This study was carried out to assess the reliability of core biopsy in predicting the grade and type of cancer accurately as obtaining this information can influence initial therapeutic decisions.Core biopsy is a method of choice for the triple assessment of breast disease as it can reliably distinguish between benign and malignant tumours, between kappa statastics.A total of 105 patients who had invasive breast carcinoma diagnosed by core biopsy in year 2001 and who subsequently underwent surgical management were included. The core biopsy results were compared with final histology with the help of A moderate level of agreement between the predicted grades and final grades was noted (kappa = 0.585). The agreement was good between predicted and final type of tumour (kappa = 0.639).Core biopsy as a predictor of grade and type has limited use at present. We suggest that initial clinical decisions should not be based on the results of core biopsy. Collins et al have shown that majority (83%) of core biopsies and excisional procedures demonstrate exact histological agreement [Core biopsy is rapidly replacing fine needle aspiration cytology (FNAC) as a procedure of choice for the triple assessment of the breast problems. Where there is access to an experienced cytopathologist, the FNAC can provide a rapid and cost effective means of triage of patients who would benefit from more expensive core biopsy . Core bigreement . Core bigreement .As the range of options for the treatment of the breast cancer widens, it has become increasingly important that clinicians are provided with accurate prognostic information to base the initial therapeutic decisions on. Prognostic factors for breast cancer have been extensively studied. Histological grade and type can be used to predict biological behaviour as has been assessed by overall survival and local recurrence for women with primary breast carcinoma -9. HistoThe aim of this study, therefore, was to see how reliable core biopsy is in predicting the grade and the type of cancers, as that could influence the further management of breast cancer.in-situ diagnosed by core biopsy and patients who underwent neo-adjuvant therapy were excluded from the study. Level of agreement between core and excision biopsy was assessed using kappa statistics.All patients with invasive breast cancer diagnosed by the core biopsy and treated subsequently by surgical excision in the year 2001, at a district general hospital were included in the study. Of the 105 patients whose records were studied retrospectively, 47 lesions were palpable and 58 lesions were screen detected. The core biopsies were performed under ultrasound guidance as a part of triple assessment and at least four cores were obtained from palpable lesions and six or more from screen detected lesions with a 22 mm automated core biopsy gun. Two dedicated breast pathologists had authorised all the reports. Age of patients ranged from 35 to 84 with a median age of 62 years. The histology reports for the core biopsy and final histology were extracted and compared. Carcinoma Of 105 patients there was no prediction of grade in 2 patients and in 19, a prediction of grade 1 or 2 or grade 2 or 3 was made. This left 84 where a clear prediction was made. On final histology 35 (33.3%) were categorised as grade I, 45 (42.8%) were grade II and 25 (23.8%) were grade III. The predicted grades versus final grade results are detailed in table Of the 84 cores in which clear prediction of grade was made 63 (75%) were correct. All 21 of grade 1's were predicted correctly, 35 (71%) of grade 2's were predicted correctly but only 7 (50%) or grade 3's were predicted correctly on core biopsy. Of the predicted grade 2's which were reclassified, 5 (10%) were downgraded and 9 (18%) were upgraded. Of the reclassified grade 3's, 6 (43%) were downgraded to grade 2 and 1 (7%) was downgraded to grade 1.Of 105 patients, 101 patients had a prediction of type made. Of 84 cases predicted to be ductal, 81 (96%) were correct and one case was reclassified as mixed histology. Of the 14 predicted to be lobular 9 (64%) were correct and one reclassified as mixed Table . Of the In general the level of agreement between the predicted grades and final grades was moderate (kappa = 0.585) and between predicted and final types was slightly better (kappa = 0.639).et al reported percutaneous, image guided biopsy to be an accurate diagnostic alternative to surgical biopsy in women with mammographically detected suspicious breast lesions [Fajardo  lesions . The fal lesions . However lesions  or amoun lesions  has not  lesions .Histological grade and type, tumour size and presence or absence of axillary node metastases is well-recognised prognostic factors of breast cancer. Tumour grade, size and nodal involvement are three factors considered in Nottingham Prognostic Index . HistoloGreen Hough 1925) was the first to categorise the breast tumours into three grades according to its differentiation. He also assessed the association of grades with "cure" though the term cure was not clearly defined . Since t was the Of the two major histological types, lobular is known for its multifocality and multicentricity and its diffusely infiltrating nature . It is iOur results suggest that the prediction of grade and type of breast cancer from core biopsy has only limited use at present. The group of patients we would like to be predicted most accurately would have been those with a high-grade and lobular type, for the reasons stated above. Our results suggest that these patients are most difficult to predict in practice. However, present study being retrospective has its own drawbacks. A prospective study specifically aimed at Kappa statistics between core biopsy and final histopathology may be able to answer this question better. Further refinements are needed in technique of core biopsy and these technical innovations will ultimately improve the results of core biopsy.The author(s) declare that they have no competing interests.AD: Original idea, planning of study, background search, data compilation and drafting the manuscript.TG: Data collection, data compilation, help with the manuscript drafting.SH: Overall supervision and guidance with the study, helped in the analysis and helped with manuscript drafting and revisions.All authors read and approved the final versionNone


Six hundred and eighty-four primary breast cancers from the International (Ludwig) Breast Cancer Study Group (IBCSG) were studied for Helix pomatia lectin (HPA) binding. There was a weak correlation between lymph node-positive and HPA positive (P = 0.04). In our series there was a large advantage in disease-free survival (DFS) and overall survival (OS) for node-negative patients (P < 0.0001 DFS and OS). However, there was no such advantage for HPA-negative patients (P = 0.23 DFS and P = 0.32 OS). We conclude that in this randomised patient group HPA is of no clinical predictive value.


