Systems biological approach to investigate the lack of familial link between Down's Syndrome & Neural Tube Disorders

Systems Biology involves the study of the interactions of biological systems and ultimately their functions. Down''s syndrome (DS) is one of the most common genetic disorders which are caused by complete, or occasionally partial, triplication of chromosome 21, characterized by cognitive and language dysfunction coupled with sensory and neuromotor deficits. Neural Tube Disorders (NTDs) are a group of congenital malformations of the central nervous system and neighboring structures related to defective neural tube closure during the first trimester of pregnancy usually occurring between days 18-29 of gestation. Several studies in the past have provided considerable evidence that abnormal folate and methyl metabolism are associated with onset of DS & NTDs. There is a possible common etiological pathway for both NTDs and Down''s syndrome. But, various research studies over the years have indicated very little evidence for familial link between the two disorders. Our research aimed at the gene expression profiling of microarray datasets pertaining to the two disorders to identify genes whose expression levels are significantly altered in these conditions. The genes which were 1.5 fold unregulated and having a p-value <0.05 were filtered out and gene interaction network were constructed for both NTDs and DS. The top ranked dense clique for both the disorders were recognized and over representation analysis was carried out for each of the constituent genes. The comprehensive manual analysis of these genes yields a hypothetical understanding of the lack of familial link between DS and NTDs. There were no genes involved with folic acid present in the dense cliques. Only – CBL, EGFR genes were commonly present, which makes the allelic variants of these genes – good candidates for future studies regarding the familial link between DS and NTDs.

Abbreviations

NTD - Neural Tube Disorders, DS - Down''s Syndrome, MTHFR - Methylenetetrahydrofolate reductase, MTRR– 5 - methyltetrahydrofolate-homocysteine methyltransferase reductase.     

载脂蛋白亚型与糖尿病合并冠心病的相关性研究

目的:探讨载脂蛋白亚型与糖尿病合并冠脉病变严重程度相关性,为预防及治疗糖尿病伴发的动脉粥样硬化性疾病提供新的依据。方法:选取440名心内科患者,根据冠脉造影有无冠脉狭窄及是否合并糖尿病分为四组:冠脉内膜光滑组94人(A组);单纯冠脉狭窄组108人(B组);糖尿病合并冠脉狭窄组共184人(C组);糖尿病冠脉无狭窄组44人(D组),记录患者空腹血糖、餐后血糖、传统血脂脂谱、载脂蛋白A(apoA)、载脂蛋白B(apoB)及两者的比值(apoB/apoA);采用Gensini评分比较传统血脂、apoA、apoB及与Gensini积分值的相关性。结果:与正常对照组比较,糖尿病冠脉无狭窄组apoB、apoB/apoA、LDL和TG升高,apoA和HDL降低,B组和C组apoA与Gensini积分值存在负相关(P=0.01570.05);apoB;apoB/apoA与Gensini积分值存在正相关(P0.0001);两组中,apoB与Gensini积分值相关系数最大(r=0.85795,0.85941),且apoB与Gensini积分值的相关性都强于LDL与积分值的相关性。结论:在糖尿病患者预测心血管风险上,apoB,apoA,apoB/apoA的测定可能优于传统的血脂指标。     

PINK1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice

The Parkinson''s disease (PD) gene, PARK6, encodes the PTEN-induced putative kinase 1 (PINK1) mitochondrial kinase, which provides protection against oxidative stress-induced apoptosis. Given the link between glucose metabolism, mitochondrial function and insulin secretion in β-cells, and the reported association of PD with type 2 diabetes, we investigated the response of PINK1-deficient β-cells to glucose stimuli to determine whether loss of PINK1 affected their function. We find that loss of PINK1 significantly impairs the ability of mouse pancreatic β-cells (MIN6 cells) and primary intact islets to take up glucose. This was accompanied by higher basal levels of intracellular calcium leading to increased basal levels of insulin secretion under low glucose conditions. Finally, we investigated the effect of PINK1 deficiency in vivo and find that PINK1 knockout mice have improved glucose tolerance. For the first time, these combined results demonstrate that loss of PINK1 function appears to disrupt glucose-sensing leading to enhanced insulin release, which is uncoupled from glucose uptake, and suggest a key role for PINK1 in β-cell function.     

