What programs the size of animal cells?

The human body is programmed with definite quantities, magnitudes, and proportions. At the microscopic level, such definite sizes manifest in individual cells - different cell types are characterized by distinct cell sizes whereas cells of the same type are highly uniform in size. How do cells in a population maintain uniformity in cell size, and how are changes in target size programmed? A convergence of recent and historical studies suggest - just as a thermostat maintains room temperature - the size of proliferating animal cells is similarly maintained by homeostatic mechanisms. In this review, we first summarize old and new literature on the existence of cell size checkpoints, then discuss additional advances in the study of size homeostasis that involve feedback regulation of cellular growth rate. We further discuss recent progress on the molecules that underlie cell size checkpoints and mechanisms that specify target size setpoints. Lastly, we discuss a less-well explored teleological question: why does cell size matter and what is the functional importance of cell size control?

Virtual screening for small-molecule pathway regulators by image-profile matching.

Identifying the chemical regulators of biological pathways is a time-consuming bottleneck in developing therapeutics and research compounds. Typically, thousands to millions of candidate small molecules are tested in target-based biochemical screens or phenotypic cell-based screens, both expensive experiments customized to each disease. Here, our uncustomized, virtual, profile-based screening approach instead identifies compounds that match to pathways based on the phenotypic information in public cell image data, created using the Cell Painting assay. Our straightforward correlation-based computational strategy retrospectively uncovered the expected, known small-molecule regulators for 32% of positive-control gene queries. In prospective, discovery mode, we efficiently identified new compounds related to three query genes and validated them in subsequent gene-relevant assays, including compounds that phenocopy or pheno-oppose YAP1 overexpression and kill a Yap1-dependent sarcoma cell line. This image-profile-based approach could replace many customized labor- and resource-intensive screens and accelerate the discovery of biologically and therapeutically useful compounds.

Association Between Metformin Use and Mortality among Patients with Type 2 Diabetes Mellitus Hospitalized for COVID-19 Infection.

INTRODUCTION: Metformin has known mechanistic benefits on COVID-19 infection due to its anti-inflammatory effects and its action on the ACE2 receptor. However, some physicians are reluctant to use it in hypoxemic patients due to potential lactic acidosis. The primary purpose of the study was to determine whether metformin use is associated with survival. We also wanted to determine whether there is a difference in outcomes in subcategories of metformin use, whether at home, in-hospital, or mixed home/in-hospital use. OBJECTIVES: This study aimed to determine an association between metformin use and mortality among patients with type 2 diabetes mellitus hospitalized for COVID-19 infection. METHODOLOGY: This was a cross-sectional analysis of data acquired from the COVID-19 database of two tertiary hospitals in Cebu from March 1, 2020, to September 30, 2020. Hospitalized adult Filipino patients with type 2 diabetes mellitus who tested positive for COVID-19 via RT-PCR were included and categorized as either metformin users or metformin non-users. RESULTS: We included 355 patients with type 2 diabetes mellitus in the study, 186 (52.4%) were metformin users. They were further categorized into home metformin users (n=109, 30.7%), in-hospital metformin users (n=40, 11.3%), and mixed home/in-hospital metformin users (n=37, 10.4%). Metformin use was associated with a lower risk for mortality compared to non-users (p=0.001; OR=0.424). In-hospital and mixed home/in-hospital metformin users were associated with lower mortality odds than non-users (p=0.002; OR=0.103 and p=0.005; OR 0.173, respectively). The lower risk for mortality was noted in metformin, regardless of dosage, from 500 mg to 2 g daily (p=0.002). Daily dose between ≥1000 mg to <2000 mg was associated with the greatest benefit on mortality (p≤0.001; OR=0.252). The survival distributions between metformin users and non-users were statistically different, showing inequality in survival (χ2=5.67, p=0.017). CONCLUSION: Metformin was associated with a lower risk for mortality in persons with type 2 diabetes mellitus hospitalized for COVID-19 disease compared to non-users. Use of metformin in-hospital, and mixed home/in-hospital metformin use, was also associated with decreased risk for mortality. The greatest benefit seen was in those taking a daily dose of ≥1000 mg to <2000 mg.