This special issue on Cell Stress and Cell Death is aimed at bringing together recent developments in the fields of cellular stress and cell death and, in particular, the interplay between cell stress responses and cell death. The special issue opens with a review by S. Fulda et al. which provides an overview of how cells can respond to stress in a variety of ways ranging from the activation of survival pathways to the initiation of cell death that eventually eliminates damaged cells. Whether cells mount a protective response or succumb to death depends to a large extent on the nature and duration of the stress as well as the cell type. For example, milder stresses can lead to protection through activation of the heat shock response or the unfolded protein response (UPR). This review also describes several types of cell death  and the mechanism by which a cell dies often depends on various exogenous factors as well as the cell's ability to handle the stress to which it is exposed. The implications of cellular stress responses for human physiology and disease are multifold and are discussed in this review in the context of some major world health issues such as diabetes, Parkinson's disease, myocardial infarction, and cancer. 2+, address this topic. In recent years there has been a significant increase in the number of papers in the field dealing with ER stress and ER stress-induced cell death. This reflects the growing recognition of the importance of the ER in cell stress and in different modes of cell death. The ER is the site of folding of membrane and secreted proteins in the cell. Physiological or pathological processes that disturb protein folding in the ER initiate a complex intracellular signal transduction pathway, known as the UPR. This response is an attempt to reestablish ER homeostasis, although it can also lead to cell death. The review by A. Samali et al. provides a comprehensive overview of current methodologies for monitoring the UPR and ER stress, and it puts together a set of criteria to assess this response, which will be useful for researchers who wish to examine these phenomena in different model systems. The UPR is essentially tailored to reestablish ER homeostasis and it can also signal through other adaptive mechanisms involving the stimulation of autophagy. However, when ER stress is persistent, the cytoprotective functions of the UPR and autophagy can switch to cell death-promoting mechanisms. A review by T. Verfaillie et al. discusses the relationship between ER stress and autophagy and the implications for cancer therapy. Recently, a variety of anticancer therapies have been linked to the induction of ER stress in cancer cells, envisaging strategies that stimulate prodeath function or block its prosurvival function, to improve tumoricidial action. A better understanding of the molecular mechanisms that determine the final outcome of UPR and autophagy activation by chemotherapeutic agents will offer new opportunities to improve existing cancer therapies as well as revealing novel targets for cancer treatment. Prolonged or severe ER stress has been linked to induction of apoptosis. Caspase activation is one of the key steps in commitment of cells to apoptosis and is dependent on mitochondrial outer membrane permeabilization (MOMP) and the release of cytochrome c from the mitochondria. The research article by S. Gupta et al. investigates the mechanism of ER stress-induced MOMP using thapsigargin as an inducer of ER stress. They genetically dissected the role of caspase-9, -3, and -2 in the induction of MOMP by ER stress using embryonic fibroblasts derived from knockout mice and also treated cells with chemical and molecular inhibitors of the mitochondrial permeability transition. Their results suggest that caspase-9 and -2, Bcl-2 family members, and the mitochondrial permeability transition pore all play a role in MOMP during ER stress-induced apoptosis. There are many molecules and cellular processes that play critical roles in normal cell signaling and survival responses, while also having a dual role in inducing cell death. A number of papers in this special issue, covering endoplasmic reticulum (ER) stress and Ca2+ is an important second messenger which is also poised at the intersection between cell survival and cell death. The review by C. Cerella et al. examines the events that occur during Ca2+ toxicity and how reparative or death pathways can be activated. They also discuss the observations that while Ca2+ can elicit these opposing responses, it also plays a role as a second messenger in signal transduction associated with cell death and survival. CaKnowledge of cell stress and cell death pathways, and the interplay between these, beneficially provides us with new ways to tackle diseases, particularly cancers and degenerative disease. Resistance to apoptosis is a feature of many cancer cells and this is the subject of the review by S. Fulda which summarizes the main mechanisms by which cancer cells evade the intrinsic and extrinsic apoptosis pathways. Generally, altered ratios of key pro- and antiapoptotic proteins are responsible for resistance to cell death; for example, altered ratios of Bcl-2 family proteins as well as increased expression of caspase inhibitors (IAPs) regulate the intrinsic pathway, while reduced sensitivity of extrinsic pathways occurs due to decreased expression of death receptors on the plasma membrane and increased expression of intracellular decoy proteins. Given this increased resistance to cell death pathways, the search for novel molecules to induce cell death in cancer cells is an important goal. Histone deacetylase inhibitors have become a promising new avenue for cancer therapy, and many are currently in clinical trials for various tumor types. The research article by N. Rivera-Del Valle et al. demonstrates that a novel hydroxamic acid histone deacetylase inhibitor, PCI-24781, exerts cytotoxicity and histone alterations in leukemia cells, via a mechanism that is dependent on caspase-8 and Fas-associated death domain. Another avenue for identifying novel therapeutic targets for cancers is study of inflammation, since many human malignancies have been strongly linked with chronic inflammation. The review by C. Sobolewski et al. describes the role of cyclooxygenase-2 in these diseases. This enzyme is a member of a family, which catalyzes the rate-limiting step of prostaglandin biosynthesis. Cyclooxygenase-2 is upregulated during both inflammation and cancer, and has been described to modulate cell proliferation and apoptosis mainly in solid tumors and more recently in hematological malignancies. Thus, the use of cyclooxygenase-2 inhibitors, together with other therapeutic strategies, may further improve the efficiency of anticancer treatments in the clinic. inhibit cell death. One such disease is Parkinson's disease, where there are currently no therapies which halt the degeneration of dopaminergic neurons. In the research article by K. Mnich et al. the ability of the endogenous cannabinoid, anandamide, to inhibit apoptotic cell death by the Parkinson mimetic, 6-hydroxydopamine, was shown. The