Insights into AlphaFold's breakthrough in neurodegenerative diseases.

Neurodegenerative diseases (ND) are disorders of the central nervous system (CNS) characterized by impairment in neurons' functions, and complete loss, leading to memory loss, and difficulty in learning, language, and movement processes. The most common among these NDs are Alzheimer's disease (AD) and Parkinson's disease (PD), although several other disorders also exist. These are frontotemporal dementia (FTD), amyotrophic lateral syndrome (ALS), Huntington's disease (HD), and others; the major pathological hallmark of NDs is the proteinopathies, either of amyloid-ß (Aß), tauopathies, or synucleinopathies. Aggregation of proteins that do not undergo normal configuration, either due to mutations or through some disturbance in cellular pathway contributes to the diseases. Artificial Intelligence (AI) and deep learning (DL) have proven to be successful in the diagnosis and treatment of various congenital diseases. DL approaches like AlphaFold (AF) are a major leap towards success in CNS disorders. This 3D protein geometry modeling algorithm developed by DeepMind has the potential to revolutionize biology. AF has the potential to predict 3D-protein confirmation at an accuracy level comparable to experimentally predicted one, with the additional advantage of precisely estimating protein interactions. This breakthrough will be beneficial to identify diseases' advancement and the disturbance of signaling pathways stimulating impaired functions of proteins. Though AlphaFold has solved a major problem in structural biology, it cannot predict membrane proteins-a beneficial approach for drug designing.

Computational insights into missense mutations in HTT gene causing Huntington's disease and its interactome networks.

BACKGROUND: Huntington's disease is a rare neurodegenerative illness of the central nervous system that is inherited in an autosomal dominant pattern. Mutant huntingtin protein is produced as a result of enlargement of CAG repeat in the N-terminal of the polyglutamine tract. AIM OF THE STUDY: Herein, we aim to investigate the mutations and their effects on the HTT gene and its genetic variants. Additionally, the protein-protein interaction of HTT with other proteins and receptor-ligand interaction with the three-dimensional structure of huntingtin protein were identified. METHODS: A comprehensive analysis of the HTT interactome and protein-ligand interaction has been carried out to provide a global picture of structure-function analysis of huntingtin protein. Mutations were analyzed and mutation verification tools were used to check the effect of mutation on protein function. RESULTS: The results showed, mutations in a single gene are not only responsible for causing a particular disease but may also cause other hereditary disorders as well. Moreover, the modification at the nucleotide level also cause the change in the specific amino acid which may disrupt the function of HTT and its interacting proteins contributing in disease pathogenesis. Furthermore, the interaction between MECP2 and BDNF lowers the rate of transcriptional activity. Molecular docking further confirmed the strong interaction between MECP2 and BDNF with highest affinity. Amino acid residues of the HTT protein, involved in the interaction with tetrabenazine were N912, Y890, G2385, and V2320. These findings proved, tetrabenazine as one of the potential therapeutic agent for treatment of Huntington's disease. CONCLUSION: These results give further insights into the genetics of Huntington's disease for a better understanding of disease models which will be beneficial for the future therapeutic studies.

Breast Cancer Screening: Common Questions and Answers.

Breast cancer is the most common nonskin cancer in women and accounts for 30% of all new cancers in the United States. The highest incidence of breast cancer is in women 70 to 74 years of age. Numerous risk factors are associated with the development of breast cancer. A risk assessment tool can be used to determine individual risk and help guide screening decisions. The U.S. Preventive Services Task Force (USPSTF) and American Academy of Family Physicians (AAFP) recommend against teaching average-risk women to perform breast self-examinations. The USPSTF and AAFP recommend biennial screening mammography for average-risk women 50 to 74 years of age. However, there is no strong evidence supporting a net benefit of mammography screening in average-risk women 40 to 49 years of age; therefore, the USPSTF and AAFP recommend individualized decision-making in these women. For average-risk women 75 years and older, the USPSTF and AAFP conclude that there is insufficient evidence to recommend screening, but the American College of Obstetricians and Gynecologists and the American Cancer Society state that screening may continue depending on the woman's health status and life expectancy. Women at high risk of breast cancer may benefit from mammography starting at 30 years of age or earlier, with supplemental screening such as magnetic resonance imaging. Supplemental ultrasonography in women with dense breasts increases cancer detection but also false-positive results.

Breast Cancer Screening: Why Can't Everyone Agree?

Screening mammography and evolving treatments have improved mortality over the last 25 years. However, breast cancer remains the second leading cause of cancer-related mortality for women in the United States. There are several contradictory recommendations regarding breast cancer screening. Familiarity with these recommendations will allow physicians to counsel their patients and ensure well-informed shared decision making.

Type 2 Diabetes Mellitus: Outpatient Insulin Management.