HLA haplotype segregation in families of type 1 diabetics

The hypothesis of linkage between HLA and a disease susceptibility (DS) locus (or loci) for type 1 diabetes was tested. HLA segregation was random among 57 non-diabetic sibs but not among 39 diabetic sibs, suggesting that susceptibility to type 1 diabetes may be due to an HLA-linked gene(s). The data did not fit a genetic model involving either a single recessive or dominant gene. The excess of HLA-identical diabetic sibs and the reduced number who were HLA-discordant compared to expected numbers indicated that factors from both paternal and maternal haplotypes were necessary for DS. In 1 of the 3 families with a diabetic parent and more than one diabetic sib, the diabetic sibs inherited different haplotypes from the affected parent, suggesting that either of these haplotypes conferred DS. HLAB 8, B 18 and B 40 were increased in frequency among 97 unrelated type 1 diabetics compared with 238 controls, especially among those with onset age less than 10 years. This early onset group may represent a subtype of type 1 diabetes.     

Combined Effects of Agitation,Macromolecular Crowding,and Interfaces on Amyloidogenesis

Amyloid formation and accumulation is a hallmark of protein misfolding diseases and is associated with diverse pathologies including type II diabetes and Alzheimer''s disease (AD). In vitro, amyloidogenesis is widely studied in conditions that do not simulate the crowded and viscous in vivo environment. A high volume fraction of most biological fluids is occupied by various macromolecules, a phenomenon known as macromolecular crowding. For some amyloid systems (e.g. α-synuclein) and under shaking condition, the excluded volume effect of macromolecular crowding favors aggregation, whereas increased viscosity reduces the kinetics of these reactions. Amyloidogenesis can also be catalyzed by hydrophobic-hydrophilic interfaces, represented by the air-water interface in vitro and diverse heterogeneous interfaces in vivo (e.g. membranes). In this study, we investigated the effects of two different crowding polymers (dextran and Ficoll) and two different experimental conditions (with and without shaking) on the fibrilization of amyloid-β peptide, a major player in AD pathogenesis. Specifically, we demonstrate that, during macromolecular crowding, viscosity dominates over the excluded volume effect only when the system is spatially non homogeneous (i.e. an air-water interface is present). We also show that the surfactant activity of the crowding agents can critically influence the outcome of macromolecular crowding and that the structure of the amyloid species formed may depend on the polymer used. This suggests that, in vivo, the outcome of amyloidogenesis may be affected by both macromolecular crowding and spatial heterogeneity (e.g. membrane turn-over). More generally, our work suggests that any factors causing changes in crowding may be susceptibility factors in AD.     

Neuropathological correlates of amyloid PET imaging in Down syndrome

Down syndrome (DS) results in an overproduction of amyloid‐β (Aβ) peptide associated with early onset of Alzheimer's disease (AD). DS cases have Aβ deposits detectable histologically as young as 12–30 years of age, primarily in the form of diffuse plaques, the type of early amyloid pathology also seen at pre‐clinical (i.e., pathological aging) and prodromal stages of sporadic late onset AD. In DS subjects aged >40 years, levels of cortical Aβ deposition are similar to those observed in late onset AD and in addition to diffuse plaques involve cored plaques associated with dystrophic neurites (neuritic plaques), which are of neuropathological diagnostic significance in AD. The purpose of this review is to summarize and discuss findings from amyloid PET imaging studies of DS in reference to postmortem amyloid‐based neuropathology. PET neuroimaging applied to subjects with DS has the potential to (a) track the natural progression of brain pathology, including the earliest stages of amyloid accumulation, and (b) determine whether amyloid PET biomarkers predict the onset of dementia. In addition, the question that is still incompletely understood and relevant to both applications is the ability of amyloid PET to detect Aβ deposits in their earliest form.     

Enhanced generation of intraluminal vesicles in neuronal late endosomes in the brain of a Down syndrome mouse model with endosomal dysfunction