protection provided by anandamide involved activation of phosphatidylinositol 3-kinase and prevention of 6-hydroxydopamine induced activation of c-Jun-NH2-terminal kinase (JNK). These data add to the growing body of literature concerning cannabinoids and Parkinson's disease. Certain other neurodegenerative diseases, termed tauopathies, feature filamentous tau-positive protein inclusions in neurons and glia, which are characterized by the expression of stress response proteins, particularly heat shock proteins (Hsps), in these inclusions. The article by L. Schwarz et al. investigated the contribution of small Hsps, Hsp27, and αB-crystallin, to neurodegenerative diseases by analyzing the association of Hsp27 with pathological lesions of tauopathies. Their results suggest distinct mechanisms for Hsp27 action in glial and neuronal cells, with prominent expression in unstressed astrocytes but with low expression observed in neurons even after stress situations.In contrast to cancers, an important aim of research into degenerative diseases is to discover novel ways to We hope that this special issue will alert researchers to some new developments in the fields of cell stress and cell death, particularly the interplay between prosurvival and prodeath responses, and how our knowledge of these can direct our efforts in discovering new therapeutic strategies for the treatment of cancers and degenerative diseases.Afshin SamaliAfshin SamaliSimone FuldaSimone FuldaAdrienne M. GormanAdrienne M. GormanOsamu HoriOsamu HoriSrinivasa M. SrinivasulaSrinivasa M. Srinivasula


Cervical cancer is the most common cancer experienced by women worldwide; however, screening techniques are very effective for reducing the risk of death. The national cervical cancer screening program was implemented in Taiwan in 1995. The objective of this study was to examine and provide evidence of the cervical cancer mortality trends for the periods before and after the screening program was implemented.Data from 1981 to 2010 of the causes of death registered were obtained from the Department of Health, Taiwan. Age-standardized mortality rates, age-specific rates, and age-period-cohort models that employed the sequential method were used to assess temporal changes that occurred between 1981 and 2010, with 1995 used as the separating year.The results showed that for both time periods of 1981 to 1995 and 1996 to 2010, age and period had significant effects, whereas the birth cohort effects were insignificant. For patients between 80 and 84 years of age, the mortality rate for 1981 to 1995 and 1996 to 2010 was 48.34 and 68.08. The cervical cancer mortality rate for 1996 to 2010 was 1.0 for patients between 75 and 79 years of age and 1.4 for patients between 80 and 84 years of age compared to that for 1981 to 1995. Regarding the period effect, the mortality trend decreased 2-fold from 1996 to 2010.The results of this study indicate a decline in cervical cancer mortality trends after the screening program involving Papanicolaou tests was implemented in 1995. However, the positive effects of the screening program were not observed in elderly women because of treatment delays during the initial implementation of the screening program. Cervical cancer is the most common and serious gynecologic malignancy worldwide. This finding highlights the urgent need to significantly increase cancer survival rates and reduce mortality through screening programs. Cervical screening methods that involve cytology tests, the Papanicolaou technique (PT), human papillomavirus (HPV) tests, and visual inspections of the cervix with 5% acetic acid (VIA) have been established to reduce the cervical cancer mortality rate by almost 60% in numerous countries ,2. NatioAccording to the World Health Organization (WHO)’s cervical cancer screening guidelines, screening is defined as testing all women at risk of cervical cancer, most of whom will not exhibit symptoms. The objective of screening is to detect precancerous changes that, if left untreated, can lead to cancer. However, screening is only effective if a well-organized follow-up and treatment system is also provided. Women who are found to have abnormalities during screening require follow-up consultations, diagnosis, and possibly treatment to prevent the development of cancer or to treat cancer in the initial stage. Several tests can be used to screen for cervical cancer. However, the Papanicolaou smear (Pap cytology) is the only test that has been applied to large populations and been shown to reduce the incidence and mortality rate of cervical cancer. Although VIA, and HPV test have shown potential, to date, no comparable evidence of their effectiveness exists. Large-scale studies are still being conducted. Regardless of the test used, the key to an effective program is to target the largest proportion of women at risk with quality screening and treatment. Organized screening programs that are designed to reach most women at risk and managed at a central level are preferable to opportunistic screening.The Bureau of Health Promotion of the Department of Health implemented the screening program in Taiwan in 1995. Under the screening policy, free annual medical examinations are provided to all Taiwanese women aged 30 years or older. Women who are sexually active are strongly advised to undergo a smear test at least once every 3 years. Women who have been diagnosed with a sexually transmitted disease, the human immunodeficiency virus, the human papillomavirus, or cervical dysplasia, and who have numerous sexual partners, should undergo testing once every year. The results of a smear test provide a reference for whether further examinations are necessary. If the test results are unclear regarding pathological changes, women are recommended to undergo a biopsy. If the biopsy indicates carcinoma in situ, women will only require a simple operation to fully cure the disease.Through a time trend analysis of mortality rates, we can evidence the efficacy of cervical screening programs. The age-period-cohort (APC) model is one of the most common statistical methods. In a previous study , a numbeth for 180.0, and ICD-10th for C53.0), exocervix , other specified sites of the cervix , and unspecified sites of the cervix uteri .Data from 1981 to 2010 of the causes of death registered were obtained from the Department of Health, Taiwan. We selected three variables for sequentially analysis, that is, age of death, period of death, and the coding of International Classification of Diseases (ICD). To determine the three factors  for time trend analysis, we first excluded patients who were aged 19 and under and patients who were aged 85 and over before separating the participants into 13 groups of 5 age bands each. Second, we separated 6 aggregations by 5 years of death for each period group. Finally, cohort groups were calculated according to age groups and period groups. Cervical cancer was defined as malignancies of the endocervix  exhibited an increasing trend before 1995, but not among younger women. i.e. the mortality risks for women aged 70 years or more increased annually before 1995; whereas