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Obesity has reached epidemic proportions and is one of the greatest challenges for public health in the twenty-first century. The macronutrient composition of diets, in particular the amount and ratio of carbohydrates, fat and protein, have received considerable attention in recent decades due to its potential relevance to the development of obesity and weight loss. The effects of various macronutrients on body weight regulation are still under debate. High-carbohydrate diets, and particularly high-fat diets, have been blamed for the increase in the prevalence of obesity. This paper shows that neither fat nor carbohydrates are fattening per se. Mixed diets with substantial amounts of fat and high-glycemic carbohydrates, like current WDs, are required to promote weight gain and obesity. High-glycemic carbohydrates are the active partner (the "driver"), which promotes fat storage through its insulinogenic effect, while fat is the passive partner (the "passenger") on the way to obesity. Elevated insulin levels (postprandial, but more importantly due to hypersecretion and hyperinsulinemia) promote fat storage and play a key role in obesogenesis and the obesity epidemic. Furthermore, mixed diets high in high-glycemic carbohydrates and fat promote fetal programming, with long-term adverse impacts on the offspring, including insulin hypersecretion, (childhood) obesity and metabolic diseases. Maternal obesity and high weight gain during pregnancy have also been linked to deleterious effects on fetal programming. As the global obesity epidemic increasingly affects women of reproductive age, a significant percentage of fetuses will experience fetal programming with a tendency towards obesity – a self-reinforcing process that further fuels the epidemic. A change in lifestyle and diet composition is needed to prevent or limit the development of obesity and related diseases. [ABSTRACT FROM AUTHOR]

Westernized populations are plagued by a plethora of chronic non-infectious degenerative diseases, termed as "civilization diseases", like obesity, diabetes, cardiovascular diseases, cancer, autoimmune diseases, Alzheimer's disease and many more, diseases which are rare or virtually absent in hunter-gatherers and other non-westernized populations. There is a growing awareness that the cause of this amazing discrepancy lies in the profound changes in diet and lifestyle during recent human history. This paper shows that the transition from Paleolithic nutrition to Western diets, along with lack of corresponding genetic adaptations, cause significant distortions of the fine-tuned metabolism that has evolved over millions of years of human evolution in adaptation to Paleolithic diets. With the increasing spread of Western diet and lifestyle worldwide, overweight and civilization diseases are also rapidly increasing in developing countries. It is suggested that the diet-related key changes in the developmental process include an increased production of reactive oxygen species and oxidative stress, development of hyperinsulinemia and insulin resistance, low-grade inflammation and an abnormal activation of the sympathetic nervous system and the renin-angiotensin system, all of which play pivotal roles in the development of diseases of civilization. In addition, diet-related epigenetic changes and fetal programming play an important role. The suggested pathomechanism is also able to explain the well-known but not completely understood close relationship between obesity and the wide range of comorbidities, like type 2 diabetes mellitus, cardiovascular disease, etc., as diseases of the same etiopathology. Changing our lifestyle in accordance with our genetic makeup, including diet and physical activity, may help prevent or limit the development of these diseases. [ABSTRACT FROM AUTHOR]

Transcription factors (TFs) play a crucial role in gene regulation by binding to specific regulatory sequences. The sequence motifs recognized by a TF can be described in terms of position frequency matrices. Searching for motif matches with a given position frequency matrix is achieved by employing a predefined score cutoff and subsequently counting the number of matches above this cutoff. In this article, we approximate the distribution of the number of motif matches based on a novel dynamic programming approach, which accounts for higher order sequence background (e.g., as is characteristic for CpG islands) and overlapping motif matches on both DNA strands. A comparison with our previously published compound Poisson approximation and a binomial approximation demonstrates that in particular for relaxed score thresholds, the dynamic programming approach yields more accurate results. [ABSTRACT FROM AUTHOR]

Motivation: Transcription factors play a crucial role in gene regulation by binding to specific regulatory sequences. The sequence motifs recognized by a transcription factor can be described in terms of position frequency matrices. When scanning a sequence for matches to a position frequency matrix, one needs to determine a cut-off, which then in turn results in a certain number of hits. In this paper we describe how to compute the distribution of match scores and of the number of motif hits, which are the prerequisites to perform motif hit enrichment analysis. Results: We put forward an improved compound Poisson model that supports general order-d Markov background models and which computes the number of motif-hits more accurately than earlier models. We compared the accuracy of the improved compound Poisson model with previously proposed models across a range of parameters and motifs, demonstrating the improvement. The importance of the order-d model is supported in a case study using CpG-island sequences. [ABSTRACT FROM AUTHOR]

