Computationally Efficient Demographic History Inference from Allele Frequencies with Supervised Machine Learning.

Inferring past demographic history of natural populations from genomic data is of central concern in many studies across research fields. Previously, our group had developed dadi, a widely used demographic history inference method based on the allele frequency spectrum (AFS) and maximum composite-likelihood optimization. However, dadi's optimization procedure can be computationally expensive.

Computationally efficient demographic history inference from allele frequencies with supervised machine learning.

Inferring past demographic history of natural populations from genomic data is of central concern in many studies across research fields. Previously, our group had developed dadi, a widely used demographic history inference method based on the allele frequency spectrum (AFS) and maximum composite likelihood optimization. However, dadi's optimization procedure can be computationally expensive.

Customized-individually-made origin® implants in total knee arthroplasty allow a reliable solution for accurate reproduction of planned implant positioning.

Purpose: To evaluate the accuracy and reproducibility of a patient-specific, customized individually made (CIM) total knee replacement (TKR) using the ORIGIN® prosthesis.

Methods: This was a prospective study conducted at a University Hospital from January 15, 2019, to April 30, 2021. The study included patients planned for an ORIGIN® CIM TKR procedure.

Demographic history inference and the polyploid continuum.

Polyploidy is an important generator of evolutionary novelty across diverse groups in the Tree of Life, including many crops. However, the impact of whole-genome duplication depends on the mode of formation: doubling within a single lineage (autopolyploidy) versus doubling after hybridization between two different lineages (allopolyploidy). Researchers have historically treated these two scenarios as completely separate cases based on patterns of chromosome pairing, but these cases represent ideals on a continuum of chromosomal interactions among duplicated genomes.

Control of β-Site Amyloid Precursor Protein-Cleaving Enzyme-1 Expression by Protein Kinase C-λ/ι and Nuclear Factor κ-B.

Unlabelled: Βackground: β-Amyloid precursor protein-cleaving enzyme-1 (BACE1) initiates the production of Aβ-peptides that form Aβ-plaque in Alzheimer's disease.

Methods: Reportedly, acute insulin treatment in normal mice, and hyperinsulinemia in high-fat-fed (HFF) obese/diabetic mice, increase BACE1 activity and levels of Aβ-peptides and phospho- -thr-231-tau in the brain; moreover, these effects are blocked by PKC-λ/ι inhibitors. However, as chemical inhibitors may affect unsuspected targets, we presently used knockout methodology to further examine PKC-λ/ι requirements.

Roles of hepatic atypical protein kinase C hyperactivity and hyperinsulinemia in insulin-resistant forms of obesity and type 2 diabetes mellitus.

Diet-induced obesity, the metabolic syndrome, type 2 diabetes (DIO/MetS/T2DM), and their adverse sequelae have reached pandemic levels. In mice, DIO/MetS/T2DM initiation involves diet-dependent increases in lipids that activate hepatic atypical PKC (aPKC) and thereby increase lipogenic enzymes and proinflammatory cytokines. These or other hepatic aberrations, via adverse liver-to-muscle cross talk, rapidly impair postreceptor insulin signaling to glucose transport in muscle.

Mind the message: Referral letter quality at a South African medical outpatient department.

Background: Some patients need referral within the health system to achieve optimal care, and referral letters are an important part of this process. Healthcare practitioners often complain that referral letters lack information, are inaccurate, or direct patients to the wrong place. Poor communication affects patient experience and outcomes, has budgetary and service planning implications, and impacts on staff relationships and morale.

Coordinated regulation of hepatic FoxO1, PGC-1α and SREBP-1c facilitates insulin action and resistance.

Unlabelled: Type 2 diabetes is characterized by insulin resistance, hyperinsulinemia and hepatic overproduction of glucose and lipids. Insulin increases lipogenic enzyme expression by activating Akt and aPKC which activate SREBP-1c; this pathway is hyperactivated in insulin-resistant states. Insulin suppresses gluconeogenic enzyme expression by Akt-dependent phosphorylation/inactivation of FoxO1 and PGC-1α; this pathway is impaired in insulin-resistant states by aPKC excess, which displaces Akt from scaffolding-protein WD40/ProF, where Akt phosphorylates/inhibits FoxO1.