no significant change in mortality trends was observed among women under 70. Present studies cannot provide a suitable explanation for this finding. The reason for these results may be a particular risk factor directly or indirectly related to age that remains unknown. However, we still propose some possible reasons causing this phenomenon for subsequent study validation. Regarding the phenomenon of multiple births among women of the post-war generation, a number of previous studies have suggested that pregnancy at an excessively early age and excessive pregnancies may be risk factors for cervical cancer . Taiwan However, the results of numerous previous studies also support the limited effectiveness of cervical cancer screening among elderly women -27; one In 2006, Lloroa  contendeth to 10th) and 5 versions (ICD-6th to 10th) of ICD codes. To the best of our knowledge, the different versions of ICD codes were developed through diagnosis and treatment. Thus, we can infer that the old version may be the primary cause of the assumption. Based on this condition, we calculated the cervical cancer mortality trends for 1981 to 2010, but we only included two versions of ICD codes. However, the death registration system in Taiwan cited ICD-9th for death certificates for 1981 to 2008, and ICD-10th for 2008 to the present. Therefore, the effects of various versions of ICD codes are the lowest in this study.However, this assumption and concept do not need to be considered in this study. Furthermore, the above conditions indicate that the study design included analysis of long-term trends and more than one version of ICD codes. In the studies conducted by Lloroa and Levi, the periods analyzed were 1955 to 1995 and 1960 to 1998, and they included 4 versions . The percentage of death-certificate-only cases (DCO%) between 1980 and 2009 show steady improvements in the quality of Taiwan Cancer Registry. The MV% increased from 82.4% between 1980 and 1984 to 89.05% between 2005 and 2009. The DCO% declined from 28.8% between 1985 and 1989 to 1.4% between 2005 and 2009.The results of this study support the effectiveness of the screening program through analysis of the results of the APC model and other standard statistic techniques. For both older and younger women in Taiwan, the screening program provided positive effects by reducing mortality rates; however, it also provided a delayed effect among elderly women. The reliability of supplementary measures following screening using Papanicolaou tests may be significant contributors. However, additional related studies with demographic analyses of the initial screening program implementation delay pattern are required for clarification in future research.PT: Papanicolaou technique; HPV: Human papillomavirus; VIA: Visual inspection of the cervix with 5% acetic acid; APC: Age-period-cohort; ICD: International classification of diseases; AIC: Akaile information criterion; WHO: World health organization; ASMR: Age-standardized mortality rate; UNOS: Cancer of the uterus at an unspecified site.The authors declare that they have no competing interests related to this manuscript.SSY participated in the design, data analysis, research implementation, results interpretation, and manuscript writing. LYP participated in the design, research implementation, and manuscript drafting and editing. JYH participated in the data analysis. DPJ and CCH contributed to the searching and management of the reference list. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/13/13/prepub


Apoptosis is a tightly regulated process: cellular survive-or-die decisions cannot be accidental and must be unambiguous. Since the suicide program may be initiated in response to numerous stress stimuli, signals transmitted through a number of checkpoints have to be eventually integrated.In order to analyze possible mechanisms of the integration of multiple pro-apoptotic signals, we constructed a simple model of the Bcl-2 family regulatory module. The module collects upstream signals and processes them into life-or-death decisions by employing interactions between proteins from three subgroups of the Bcl-2 family: pro-apoptotic multidomain effectors, pro-survival multidomain restrainers, and pro-apoptotic single domain BH3-only proteins. Although the model is based on ordinary differential equations (ODEs), it demonstrates that the Bcl-2 family module behaves akin to a Boolean logic gate of the type dependent on levels of BH3-only proteins (represented by Bad) and restrainers (represented by Bcl-xL). A low level of pro-apoptotic Bad or a high level of pro-survival Bcl-xL implies gate AND, which allows for the initiation of apoptosis only when two stress stimuli are simultaneously present: the rise of the p53 killer level and dephosphorylation of kinase Akt. In turn, a high level of Bad or a low level of Bcl-xL implies gate OR, for which any of these stimuli suffices for apoptosis.analogous inputs into a digital survive-or-die decision.Our study sheds light on possible signal integration mechanisms in cells, and spans a bridge between modeling approaches based on ODEs and on Boolean logic. In the proposed scheme, logic gates switching results from the change of relative abundances of interacting proteins in response to signals and involves system bistability. Consequently, the regulatory system may process two  Apoptosis is a programmed cell death required for removal of infected, damaged or unwanted cells . It assic from mitochondria results in the formation of apoptosome  and activation of caspase-9 [c, which ensures that the apoptotic decision is irreversible [In mammalian cells, apoptosis can be induced via two classes of apoptotic pathways: extrinsic and intrinsic ,7. In boaspase-9 , which aaspase-9 ,12 respoaspase-9 . Caspaseversible ,15.α, TWEAL and Trail) [κB-mediated) signals are induced. Caspase-8 and -10 recruited to death receptors autoactivate themselves and activate further effector caspases (caspase-3 and -7) either by direct processing or by engaging the intrinsic death pathway [The extrinsic apoptotic pathways, also known as ‘death receptor pathways’, are initiated through the activation of membrane death receptors, including Fas, TNFR, DR3 and DR4/DR5, by their respective ligands  ,17. Enga pathway .c. This process is regulated by the Bcl-2 family proteins, which share up to four BH (Bcl-2 homology) domains. The proteins can be classified as: pro-apoptotic multidomain effectors (Bax and Bak), pro-survival multidomain restrainers  and pro-apoptotic single domain BH3-only upstream sentinels  [The intrinsic apoptotic pathway is also called the mitochondrial pathway because it is associated with the disruption of mitochondrial outer membranes and consequent release of cytochrome  others) ,19.bax or bak affects apoptosis only slightly, but deletion of both these genes dramatically impairs apoptosis in many tissues [bim–/–bid–/– mice develop rather normally [L:Bad heterodimers, no Bax:Bcl-xL heterodimers are present [θ) instead of Bcl-2 family pro-survival restrainers [Bax and Bak are effectors directly responsible for the mitochondrial outer membrane permeabilization via either channel formation  or openi tissues ,25. Desp tissues ,27) can  tissues -30 . Oth tissues ,27,34,35normally . Additionormally , and thenormally ,39. The normally ,41. This present ,42. In ntrainers -45. Althtrainers .