Down syndrome (DS) is a human genetic disease caused by trisomy of chromosome 21 and characterized by early developmental brain abnormalities. Dysfunctional endosomal pathway in neurons is an early event of DS and Alzheimer's disease. Recently, we have demonstrated that exosome secretion is upregulated in human DS postmortem brains, in the brain of the trisomic mouse model Ts[Rb(12.17¹⁶)]2Cje (Ts2) and by DS fibroblasts as compared with disomic controls. High levels of the tetraspanin CD63, a regulator of exosome biogenesis, were observed in DS brains. Partially blocking exosome secretion by DS fibroblasts exacerbated a pre‐existing early endosomal pathology. We thus hypothesized that enhanced CD63 expression induces generation of intraluminal vesicles (ILVs) in late endosomes/multivesicular bodies (MVBs), increasing exosome release as an endogenous mechanism to mitigate endosomal abnormalities in DS. Herein, we show a high‐resolution electron microscopy analysis of MVBs in neurons of the frontal cortex of 12‐month‐old Ts2 mice and littermate diploid controls. Our quantitative analysis revealed that Ts2 MVBs are larger, more abundant, and contain a higher number of ILVs per neuron compared to controls. These findings were further corroborated biochemically by Western blot analysis of purified endosomal fractions showing higher levels of ILVs proteins in the same fractions containing endosomal markers in the brain of Ts2 mice compared to controls. These data suggest that upregulation of ILVs production may be a key homeostatic mechanism to alleviate endosomal dysregulation via the endosomal–exosomal pathway.     

Loss of Yme1L perturbates mitochondrial dynamics

Yme1L is an AAA protease that is embedded in the mitochondrial inner membrane with its catalytic domain facing the mitochondrial inner-membrane space. However, how Yme1L regulates mammalian mitochondrial function is still obscure. We find that endogenous Yme1L locates at punctate structures of mitochondria, and that loss of Yme1L in mouse embryonic fibroblast (MEF) cells results in mitochondrial fragmentation and leads to significant increased ‘kiss-and-run'' type of mitochondrial fusion; however, Yme1L knockdown (shYme1L (short hairpin-mediated RNA interference of Yme1L)) cells still remain normal mitochondrial fusion although shYme1L mitochondria have a little bit less fusion and fission rates, and the shYme1L-induced fragmentation is due to a little bit more mitochondrial fission than fusion in cells. Furthermore, shYme1L-induced mitochondrial fragmentation is independent on optic atrophy 1 (OPA1) S1 or S2 processing, and shYme1L results in the stabilization of OPA1 long form (L-OPA1); in addition, the exogenous expression of OPA1 or L-OPA1 facilitates the shYme1L-induced mitochondrial fragmentation, thus this fragmentation induced by shYme1L appears to be associated with L-OPA1''s stability. ShYme1L also causes a slight increase of mitochondrial dynamics proteins of 49 kDa and mitochondrial fission factor (Mff), which recruit mitochondrial key fission factor dynamin-related protein 1 (Drp1) into mitochondria in MEF cells, and loss of Drp1 or Mff inhibits the shYme1L-induced mitochondrial fragmentation. In addition, there is interaction between SLP-2 with Yme1L and shYme1L cells retain stress-induced mitochondrial hyperfusion. Taken together, our results clarify how Yme1L regulates mitochondrial morphology.     

Podocyte as A Potential Target of Inflammation: Role of Pioglitazone Hydrochloride in Patients With Type 2 Diabetes

ObjectiveTo observe the effects of pioglitazone hydrochloride on urinary sediment podocalyxin and monocyte chemoattractant protein-1 (MCP-1) excretion in patients with type 2 diabetes and to explore its possible renoprotective mechanisms.MethodsNinety-eight patients with uncontrolled type 2 diabetes, who were previously prescribed metformin, acarbose, or both, were randomly assigned to a DP group (add-on pioglitazone; n = 49) or a DS group (add-on sulfonylurea; n = 49).ResultsAfter 12 weeks of treatment, both add-on pioglitazone therapy (the DP group) and add-on sulfonylurea therapy (the DS group) demonstrated a similar improvement in fasting blood glucose and hemoglobin A_1c, but systolic and diastolic blood pressure declined significantly in only the DP group. Moreover, the DP group showed significantly better efficacy in reducing urinary MCP-1 excretion in comparison with the DS group. Furthermore, both urinary albumin and urinary sediment podocalyxin excretion decreased significantly in the DP group but not in the DS group. The urinary sediment podocalyxin to creatinine ratio had a positive correlation with urinary albumin to creatinine ratio (r = 0.624; P < .01) and urinary MCP-1 to creatinine ratio (r = 0.346; P < .01).ConclusionPioglitazone treatment revealed a podocyte-protective capacity in patients with type 2 diabetes, and the underlying mechanisms may be partly attributed to its effective suppression of excessive local renal inflammation. (Endocr Pract. 2012;18:493-498)     