Atypical PKC, PKCλ/ι, activates β-secretase and increases Aβ and phospho-tau in mouse brain and isolated neuronal cells, and may link hyperinsulinemia and other aPKC activators to development of pathological and memory abnormalities in Alzheimer's disease.

Hyperinsulinemia activates brain Akt and PKC-λ/ι and increases Aβ and phospho-tau in insulin-resistant animals. Here, we examined underlying mechanisms in mice, neuronal cells, and mouse hippocampal slices. Like Aβ, β-secretase activity was increased in insulin-resistant mice and monkeys.

Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice.

PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings.

Brain Insulin Signaling Is Increased in Insulin-Resistant States and Decreases in FOXOs and PGC-1α and Increases in Aβ1-40/42 and Phospho-Tau May Abet Alzheimer Development.

Increased coexistence of Alzheimer disease (AD) and type 2 diabetes mellitus (T2DM) suggests that insulin resistance abets neurodegenerative processes, but linkage mechanisms are obscure. Here, we examined insulin signaling factors in brains of insulin-resistant high-fat-fed mice, ob/ob mice, mice with genetically impaired muscle glucose transport, and monkeys with diet-dependent long-standing obesity/T2DM. In each model, the resting/basal activities of insulin-regulated brain protein kinases, Akt and atypical protein kinase C (aPKC), were maximally increased.

BMI-related progression of atypical PKC-dependent aberrations in insulin signaling through IRS-1, Akt, FoxO1 and PGC-1α in livers of obese and type 2 diabetic humans.

Information on insulin resistance in human liver is limited. In mouse diet-induced obesity (DIO), hepatic insulin resistance initially involves: lipid+insulin-induced activation of atypical protein kinase C (aPKC); elevated Akt activity/activation but selective impairment of compartmentalized Akt-dependent FoxO1 phosphorylation; and increases in gluconeogenic and lipogenic enzymes. In advanced stages, e.

Hepatic insulin resistance in ob/ob mice involves increases in ceramide, aPKC activity, and selective impairment of Akt-dependent FoxO1 phosphorylation.

Pathogenesis of insulin resistance in leptin-deficient ob/ob mice is obscure. In another form of diet-dependent obesity, high-fat-fed mice, hepatic insulin resistance involves ceramide-induced activation of atypical protein kinase C (aPKC), which selectively impairs protein kinase B (Akt)-dependent forkhead box O1 protein (FoxO1) phosphorylation on scaffolding protein, 40 kDa WD(tryp-x-x-asp)-repeat propeller/FYVE protein (WD40/ProF), thereby increasing gluconeogenesis. Resultant hyperinsulinemia activates hepatic Akt and mammalian target of rapamycin C1, and further activates aPKC; consequently, lipogenic enzyme expression increases, and insulin signaling in muscle is secondarily impaired.

Atypical PKC: a target for treating insulin-resistant disorders of obesity, the metabolic syndrome and type 2 diabetes mellitus.

Introduction: The prevalence of obesity, the metabolic syndrome and type 2 diabetes mellitus have reached pandemic levels. Present therapies do not directly target the key factor responsible for the insulin resistance that underlies the development of these syndromes.

Areas Covered: This review focuses on hepatic atypical PKC (aPKC) as a key target for treating these disorders.

Requirements for pseudosubstrate arginine residues during autoinhibition and phosphatidylinositol 3,4,5-(PO₄)₃-dependent activation of atypical PKC.

Atypical PKC (aPKC) isoforms are activated by the phosphatidylinositol 3-kinase product phosphatidylinositol 3,4,5-(PO4)3 (PIP3). How PIP3 activates aPKC is unknown. Although Akt activation involves PIP3 binding to basic residues in the Akt pleckstrin homology domain, aPKCs lack this domain.

PKCλ haploinsufficiency prevents diabetes by a mechanism involving alterations in hepatic enzymes.