γ and UV irradiation, nutrient deprivation, viral infection, hypoxia and increased intracellular calcium concentration [Bcl-2 family proteins are activated or inhibited in response to numerous stress factors including heat shock, ntration ,48. In tntration ,50 and 2ntration -53.In not onco-transformed cells, p53 protein remains inactive . In respIn healthy cells but also frequently in cancer cells, Akt, in contrast to p53, maintains its  activity and suppresses apoptotic signals by phosphorylating and thereby inhibiting pro-apoptotic Bad . Akt actInterestingly, phosphorylation of p53 at Ser46 enables it to activate expression of phosphatase PTEN ,73, whicHere we review mathematical models of the apoptotic pathway, which are relevant to our study.et al. [c–Apaf dimers) is a key element ensuring bistability in survival-or-death decisions. They examined the influence of Bax and Bcl-2 synthesis and degradation rates, as well as the number of mitochondrial permeability transition pores (MPTPs) on the cell response to apoptotic stimuli. The model predicts that above some critical Bax degradation rate the system is monostable and cells survive. Bistability arises for Bax degradation smaller than critical, while the cell fate depends on the initial level of caspase-3. When the number of MPTPs is large, the bistability vanishes and the apoptosis is initiated regardless of the initial condition.Stucki and Simon  have focet al.  describeet al. [L . In the model the pro-survival action of Akt relies on Bad phosphorylation which primes it for degradation. The authors demonstrated that repeated oscillations of the p53 level lead to the depletion of Bcl-2 and Bcl-xL, which is considered as a marker of apoptosis. Antagonism between pro-apoptotic signals of p53 and pro-survival signals of Akt can also lead to bistability, which, if DNA repair is not accomplished in time, allows for termination of p53 oscillations [et al. [et al. [Wee et al.  analyzedllations -81, signllations ,83. In cllations ,82,83, L [et al.  construc [et al.  proposedet al. [et al. [c and caspase-3. In correspondence to the model proposed here, the study of Wee et al. [et al. [In summary, the above models revealed that apoptosis is possible based on the system bistability, which makes the apoptotic decision irreversible. Bagci et al.  showed t [et al.  bistabile et al.  indicate [et al.  presentewhether the interaction network of Bcl-2 family proteins allows for the integration of apoptotic signals, and if yes, whether this signal integration is analogous to Boolean logic gates. Boolean networks are used to model various regulatory pathways, including apoptotic ones [et al. [L.In this study we aim to address the question, tic ones , however [et al.  we focusode23tb solver implemented in MATLAB . The source code is available as the Additional file The system of ODEs following the proposed model was solved using the bax is well-established [L was reported between Bax and Bad, with the latter having higher affinity [L is selected to represent the group of restrainers. Neutralization of Bcl-xL is the primary pro-apoptotic function of Bad [L binding [Our model of the apoptotic decision module involves the following components: p53, Akt, scaffolding protein 14-3-3, caspases, and the Bcl-2 family proteins. The evidence that p53 serves as a transcription factor for ablished . Contrarablished . The comaffinity . For then of Bad ,88, and  binding . Thus, Bc from the mitochondrial intermembrane space [c enables the formation of the apoptosome, which in turn initiates the downstream caspase program [c creating positive feedback loop, which introduces bistability and makes the apoptotic decision irreversible [Active Bax, when freed from its antagonists, releases cytochrome ne space . Release program . In the versible ,15,83. Ip) and p53 in its killer form  will serve as inputs. Surviving cells are characterized by high level of Aktp and lack (or very low level) of p53killer. In these cells, most of Bad remains in the phosphorylated form (denoted Badp) bound to Scaffold14-3-3, while Bax is inhibited (sequestered) by Bcl-xL[u) may bind to Bcl-xL, which limits the amount of Bcl-xL protein available for inhibiting Bax. The steady state is controlled by the total levels of Bad (Badtot) and Bcl-xL (Bcl-xL tot), which will be considered as parameters in the model. The fraction of Bcl-xL bound to Bad increases with Badtot rendering cells of high Bad level more prone to apoptosis. In the model Figure , levels by Bcl-xL. UnphospWe consider two pro-apoptotic stimuli, which may lead to the accumulation of free Bax and consequent apoptosis: killer, which triggers Bax transcription and Bax protein accumulation;1) increase of the level of p53Aktp and corresponding increase of the level of unphosphorylated Akt (Aktu).2) dephosphorylation of Akt, i.e. decrease of 14-3-3. Dephosphorylated Bad captures Bcl-xL which eventually releases Bax.Akt dephosphorylation is followed by the dephosphorylation of Bad and its release from ScaffoldImportant notice: We assume that the total level of Akt (Akttot=Aktp+Aktu) remains constant. Under this assumption, the appearance of unphosphosphorylated Akt (Aktu) will be considered as a pro-apoptotic stimulus. The strength of both pro-apoptotic stimuli will be thus measured by p53killer and Aktu.mRNA, Bax, Bcl-xL, Bax:Bcl-xL, Bcl-xL:Badu, Badu, Badp, Badp:Scaffold14-3-3, Scaffold14-3-3, pro-caspases and caspases. The mathematical representation of the apoptotic module consists of 11 ordinary differential equations for levels of molecular species or their complexes: BaxmRNA transcription, induced by p53 killer, is modeled according to the sigmoidal kinetics  [Baxequal 2) . The cubequal 2) . Model pCasp with Bax considered as a bifurcation parameter. Casp undergoes the saddle-node bifurcation at Bax=Baxbif≃5000 (with Casp≃1000). Below the bifurcation point there exist three steady states: one unstable and two stable corresponding to low (<1000) and high (>9.9 × 104) caspase levels. Above the bifurcation point there exists the unique stable steady state characterized by high Casp. The structure of the bifurcation diagram ensures that the apoptotic switch is irreversible, i.e. once the system switches to the apoptotic state, it may not switch back even if the level of free effectors, Bax, drops to zero. The apoptotic switch occurs when Bax exceeds Baxbif for sufficiently long time; as we will show later, short excursions of Bax over Baxbif do not induce apoptosis. For the steady state analysis, however, the states with Bax>Baxbif will be interpreted as apoptotic.The last two equations exhibit bistability. In Figure p53killer and Aktu. In this section, we consider digital steady-state inputs: the signal from p53killer is assumed to be logic 0 for p53killer=0, and is assumed logic 1 for 0 for Aktu=0  and is considered logic 1 when Aktu=Akttot=2 × 105. Intermediate