Effects of Temperature on Development of Heterodera glycines on Glycine max and Phaseolus vulgaris

Soybean cyst nematode resistant ''Fayette'' and susceptible ''Williams 79'' soybeans (Glycine max) and resistant ''WIS (RRR) 36'' and susceptible ''Eagle'' snap beans (Phaseolus vulgaris) were used in determining the effects of host and temperature on the development, female production, sex ratios, and host response to Heterodera glycines. Temperatures were maintained constant at 16, 20, 24, 28, and 32 C using water-filled tanks. The most rapid development and greatest female production occurred between 20 and 28 C. The equation DS = 5(10⁻⁶)x²y² - 3(10⁻⁴)x²y - 2.8(10⁻³)x² - 1.94(10⁻²)y² + 0.4288x + 1.0220y - 12.7185, where DS = developmental stage, X = time, and Y = temperature, predicted the developmental stage of the nematode and accounted for 84% of the variation. Male : female ratios did not differ within this range and were generally less than one. At all temperatures the resistant soybean produced the greatest number of necrotic responses to H. glycines infection, followed by the resistant snap bean. The susceptible soybean and snap bean produced the fewest necrotic responses.     

Association analysis of common variants in FOXO3 with type 2 diabetes in a South Indian Dravidian population

Recent studies have identified common variants in forkhead box O3 gene (FOXO3) to be strongly associated with longevity in different populations. But studies have not been carried out to analyse the role of common variants in FOXO3 with type 2 diabetes. Since type 2 diabetes is an age related disorder and FOXO proteins play an important role in the regulation of metabolism, we studied the role of common variants in FOXO3 for association with type 2 diabetes. The study was carried out in 994 type 2 diabetic samples and 984 normoglycemic control samples from a South Indian Dravidian population. In our analysis, we found that there was no association between any of the selected SNPs in FOXO3 with type 2 diabetes. Analysis of these SNPs with diabetes related biochemical and clinical parameters also did not reveal any significant association. Haplotype association of SNPs in FOXO3 with type 2 diabetes was observed, but the frequency of the haplotypes was considerably lower and they do not remain significant after correction for multiple testing. In conclusion, we did not observe any association of SNPs in FOXO3 with type 2 diabetes and related parameters suggesting an entirely different mechanism by which these SNPs influence longevity. However additional studies in other populations are required to completely rule out the association of common variants in FOXO3 with type 2 diabetes.     

Exosome release and cargo in Down syndrome

Down syndrome (DS) is a multisystem disorder affecting 1 in 800 births worldwide. Advancing technology, medical treatment, and social intervention have dramatically increased life expectancy, yet there are many etiologies of this disorder that are in need of further research. The advent of the ability to capture extracellular vesicles (EVs) in blood from specific cell types allows for the investigation of novel intracellular processes. Exosomes are one type of EVs that have demonstrated great potential in uncovering new biomarkers of neurodegeneration and disease, and also that appear to be intricately involved in the transsynaptic spread of pathogenic factors underlying Alzheimer's disease and other neurological diseases. Exosomes are nanosized vesicles, generated in endosomal multivesicular bodies (MVBs) and secreted by most cells in the body. Since exosomes are important mediators of intercellular communication and genetic exchange, they have emerged as a major research focus and have revealed novel biological sequelae involved in conditions afflicting the DS population. This review summarizes current knowledge on exosome biology in individuals with DS, both early in life and in aging individuals. Collectively these studies have demonstrated that complex multicellular processes underlying DS etiologies may include abnormal formation and secretion of extracellular vesicles such as exosomes.     

Application of a Mouse Ligated Peyer’s Patch Intestinal Loop Assay to Evaluate Bacterial Uptake by M cells