Tissue-specific knockout (KO) of atypical protein kinase C (aPKC), PKC-λ, yields contrasting phenotypes, depending on the tissue. Thus, whereas muscle KO of PKC-λ impairs glucose transport and causes glucose intolerance, insulin resistance, and liver-dependent lipid abnormalities, liver KO and adipocyte KO of PKC-λ increase insulin sensitivity through salutary alterations in hepatic enzymes. Also note that, although total-body (TB) homozygous KO of PKC-λ is embryonic lethal, TB heterozygous (Het) KO (TBHetλKO) is well-tolerated.

Akt-dependent phosphorylation of hepatic FoxO1 is compartmentalized on a WD40/ProF scaffold and is selectively inhibited by aPKC in early phases of diet-induced obesity.

Initiating mechanisms that impair gluconeogenic enzymes and spare lipogenic enzymes in diet-induced obesity (DIO) are obscure. Here, we examined insulin signaling to Akt and atypical protein kinase C (aPKC) in liver and muscle and hepatic enzyme expression in mice consuming a moderate high-fat (HF) diet. In HF diet-fed mice, resting/basal and insulin-stimulated Akt and aPKC activities were diminished in muscle, but in liver, these activities were elevated basally and were increased by insulin to normal levels.

Impairment of insulin-stimulated glucose transport and ERK activation by adipocyte-specific knockout of PKC-λ produces a phenotype characterized by diminished adiposity and enhanced insulin suppression of hepatic gluconeogenesis.

Tissue-specific knockout (KO) of atypical protein kinase C-λ (PKC-λ) impairs insulin-stimulated glucose transport in muscle (M) and lipid synthesis in liver (L), thereby producing insulin resistance in MλKO mice and insulin-hypersensitivity in LλKO mice. Here, we generated mice with KO of PKC-λ in adipocytes, i.e.

Hepatic Atypical Protein Kinase C: An Inherited Survival-Longevity Gene that Now Fuels Insulin-Resistant Syndromes of Obesity, the Metabolic Syndrome and Type 2 Diabetes Mellitus.

This review focuses on how insulin signals to metabolic processes in health, why this signaling is frequently deranged in Western/Westernized societies, how these derangements lead to, or abet development of, insulin-resistant states of obesity, the metabolic syndrome and type 2 diabetes mellitus, and what our options are for restoring insulin signaling, and glucose/lipid homeostasis. A central theme in this review is that excessive hepatic activity of an archetypal protein kinase enzyme, "atypical" protein kinase C (aPKC), plays a critically important role in the development of impaired glucose metabolism, systemic insulin resistance, and excessive hepatic production of glucose, lipids and proinflammatory factors that underlie clinical problems of glucose intolerance, obesity, hepatosteatosis, hyperlipidemia, and, ultimately, type 2 diabetes. The review suggests that normally inherited genes, in particular, the aPKC isoforms, that were important for survival and longevity in times of food scarcity are now liabilities in times of over-nutrition.

Metformin action in human hepatocytes: coactivation of atypical protein kinase C alters 5'-AMP-activated protein kinase effects on lipogenic and gluconeogenic enzyme expression.

Aims/hypothesis: Atypical protein kinase C (aPKC) levels and activity are elevated in hepatocytes of individuals with type 2 diabetes and cause excessive increases in the levels of lipogenic and gluconeogenic enzymes; aPKC inhibitors largely correct these aberrations. Metformin improves hepatic gluconeogenesis by activating 5'-AMP-activated protein kinase (AMPK). However, metformin also activates aPKC in certain tissues; in the liver, this activation could amplify diabetic aberrations and offset the positive effects of AMPK.

Atypical protein kinase C in cardiometabolic abnormalities.

Purpose Of Review: To review the aberrations of insulin signaling to atypical protein kinase C (aPKC) in muscle and liver that generate cardiovascular risk factors, including obesity, hypertriglyceridemia, hypercholesterolemia, insulin resistance and glucose intolerance in type 2 diabetes mellitus (T2DM), and obesity-associated metabolic syndrome (MetSyn).

Recent Findings: aPKC and Akt mediate the insulin effects on glucose transport in muscle and synthesis of lipids, cytokines and glucose in liver. In T2DM, whereas Akt and aPKC activation are diminished in muscle, and hepatic Akt activation is diminished, hepatic aPKC activation is conserved.