input values of Aktu∈ will be analyzed in a forthcoming section.We demonstrate that apoptosis can be controlled in a manner similar to logic gates OR and AND with inputs defined as Badtot=2 × 105, while gate AND is achieved for Badtot=0.6 × 105; here, for both gates we assume the same Bcl-xL tot=1 × 105. Surviving cell steady state is associated with conditions in which both apoptotic signals are equal zero. In these cells  Bad is bound to Bcl-xL. Rest of Bcl-xL sequesters Bax or remains free. Free Bcl-xL may be considered as the anti-apoptotic buffer, which may potentially capture the excess of Bax. This buffer of free Bcl-xL is small (about 104 molecules) for gate OR  for gate AND  is released.Accordingly, to trigger apoptosis, gate OR Figure  requiresL is larger  and eventually triggers apoptosis  level of (free) Bcl-xr Figure , Table 2L Figure B. The siL Figure C. HoweveL , dephosphorylated Bad is not able to displace Bax from its complex with Bcl-xL: high abundance of Bcl-xL allows it to restrain whole Badu and whole Bax at the same time.Alternatively, gate OR may be transformed into gate AND (denoted AND* to avoid confusion) by a significant increase of the level of pro-survival Bcl-xL Figure , Table 2In the next section we summarize the above numerical analysis introducing approximate formulas defining OR and AND gates.An important property of the model is that, as long as steady-state solutions are considered, a change of any of its 20 parameters can be compensated by a proper change of other (conjugate) parameter(s). Therefore, steady-state concentrations of proteins depend on clusters of parameters rather than on individual parameter values. We identified 7 such parameter clusters, which define ‘macro-parameters’ Table . When co1/m3, 1/m4, and 1/m5 are larger than the characteristic numbers of molecules, all allowed complexes are formed. The conditionm3≪m4 implies that Bcl-xL binds preferentially to Badu and therefore free Bax is released only whenBased on the macro-parameters one can obtain approximate algebraic formulas which must be satisfied for a given gate type. First, let us notice that since all  dissociation constants Baxbif, the cell sets in the apoptotic state; in the opposite case the cell survives. The amount of Badu is (1−m6)Badtot. In this way we obtain simple inequalities defining logic gates. These inequalities, given in Tables When the level of free Bax exceedsp53killer andAktu both in the range , assuming levels ofBadtot andBcl-xL tot adequate to the gate type (Table Bax = Baxbif=5000 isoline (white line) separates inputs {p53killer,Aktu} leading either to apoptosis or to survival. In gate OR -plane for different levels ofBadtot. For {p53killer,Aktu} “above” each isoline value the cell undergoes apoptosis, whenever itsBadtot is greater or equalBadtot value for that isoline. Gate AND arises forBadtot≲0.9 × 105, while gate OR arises forBadtot∈ the full dephosphorylation of Akt (Aktu= Akttot) leads to apoptosis (for an arbitraryp53killer) but the increase ofp53killer to its highest assumed value  needed to trigger apoptosis. We assume that before and after the stimulation phasep53killer=0 andAktu=0. The transient stimulation by p53killer and/or Aktu may cause that the caspase level passes a threshold above which the apoptotic decision is irreversible. This threshold caspase level (≈2 × 103) is determined by the value of the unstable steady state forBax = 0, see the bifurcation diagram  that such stimulation lasting sufficiently long leads to apoptosis. Here we estimated that the minimal duration of the stimulation phase is 10.5 hours. In Figure Bax reaches 1.3 × 104>Baxbif and Casp reaches 1.6 × 103>Caspbif, the system returns to the initial steady state of the low caspase level. In Figure Bax returns to its initial steady state. In the case of gate AND*, the minimal duration of the stimulation phase (for the same stimulation) is 20.5 hours.For the gate AND we consider stimulation during whichp53killer signal  data, but allows also for a more precise description. Wittman and colleagues  introduckiller and pro-survival signals from Akt. The final output of the module is the level of caspase-3, which (in the model) is activated by Bax (or Bak), but also auto-catalytically, which renders the apoptotic decision irreversible. After the caspase level surpassed unstable steady state, the presence of Bax is no longer needed, since caspase autoactivation suffices for their further build-up and execution of apoptosis. Caspase activation requires that free Bax surpasses a threshold of about 5000 molecules per cell, and remains over this level for sufficiently long time. The regulation of Bcl-2 family module can be summarized as follows: in resting cells, Bax (chosen as a representative for pro-apoptotic multidomain effectors) remains in the inactive form bound to Bcl-xL (chosen as a representative for anti-apoptotic restrainers), while most of Bad (chosen as a representative for BH3-only pro-apoptotic proteins) is in the phosphorylated form bound to Scaffold14-3-3. The signal coming from p53 leads to the accumulation of Bax, while the signal coming from Akt (Akt dephosphorylation) results in Bad dephosphorylation. Dephosphorylated Bad may release Bax from Bcl-xL. In this way, both mechanisms contribute to the appearance of free Bax.The considered mitochondrial apoptotic module integrates pro-apoptotic signals from p53L, have relatively small reservoir of free Bcl-xL (required to inhibit/sequester Bax) and thus are more prone to apoptosis. In these cells apoptosis follows from p53killer accumulation or Akt dephosphorylation (gate OR); a BH3-domain mimetic, ABT-737, which mirrors binding capacities of Bad and engages pro-survival proteins (mostly Bcl-2), was shown to induce Bax/Bak-dependent killing [L have much larger reservoir of free Bcl-xL and in these cells apoptosis requires both signals simultaneously (gate AND); this is consistent with experimental results showing that the overexpression of Bcl-xL blocks apoptosis [L level, which confirms that levels of these proteins are important in regulating cell sensitivity to apoptosis.Cells characterized by high Bad level or/and low level of Bcl-x killing . Cells cpoptosis . We demo14-3-3, decreased caspase activity, and consequently enhanced cell viability [It is known that Bad modifications, which interfere with Bad phosphorylation, can make cells more or less sensitive to apoptosis. Bad phosphorylation is limited by PRMT1-mediated methylation of two Bad arginine residues (Arg94 and Arg96), which prevents Akt-mediated phosphorylation of Bad at Ser99. Respectively, decreased methylation of Bad increases the fraction of phosphorylated Bad leading to its enhanced sequestration to Scaffoldiability ,96.L level) apoptosis can result only from the simultaneous presence of both pro-apoptotic signals, i.e. elevated p53killer level and Akt dephosphorylation . Radiotherapy against these cells which leads to the increase of p53killer level (via DNA damage) should be accompanied by the inhibition of pro-survival Akt pathway in order to be effective. In turn, it suggests that cells characterized by high Bad