The inside of our gut is inhabited with enormous number of commensal bacteria. The mucosal surface of the gastrointestinal tract is continuously exposed to them and occasionally to pathogens. The gut-associated lymphoid tissue (GALT) play a key role for induction of the mucosal immune response to these microbes^{1, 2}. To initiate the mucosal immune response, the mucosal antigens must be transported from the gut lumen across the epithelial barrier into organized lymphoid follicles such as Peyer''s patches. This antigen transcytosis is mediated by specialized epithelial M cells^{3, 4}. M cells are atypical epithelial cells that actively phagocytose macromolecules and microbes. Unlike dendritic cells (DCs) and macrophages, which target antigens to lysosomes for degradation, M cells mainly transcytose the internalized antigens. This vigorous macromolecular transcytosis through M cells delivers antigen to the underlying organized lymphoid follicles and is believed to be essential for initiating antigen-specific mucosal immune responses. However, the molecular mechanisms promoting this antigen uptake by M cells are largely unknown. We have previously reported that glycoprotein 2 (Gp2), specifically expressed on the apical plasma membrane of M cells among enterocytes, serves as a transcytotic receptor for a subset of commensal and pathogenic enterobacteria, including Escherichia coli and Salmonella enterica serovar Typhimurium (S. Typhimurium), by recognizing FimH, a component of type I pili on the bacterial outer membrane ⁵. Here, we present a method for the application of a mouse Peyer''s patch intestinal loop assay to evaluate bacterial uptake by M cells. This method is an improved version of the mouse intestinal loop assay previously described ^{6, 7}. The improved points are as follows: 1. Isoflurane was used as an anesthetic agent. 2. Approximately 1 cm ligated intestinal loop including Peyer''s patch was set up. 3. Bacteria taken up by M cells were fluorescently labeled by fluorescence labeling reagent or by overexpressing fluorescent protein such as green fluorescent protein (GFP). 4. M cells in the follicle-associated epithelium covering Peyer''s patch were detected by whole-mount immunostainig with anti Gp2 antibody. 5. Fluorescent bacterial transcytosis by M cells were observed by confocal microscopic analysis. The mouse Peyer''s patch intestinal loop assay could supply the answer what kind of commensal or pathogenic bacteria transcytosed by M cells, and may lead us to understand the molecular mechanism of how to stimulate mucosal immune system through M cells.     

Mitochondrial dysfunction and complications associated with diabetes

Background

Diabetes is a metabolic syndrome that results in chronically increased blood glucose (hyperglycaemia) due to defects either in insulin secretion consequent to the loss of beta cells in the pancreas (type 1) or to loss of insulin sensitivity in target organs in the presence of normal insulin secretion (type 2). Long term hyperglycaemia can lead to a number of serious health-threatening pathologies, or complications, especially in the kidney, heart, retina and peripheral nervous system.

Scope of review

Here we summarise the current literature on the role of the mitochondria in complications associated with diabetes, and the limitations and potential of rodent models to explore new modalities to limit complication severity.

Major conclusions

Prolonged hyperglycaemia results in perturbation of catabolic pathways and in an over-production of ROS by the mitochondria, which in turn may play a role in the development of diabetic complications. Furthermore, current models don't offer a comprehensive recapitulation of these complications.

General significance

The onset of complications associated with type 1 diabetes can be varied, even with tightly controlled blood glucose levels. The potential role of inherited, mild mitochondrial dysfunction in accelerating diabetic complications, both in type 1 and 2 diabetes, remains unexplored. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.     

A high‐fat diet exacerbates the Alzheimer's disease pathology in the hippocampus of the App NL−F/NL−F knock‐in mouse model

Insulin resistance and diabetes mellitus are major risk factors for Alzheimer''s disease (AD), and studies with transgenic mouse models of AD have provided supportive evidence with some controversies. To overcome potential artifacts derived from transgenes, we used a knock‐in mouse model, App^{NL−F/NL−F} , which accumulates Aβ plaques from 6 months of age and shows mild cognitive impairment at 18 months of age, without the overproduction of APP. In the present study, 6‐month‐old male App^{NL−F/NL−F} and wild‐type mice were fed a regular or high‐fat diet (HFD) for 12 months. HFD treatment caused obesity and impaired glucose tolerance (i.e., T2DM conditions) in both wild‐type and App^{NL−F/NL−F} mice, but only the latter animals exhibited an impaired cognitive function accompanied by marked increases in both Aβ deposition and microgliosis as well as insulin resistance in the hippocampus. Furthermore, HFD‐fed App^{NL−F/NL−F} mice exhibited a significant decrease in volume of the granule cell layer in the dentate gyrus and an increased accumulation of 8‐oxoguanine, an oxidized guanine base, in the nuclei of granule cells. Gene expression profiling by microarrays revealed that the populations of the cell types in hippocampus were not significantly different between the two mouse lines, regardless of the diet. In addition, HFD treatment decreased the expression of the Aβ binding protein transthyretin (TTR) in App^{NL−F/NL−F} mice, suggesting that the depletion of TTR underlies the increased Aβ deposition in the hippocampus of HFD‐fed App^{NL−F/NL−F} mice.     