In patients with type 2 diabetes mellitus, insulin may be used to augment therapy with oral glycemic medications or as insulin replacement therapy. The American Diabetes Association suggests the use of long-acting (basal) insulin to augment therapy with one or two oral agents or one oral agent plus a glucagon-like peptide 1 receptor agonist when the A1C level is 9% or more, especially if the patient has symptoms of hyperglycemia or catabolism. Insulin regimens should be adjusted every three or four days until targets of self-monitored blood glucose levels are reached. A fasting and premeal blood glucose goal of 80 to 130 mg per dL and a two-hour postprandial goal of less than 180 mg per dL are recommended. Insulin use is associated with hypoglycemia and weight gain. Insulin analogues are as effective as human insulin at lowering A1C levels with lower risk of hypoglycemia, but they have significantly higher cost. Patients with one or more episodes of severe hypoglycemia (i.e., requiring assistance from others for treatment) may benefit from a short-term relaxation of glycemic targets. Several new insulin formulations have been approved recently that are associated with less risk of hypoglycemia compared with older formulations. The goals of therapy should be individualized based on many factors, including age, life expectancy, comorbid conditions, duration of diabetes, risk of hypoglycemia, cost, patient motivation, and quality of life.

Disability evaluations: more than completing a form.

According to the World Health Organization, more than 1 billion persons worldwide have a disability. In the United States, more than 56 million American workers have some form of disability; of these, more than 38 million persons have a severe disability. Blacks and Hispanics are among the groups with the highest disability rates, as well as older patients. Conditions that most often lead to disability include arthritis, back or spine problems, and heart conditions. Common limitations include the inability to walk three city blocks or to climb a flight of stairs. Patients with a disability experience health disparities and barriers to appropriate health care. Disability impacts family members and caregivers, as well as patients. Impairment, disability, and handicap are key terms that physicians must understand to properly evaluate patients and make appropriate recommendations. Social Security Disability Insurance and workers' compensation are the two largest disability programs in the United States. The U.S. Department of Veterans Affairs provides disability benefits for veterans, and private disability insurance may be provided by the employer or purchased by the employee. Family physicians can perform the initial evaluation, consult appropriate subspecialists, complete the necessary paperwork, and answer questions from the patient, employer, or disability agency.

Nonpharmacologic Management of Chronic Insomnia.

Insomnia affects 10% to 30% of the population with a total cost of $92.5 to $107.5 billion annually. Short-term, chronic, and other types of insomnia are the three major categories according to the International Classification of Sleep Disorders, 3rd ed. The criteria for diagnosis are difficulty falling asleep, difficulty staying asleep, or early awakening despite the opportunity for sleep; symptoms must be associated with impaired daytime functioning and occur at least three times per week for at least one month. Factors associated with the onset of insomnia include a personal or family history of insomnia, easy arousability, poor self-reported health, and chronic pain. Insomnia is more common in women, especially following menopause and during late pregnancy, and in older adults. A comprehensive sleep history can confirm the diagnosis. Psychiatric and medical problems, medication use, and substance abuse should be ruled out as contributing factors. Treatment of comorbid conditions alone may not resolve insomnia. Patients with movement disorders (e.g., restless legs syndrome, periodic limb movement disorder), circadian rhythm disorders, or breathing disorders (e.g., obstructive sleep apnea) must be identified and treated appropriately. Chronic insomnia is associated with cognitive difficulties, anxiety and depression, poor work performance, decreased quality of life, and increased risk of cardiovascular disease and all-cause mortality. Insomnia can be treated with nonpharmacologic and pharmacologic therapies. Nonpharmacologic therapies include sleep hygiene, cognitive behavior therapy, relaxation therapy, multicomponent therapy, and paradoxical intention. Referral to a sleep specialist may be considered for refractory cases.

Care of the homeless: an overview.

Homelessness affects men, women, and children of all races and ethnicities. On any given night, more than 610,000 persons in the United States are homeless; a little more than one-third of these are families. Homeless persons are more likely to become ill, have greater hospitalization rates, and are more likely to die at a younger age than the general population. The average life span for a homeless person is between 42 and 52 years. Homeless children are much sicker and have more academic and behavioral problems. Insufficient personal income and the lack of affordable housing are the major reasons for homelessness. Complex, advanced medical problems and psychiatric illnesses, exacerbated by drug and alcohol abuse, in combination with the economic and social issues (such as the lack of housing and proper transportation) make this subset of the population a unique challenge for the health care system, local communities, and the government. An integrated, multidisciplinary health care team with an outreach focus, along with involvement of local and state agencies, seems best suited to address the components needed to ensure quality of care, to help make these patients self-sufficient, and to help them succeed. Family physicians are well suited to manage the needs of the homeless patient, provide continuity of care, and lead these multidisciplinary teams.