level, or low Bcl-xL level are very prone to apoptosis, which can follow even from growth factor withdrawal.In the therapeutic context, our findings suggest that in some (cancerous) cell lines or cell mutants . Such regulation is based on stoichiometry of interacting proteins, and introduces dynamical thresholds for all protein levels, which, when surpassed, change output from NO to YES. Specifically, apoptosis arises when the level of anti-apoptotic restrainers is surpassed by the combined levels of pro-apoptotic unphosphorylated BH3-only proteins (controlled by Akt) and pro-apoptotic effectors (controlled by p53). We demonstrated that the transition between OR and AND gates is accomplished by the change of a level of single component , without any modification of topology of the network or even kinetic rate parameters.We demonstrated that the mitochondrial apoptotic module may process signals in the way similar to logic gates OR and AND, which suggests a mechanism of the integration of apoptotic and survival signals before the death-or-survival decision is reached. The correspondence between ODEs and Boolean logic arises due to the high affinity, competitive binding of two subfamilies of pro-apoptotic proteins, multidomain effectors (represented by Bax) and BH3-only proteins (represented by Bad) to anti-apoptotic restrainers (represented by Bcl-xThe authors declare that they have no conflict of interest.TL and MK conceived of the study. MNB, BH and MK analyzed the model and performed simulations. All authors wrote and approved the manuscript.Matlab source code.Click here for file


Fluocinolone acetonide slow release implant (Iluvien®) was approved in December 2013 in UK for treatment of eyes which are pseudophakic with DMO that is unresponsive to other available therapies. This approval was based on evidence from FAME trials which were conducted at a time when ranibizumab was not available. There is a paucity of data on implementation of guidance on selecting patients for this treatment modality and also on the real world outcome of fluocinolone therapy especially in those patients that have been unresponsive to ranibizumab therapy.Retrospective study of consecutive patients treated with fluocinolone between January and August 2014 at three sites were included to evaluate selection criteria used, baseline characteristics and clinical outcomes at 3-month time point.Twenty two pseudophakic eyes of 22 consecutive patients were included. Majority of patients had prior therapy with multiple intravitreal anti-VEGF injections. Four eyes had controlled glaucoma. At baseline mean VA and CRT were 50.7 letters and 631 μm respectively. After 3 months, 18 patients had improved CRT of which 15 of them also had improved VA. No adverse effects were noted. One additional patient required IOP lowering medication. Despite being unresponsive to multiple prior therapies including laser and anti-VEGF injections, switching to fluocinolone achieved treatment benefit.The patient level selection criteria proposed by NICE guidance on fluocinolone appeared to be implemented. This data from this study provides new evidence on early outcomes following fluocinolone therapy in eyes with DMO which had not responded to laser and other intravitreal agents. Diabetic Macular Oedema (DMO) is one of the leading causes of blindness in the working-age population , 2 In thThere are currently three corticosteroid agents that have been used for DMO; triamcinolone , fluocinThis retrospective study reports the initial real world experience of implementation of TA301 in the clinical setting, in particular, the patient level criteria used for selection of patients for intravitreal fluocinolone implant, the initial treatment response and the short term safety profile.Consecutive patients treated at each of three hospital departments using fluocinolone implant for DMO according to NICE guidance (TA301) between January 2014 and August 2014 were identified at each site using their respective patient database systems for tracking patients on intravitreal therapies. The study involved collection of data retrospectively from case notes and OCT scans performed as part of patients’ standard care pathways at each institution, approval by Ethics Committee was not required according to the institutional review policies at each site. Case notes review was performed and data were collected at baseline, which was at the time of fluocinolone implant and at the visit nearest to the 3 month time-point of follow-up. At the baseline time-point, data were collected on demographics, visual acuity (treated and fellow eyes), OCT parameters, IOP, IOP lowering medication use, presence of co-existing ocular pathology and prior laser for DMO and DR or intravitreal therapy and duration of DMO. At the 3 month time-point, data were collected on visual acuity (treated eyes), IOP, IOP lowering medication use and OCT parameters. Snellen visual acuity was converted using a standard estimation method so that all acuity data was presented in terms of number of ETDRS letters. The type of conversion method we used would convert 6/60 to 35 letters and 6/6 to 85 letters as obtained when an ETDRS acuity is used at 2 meters for acuity scoring. , 13. DesA total of 22 patients (14 M:8 F) aged between 42 and 85 years (mean 67.2 years) were included. Nineteen patients had Type-2 and 3 patients had Type-1 diabetes mellitus; mean duration of diabetes was 17.9 years (range: 3–60). All patients had unilateral fluocinolone implants ie; 11 right and 11 left eyes treated.Visual acuity conversion for Snellen fraction to ETDRS was required for five patients. In all other patients, acuity scores were captured directly using ETDRS chart. Treated eyes had mean baseline visual acuity of 50.7 letters and mean CRT of 631 μm. Twenty two eyes had foveal eversion and 13 eyes had pre-existing vitreo-retinal interface abnormalities. Majority of eyes had prior laser of either macular or pan retinal photocoagulation. All 22 eyes had prior intravitreal therapy. Thirteen eyes had prior ranibizumab or bevacizumab, 3 eyes had both ranibizumab and bevacizumab and 6 eyes had prior intravitreal triamcinolone for DMO. Mean duration of DMO was 26.2 months (range: 9-47). All patients had a minimum of 8 weeks wash out period after using Anti-VEGF before having the fluocinolone implant.Fellow eyes had visual acuities ranging from NPL to 85 letters. In 11 patients, the fellow eye had visual acuities equal to or worse than treated eyes. Baseline characteristics of 22 treated eyes are shown in Table At the 3 month time-point, mean change in BCVA for all patients was +6.4 ETDRS letters . A gain of >0 letters was seen in 21 eyes (95.4 %); 0-4 letters in 4 eyes (18.1 %), 5-9 letters in 7 eyes (31.8 %) and ≥10 letters in 6 eyes (27.2 %), CRT after three months reduced by 148.9 μm . A total of 18 out of 22 eyes (81.8 %) showed some reduction in CRT at 3-months. In the 4 eyes without CRT improvement, the mean increase in CRT was 134.75 μm .Overall, 15 patients (68.2 %) showed some improvement in both visual acuity and CRT, 3 patients (13.6 %) showed some visual gain without any reduction