Natural killer lymphocytes (NKL) in gingival biopsy specimens of 13 patients with advanced periodontitis and 6 normal control subjects have been evaluated by the monoclonal antibody NC 1, anti-B4 and a double immunoenzymatic labeling technique, combining the peroxidase-anti-peroxidase (PAP) method with the alkaline-phosphatase-anti-alkaline-phosphatase (A PAAP) technique. Mononuclear cells with NX-activity (NKA) were mainly accumulated in the upper to middle third of the periodontal pocket. The concentration of NC-1-positive cells (CNC) of the baseline biopsy specimens was significantly increased at p = 0.05 compared to the CNC after hygiene training. The statistical difference rose to p = 0.01 following scaling, root planing and curettage therapy. The healthy gingiva of control subjects showed an average of 1-2 NKL, and no statistical difference could be found when compared to the CNC of the biopsy specimens of patients after periodontal therapy. These data support the hypothesis that antibody-dependent cytotoxic immunoreactive lymphocytes in chronic inflammatory periodontal disease can be reduced by scaling and root planing therapy. [ABSTRACT FROM AUTHOR]

Benign prostatic hyperplasia and hypertension are common age-related comorbidities. Although the etiology of benign prostatic hyperplasia (BPH) is still largely unresolved and poorly understood, a significant age-independent association was found between BPH and hypertension, indicating a common pathophysiological factor for both diseases. It has previously been suggested that the development of essential hypertension may be related to diet-induced hyperinsulinemia. This study follows the question, whether BPH may develop due to the same mechanism, thereby explaining the well-known comorbidity of these 2 disorders. The scientific evidence presented shows that BPH and hypertension share the same pathophysiological changes, with hyperinsulinemia as the driving force. It further shows that significant dietary changes during human history cause disruption of a finely tuned metabolic balance that has evolved over millions of years of evolution: high-insulinemic food, typical of current "Western" diets, has the potential to cause hyperinsulinemia and insulin resistance, as well as an abnormally increased activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system, alterations that play a pivotal role in the pathogenesis of BPH and hypertension. [ABSTRACT FROM AUTHOR]

The study explores the intricate relationship between aging and the development of noncommunicable diseases [NCDs], focusing on whether these diseases are inevitable consequences of aging or primarily driven by lifestyle factors. By examining epidemiological data, particularly from hunter-gatherer societies, the study highlights that many NCDs prevalent in modern populations are rare in these societies, suggesting a significant influence of lifestyle choices. It delves into the mechanisms through which poor diet, smoking, and other lifestyle factors contribute to systemic physiological imbalances, characterized by oxidative stress, insulin resistance and hyperinsulinemia, and dysregulation of the sympathetic nervous system, the renin-angiotensin-aldosterone system, and the immune system. The interplay between this pattern and individual factors such as genetic susceptibility, biological variability, epigenetic changes and the microbiome is proposed to play a crucial role in the development of a range of age-related NCDs. Modified biomolecules such as oxysterols and advanced glycation end products also contribute to their development. Specific diseases such as benign prostatic hyperplasia, Parkinson's disease, glaucoma and osteoarthritis are analyzed to illustrate these mechanisms. The study concludes that while aging contributes to the risk of NCDs, lifestyle factors play a crucial role, offering potential avenues for prevention and intervention through healthier living practices. One possible approach could be to try to restore the physiological balance, e.g. through dietary measures [e.g. Mediterranean diet, Okinawan diet or Paleolithic diet] in conjunction with [a combination of] pharmacological interventions and other lifestyle changes.

Non-communicable diseases, like diabetes, cardiovascular diseases, cancer, stroke, chronic obstructive pulmonary disease, osteoporosis, arthritis, Alzheimer's disease and other more are a leading cause of death in almost all countries. Lifestyle factors, especially poor diet and tobacco consumption, are considered to be the most important influencing factors in the development of these diseases. The Western diet has been shown to cause a significant distortion of normal physiology, characterized by dysregulation of the sympathetic nervous system, renin-angiotensin aldosterone system, and immune system, as well as disruption of physiological insulin and oxidant/antioxidant homeostasis, all of which play critical roles in the development of these diseases. This paper addresses the question of whether the development of smoking-related non-communicable diseases follows the same pathophysiological pattern. The evidence presented shows that exposure to cigarette smoke and/or nicotine causes the same complex dysregulation of physiology as described above, it further shows that the factors involved are strongly interrelated, and that all of these factors play a key role in the development of a broad spectrum of smoking-related diseases. Since not all smokers develop one or more of these diseases, it is proposed that this disruption of normal physiological balance represents a kind of pathogenetic "basic toolkit" for the potential development of a range of non-communicable diseases, and that the decision of whether and what disease will develop in an individual is determined by other, individual factors ("determinants"), such as the genome, epigenome, exposome, microbiome, and others. The common pathophysiological pattern underlying these diseases may provide an explanation for the often poorly understood links between non-communicable diseases and disease comorbidities. The proposed pathophysiological process offers new insights into the development of non-communicable diseases and may influence the direction of future research in both prevention and therapy., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kopp.)