Cell size homeostasis is maintained by CDK4-dependent activation of p38 MAPK.

While molecules that promote the growth of animal cells have been identified, it remains unclear how such signals are orchestrated to determine a characteristic target size for different cell types. It is increasingly clear that cell size is determined by size checkpoints-mechanisms that restrict the cell cycle progression of cells that are smaller than their target size. Previously, we described a p38 MAPK-dependent cell size checkpoint mechanism whereby p38 is selectively activated and prevents cell cycle progression in cells that are smaller than a given target size. In this study, we show that the specific target size required for inactivation of p38 and transition through the cell cycle is determined by CDK4 activity. Our data suggest a model whereby p38 and CDK4 cooperate analogously to the function of a thermostat: while p38 senses irregularities in size, CDK4 corresponds to the thermostat dial that sets the target size.

Diabetes-Related Attitudes of Health Care Providers in Rural Health Centers in Aklan, Philippines using the Filipino Version of Diabetes Attitude Scale (DAS-3).

OBJECTIVE: To determine the beliefs and attitudes towards diabetes of rural health care providers in Aklan, Philippines using the Diabetes Attitude Scale 3 (DAS-3) and to determine factors associated with it. METHODOLOGY: This is a cross-sectional analytic survey. A total of 339 health care providers were given self-administered DAS-3 questionnaires. Additional data gathered included their age, highest educational attainment, position, municipality class, diabetes as a co-morbidity, attendance to diabetes classes, and family history of diabetes. RESULTS: Rural health care providers showed an overall mean positive attitude score of 3.5 using the DAS-3 questionnaire. In decreasing order, mean scores of participants according to subscale is as follows: "Need for Special Training in Education" (4.13) >"Autonomy of diabetes for patients" (3.70) >"Psychosocial Impact of Diabetes" (3.60) >"Value of Tight Glucose Control" (3.14) and "Seriousness of Type 2 Diabetes" (3.09). Physicians have the highest mean scores consistently in all subscales compared to other health care providers. Among the different factors considered, educational attainment (p=0.005) and work position (p=<0.001) were found out to affect attitude score of health care providers. CONCLUSION: This study has shown that the majority of the rural health care providers believe in the need for special training of healthcare providers, psychosocial impact of diabetes and patient autonomy in diabetes self-care. However, the majority still do not strongly believe in the seriousness of diabetes and the benefits of tight sugar control. Educational attainment and work position are the consistent factors that impact diabetes-related attitude; therefore, the need to strengthen continuous medical education among health care providers.

Size uniformity of animal cells is actively maintained by a p38 MAPK-dependent regulation of G1-length.

Animal cells within a tissue typically display a striking regularity in their size. To date, the molecular mechanisms that control this uniformity are still unknown. We have previously shown that size uniformity in animal cells is promoted, in part, by size-dependent regulation of G1 length. To identify the molecular mechanisms underlying this process, we performed a large-scale small molecule screen and found that the p38 MAPK pathway is involved in coordinating cell size and cell cycle progression. Small cells display higher p38 activity and spend more time in G1 than larger cells. Inhibition of p38 MAPK leads to loss of the compensatory G1 length extension in small cells, resulting in faster proliferation, smaller cell size and increased size heterogeneity. We propose a model wherein the p38 pathway responds to changes in cell size and regulates G1 exit accordingly, to increase cell size uniformity.