Alkylsulfanyl analogs as potent α2δ ligands

We identified novel (3R, 5S)-3-aminomethyl-5-methanesulfanyl hexanoic acid (5a: DS75091588) and (3R, 5S)-3-aminomethyl-5-ethanesulfanyl hexanoic acid (6a: DS18430756) as sulfur-containing γ-amino acid derivatives that were useful for the treatment of neuropathic pain. These two compounds exhibited a potent analgesic effect in animal models of both type I diabetes and type II diabetes, and good pharmacokinetics.     

Inhibiting toxic aggregation of amyloidogenic proteins: A therapeutic strategy for protein misfolding diseases

Background

The deposition of self-assembled amyloidogenic proteins is associated with multiple diseases, including Alzheimer's disease, Parkinson's disease and type 2 diabetes mellitus. The toxic misfolding and self-assembling of amyloidogenic proteins are believed to underlie protein misfolding diseases. Novel drug candidates targeting self-assembled amyloidogenic proteins represent a potential therapeutic approach for protein misfolding diseases.

Scope of review

In this perspective review, we provide an overview of the recent progress in identifying inhibitors that block the aggregation of amyloidogenic proteins and the clinical applications thereof.

Major conclusions

Compounds such as polyphenols, certain short peptides, and monomer- or oligomer-specific antibodies, can interfere with the self-assembly of amyloidogenic proteins, prevent the formation of oligomers, amyloid fibrils and the consequent cytotoxicity.

General significance

Some inhibitors have been tested in clinical trials for treating protein misfolding diseases. Inhibitors that target the aggregation of amyloidogenic proteins bring new hope to therapy for protein misfolding diseases.     

Overall and central obesity and risk of type 2 diabetes in U.S. black women

Objective: Obesity has risen to epidemic proportions in the United States, leading to an emerging epidemic of type 2 diabetes. African‐American women are disproportionately affected by both conditions. While an association of overall obesity with increasing risk of diabetes has been documented in black women, the effect of fat distribution, specifically abdominal obesity, has not been studied. We examined the association of BMI, abdominal obesity, and weight gain with risk of type 2 diabetes. Research Methods and Procedures: During eight years of follow‐up of 49,766 women from the Black Women's Health Study, 2472 incident cases of diabetes occurred. Cox proportional hazard models were used to estimate incidence rate ratios (IRRs), with control for age, physical activity, family history of diabetes, cigarette smoking, years of education, and time period of data collection. Results: Sixty‐one percent of participants had a BMI ≥25 kg/m² (WHO definition of overweight). Compared with a BMI of <23 kg/m², the IRR for a BMI of >45 kg/m² was 23 (95% confidence interval, 17.0 to 31.0). The IRR for the highest quintile of waist‐to‐hip ratio relative to the lowest was 2.3 (95% confidence interval, 2.0 to 2.7) after control for BMI. Furthermore, at every level of BMI, an increased risk was observed for high waist‐to‐hip ratio relative to low. Discussion: Central obesity, as well as overall obesity, is a strong risk factor for diabetes in African‐American women. Efforts to reduce the prevalence of obesity in African‐American women are of paramount importance.     

Mechanical stress,fracture risk and beak evolution in Darwin's ground finches (Geospiza)

Darwin''s finches have radiated from a common ancestor into 14 descendent species, each specializing on distinct food resources and evolving divergent beak forms. Beak morphology in the ground finches (Geospiza) has been shown to evolve via natural selection in response to variation in food type, food availability and interspecific competition for food. From a mechanical perspective, however, beak size and shape are only indirectly related to birds'' abilities to crack seeds, and beak form is hypothesized to evolve mainly under selection for fracture avoidance. Here, we test the fracture-avoidance hypothesis using finite-element modelling. We find that across species, mechanical loading is similar and approaches reported values of bone strength, thus suggesting pervasive selection on fracture avoidance. Additionally, deep and wide beaks are better suited for dissipating stress than are more elongate beaks when scaled to common sizes and loadings. Our results illustrate that deep and wide beaks in ground finches enable reduction of areas with high stress and peak stress magnitudes, allowing birds to crack hard seeds while limiting the risk of beak failure. These results may explain strong selection on beak depth and width in natural populations of Darwin''s finches.