostic data are available on hydroa vacciniforme (HV)-like lymphoproliferative diseases (HVLPD). METHODS: This systematic review searched HVLPD reports in Medline via PubMed, Embase, Cochrane, and CINAHL databases in October 2020. RESULTS: A total of 393 patients (65 classic HV, 328 severe HV/HV-like T-cell lymphoma [HVLL]) were analyzed. Among severe HV/HVLL cases, 56.0% were Asians, whereas 3.1% were Caucasians. Facial edema, hypersensitivity to mosquito bites, the onset of skin lesion, and percentage of severe HV/HVLL differed significantly by race. Progression to systemic lymphoma was confirmed in 9.4% of HVLPD patients. Death occurred in 39.7% patients with severe HV/HVLL. Facial edema was the only risk factor associated with progression and overall survival. Mortality risk was higher in Latin Americans than in Asians and Caucasians. CD4/CD8 double-negativity was significantly associated with the worst prognosis and increased mortality. CONCLUSION: HVLPD is a heterogeneous entity with variable clinicopathological features associated with genetic predispositions.

Classification of Alzheimer's Progression Using fMRI Data.

In the last three decades, the development of functional magnetic resonance imaging (fMRI) has significantly contributed to the understanding of the brain, functional brain mapping, and resting-state brain networks. Given the recent successes of deep learning in various fields, we propose a 3D-CNN-LSTM classification model to diagnose health conditions with the following classes: condition normal (CN), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and Alzheimer's disease (AD). The proposed method employs spatial and temporal feature extractors, wherein the former utilizes a U-Net architecture to extract spatial features, and the latter utilizes long short-term memory (LSTM) to extract temporal features. Prior to feature extraction, we performed four-step pre-processing to remove noise from the fMRI data. In the comparative experiments, we trained each of the three models by adjusting the time dimension. The network exhibited an average accuracy of 96.4% when using five-fold cross-validation. These results show that the proposed method has high potential for identifying the progression of Alzheimer's by analyzing 4D fMRI data.

A risk-based approach to cumulative effects assessment for large marine ecosystems to support transboundary marine spatial planning: A case study of the yellow sea.

Cumulative effects assessment (CEA) should be conducted at ecologically meaningful scales such as large marine ecosystems to halt further ocean degradation caused by anthropogenic pressures and facilitate ecosystem-based management such as transboundary marine spatial planning (MSP). However, few studies exist at large marine ecosystems scale, especially in the West Pacific seas, where countries have different MSP processes yet transboundary cooperation is paramount. Thus, a step-wise CEA would be informative to help bordering countries set a common goal. Building on the risk-based CEA framework, we decomposed CEA into risk identification and spatially-explicit risk analysis and applied it to the Yellow Sea Large Marine Ecosystem (YSLME), aiming to understand the most influential cause-effect pathways and risk distribution pattern. The results showed that (1) seven human activities including port, mariculture, fishing, industry and urban development, shipping, energy, and coastal defence, and three pressures including physical loss of seabed, input of hazardous substances, nitrogen, and phosphorus enrichment were the leading causes of environmental problems in the YSLME; (2) benthic organisms, fishes, algae, tidal flats, seabirds, and marine mammals were the most vulnerable ecosystem components on which cumulative effects acted; (3) areas with relatively high risk mainly concentrated on nearshore zones, especially Shandong, Liaoning, and northern Jiangsu, while coastal bays of South Korea also witnessed high risk; (4) certain risks could be observed in the transboundary area, of which the causes were the pervasive fishing, shipping, and sinking of pollutants in this area due to the cyclonic circulation and fine-grained sediments. In future transboundary cooperation on MSP, risk criteria and evaluation of existing management measures should be incorporated to determine whether the identified risk has exceeded the acceptable level and identify the next step of cooperation. Our study presents an example of CEA at large marine ecosystems scale and provides a reference to other large marine ecosystems in the West Pacific and elsewhere.