Polyostotic fibrous dysplasia in a young female with McCune Albright syndrome

BACKGROUND AND SIGNIFICANCE: McCune Albright Syndrome (MAS) is a rare disorder characterized by the clinical triad of precocious puberty, polyostotic fibrous dysplasia of the bones and café-au-lait spots. Prevalence is estimated at 1/100,000-1/1,000,000. We report a case of polyostotic fibrous dysplasia in a patient with McCune Albright Syndrome who had symptomatic relief of hip pains and non-recurrence of stress fractures in a dysplastic right hip bone following treatment with loading intravenous pamidronate followed by an oral alendronate for almost a year, as an off-label indication. While intravenous bisphosphonates have been well-recognized in the treatment of fibrous dysplasia, only case reports are available to support its utility.CASE REPORT: We report an 18 year old female with leg length discrepancy following repeated episodes of hip fracture for the past six years. She was referred to the Philippine General Hospital for recurrent severe leg pains which occurred usually at menstrual mid-cycle. This condition was associated with lateral bowing of the proximal part of the right thigh, widening of the right hip region, and shortening of the right lower limb also known as Shepherd's Crook deformity. She also had café-au-lait spots at the back of her left legs and buttocks. Skeletal survey showed radiolucent medullary expansile lytic lesions with ground glass appearance of the right femur, tibia, fibula, humerus, scapula, pubis, ischium, carpal and metacarpal bones. Patient was noted to have short stature with height of 142 cm. Arm span was 139 cms, upper body segment (crown to the coccyx) was 70cms while lower body segment (coccyx to heel left foot) was 72 cms. The difference between the left and right leg was 7 cms. Mean parental height was 160 cm. She was then referred to the Endocrinology service of this institution for evaluation of the short stature and associated endocrinopathies. On review, she had adrenarche at 8 years old followed by menarche at 10 years old. She had no goiter. She had no cushingoid features. Patient had irregular menstrual cycles with oligomenorrhea (cycle: 60-180 days). Breast development and pubic hair were staged Tanner 5. In the approach to short stature where height age is less than either the bone age or chronological age, constitutionaldwarfism, hypothyroidism, growth hormone deficiency and fibrous dyplasia must be ruled out. Constitutional dwarfism was ruled out with a midparental height of 160 cm. A normal free thyroxine (17, normal: 9-23 pmol/L), thyroid stimulating hormone (2.4, normal: 0.25-4 ulU/ml) ruled out hypothyroidism, and a normal IGF-1 (103, normal: 91-223 nmol/L) ruled out growth hormone deficiency. This left us with the consideration of fibrous dysplasia of the bone which was consistent with the earlier radiographic findings. The combination ofpolyostotic fibrous dysplasia and café au lait spots led to the impression of McCune Albright Syndrome. The most common endocrinopathy associated with McCune Albright Syndrome is a peripheral hyperfunctioning ovaries which also harbors the G-protein mutation. This was evident in our case with a high estrogen (655.8, normal: 50-250 pg/ml) and suppressed LH (1.2, normal: 1.5-5 pg/ml) and FSH (3, normal 3.5-12.5 pg/ml) with a transrectal ultrasound finding of a 2.6 x 1.7 x 1.6 cm cyst at the right ovary. This precipitated the precocious puberty andearly closure of the epiphyseal plates resulting to short stature. To screen for other endocrinopathies, a 24 hour urine free cortisol (44, 20-90 ug/day), serum prolactin (15ng/ml, normal: 0-30ng/ml), free thyroxine (17, normal: 9-23.2 pmol/L) and parathyroid hormone (13.9, normal 10-65pg/ml) was documented and ruled out associated hypercortisolemia, prolactinoma, hyperthyroidism and hyperparathyroidism respectively. The patient had no history of change in shoe size, and no coarsening of facial features that was suggestive ofacromegaly.                                                                                                                                           TREATMENT: Pat ient underwent bone graf t ing and osteotomy to correct the shepherd's crook deformity. Three cycles of intravenous pamidronate infusion in three consecutive days was given prior to the operation. Postoperatively, patient tolerated the procedure and was discharged after three days.OUTCOME: Shepherd's crook deformity was successfully corrected. Patient still had limp but with no pain and no new fractures for almost a year already. At present she is maintained on alendronate 70mg 1 tab once a week and calcium 1 gram per day.CONCLUSION: We repor t a case of McCune Albright Syndrome presenting with bone deformity which was later diagnosed to be fibrous dysplasia with polyostotic involvement, and was successfully treated with initial intravenous bi sphosphonates maintained on oral bisphosphonates following a surgical procedure to correct the shepherd's crook deformity. At present, she has had no new fractures.