in CRT, another 3 patients (13.6 %) achieved a reduction in CRT without any corresponding visual gain and 1 patient (4.5 %) did not show any improvement in visual acuity or CRT.Of the 5 eyes which had undergone prior vitrectomy, visual acuity was improved by +7.2 letters (range: 0 to +14) and CRT reduced by 176.8 (range:-714 to +385). Four of 5 eyes showed both a reduction in CRT with improved visual acuity but one patient had reduced CRT (-345) with no gain in visual acuity.One patient worsened by 11 letters and had increase in CRT of 385 μm; this particular patient had received prior treatment with macular laser and four ranibizumab and one triamcinolone intravitreal injections.Mean baseline IOP was 16.9 mmHg , with the mean change of 0.3 mmHg  at month 3. No cases with substantial elevation in IOP were documented in the short follow up period. Of 22 eyes, four eyes, were receiving IOP-lowering drops (timolol and/or latanoprost) prior to fluocinolone implant. Following implant an additional one eye needed IOP lowering medication.Our study set out to evaluate two important aspects in the use of fluocinolone acetonide in the real world clinical setting for treatment of DMO; firstly, the characteristics of patients selected for treatment by clinicians and secondly, the early treatment response seen in their patients.In terms of selection, we found that fluocinolone implant was used infrequently in patients with DMO. In all three sites, there were only 22 procedures performed in three sites in the 8-month period following approval of fluocinolone by NICE. Given the large number of patients needing repeated injections of ranibizumab for DMO at these sites , this inIn terms of early outcome, we found promising results with 18 out of 22 eyes reported to have visual gain and 18 out of 22 eyes with at least a reduction in CRT at month 3 time-point. Figure There were limitations in the design of this real world study. The selection of patients for therapy is a complex process involving careful explanation and the confidence expressed by the treating clinician at counselling and a final decision made with the patient preference. It was possible that many other patients who were eligible for therapy but declined due to the risk factors involved. We could not capture those patients who declined treatment with our retrospective design and this study may represent the highest threshold for using fluocinolone at this early stage of implementing NICE guidance. We also captured basic baseline data on patient selection. We were unable in the scope of this study to capture the timescale and progression of DMO in these patients. We recognise that other factors, including the recent worsening of oedema or visual acuity and the frequency of previous visits do have an impact on tendency to use fluocinolone and these factors were not be captured uniformly in this retrospective design.The strength of this study was the accuracy of the representation of those patients who were treated with fluocinolone. The sites selected were medium sized district general hospital settings as well as large teaching hospital centres which enables translation of our results to the majority of hospital eye departments. The inclusion of all consecutively treated patients in an 8-month period ensured a representative cohort of patients for reporting of a potentially wide spectrum of selection criteria used or variable response to treatment.Numerous review articles have been published mentioning fluocinolone therapy for DMO but there is a paucity of published data on use of fluocinolone 0.2 μg/day or iluvien® outside the experience of the FAME trial , 17. We


Recently, the shape and design of the panel on the official ball used in the FIFA World Cup was considerably different from that of a conventional soccer ball . Depending on the number of different panels and their orientation, the aerodynamic force experienced by a ball is believed to change, which in turn changes the ball trajectory. However, not much is known about the impact of the surface forms of a ball on its aerodynamics. Therefore, in the present study, 10 different types of soccer balls were produced and their aerodynamic properties were studied by wind tunnel experiments. The results confirmed that the aerodynamic force acting on the ball varied considerably depending on the existence of dimples on the ball surface. In addition, the 4 types of soccer balls, which had different kinds of roughness, revealed that even balls having the same number and shapes of panels experienced greatly varying aerodynamic forces depending on the surface form of the balls. In particular, with the FIFA World Cup tournament in mind, significant changes have been made to the shape and design of the panel of its official soccer ball. The Teamgeist, which was the official ball of the 2006 FIFA World Cup held in Germany, was made of 14 panels, and its form was quite different from the typical form of a conventional soccer ball, which had 32 hexagonal and pentagonal panels. Subsequently, the 8 panel Jabulani (Adidas) was used in the 2010 FIFA World Cup held in South Africa. Later, in the 2013 FIFA Confederations Cup held in Brazil, the 32 panel Cafusa (Adidas) was used as the official ball. The Cafusa had the same number of panels as a conventional ball. However, the panel arrangement of the Cafusa varied depending on the direction of the panel and was quite different from the simple hexagonal and pentagonal panel arrangement of the conventional ball. Then, a ball  consisting of 6 panels was used as the official ball in the 2014 FIFA World Cup held in Brazil. The trajectory of this ball was reported to be stable compared to those of other official balls , 8, 9.The 6 panel Beau Jeu (Adidas), whose panel shape is similar to that of the 6 panel Brazuca but has a slightly different surface form, has been selected as the official ball of the 2016 EURO Cup. The surface of the Beau Jeu has small uneven uniformly arranged square projections; this feature differentiates it from the Brazuca, which has square projections that spread out giving a wave-like appearance . ConsideIt is known that a major aerodynamic characteristic of a sports ball is the rapid decrease in the aerodynamic drag when the boundary layer around the ball transitions from laminar flow to turbulent flow during the flight of the ball In this study, the pattern of the surface of a soccer ball (surface form including the presence or absence of dimples) is investigated using wind tunnel experiments to determine its impact on the aerodynamic characteristics of the ball. The results confirm that the aerodynamic force acting on the ball vary greatly depending on the impediments on the surface of the soccer ball.22.1−1, the nozzle size was 1.5 m × 1.5 m, the wind speed distribution was within ±0.5%, the degree of turbulence was less than 0.1%, and the blockage of the measured soccer ball was within 5% of the nozzle size. For example, when the wind speed was set to 25 m s−1, the measured mean wind speed was 25.28 m s−1, with a standard deviation from the measurement position in the range −0.46 to 0.45 and a wind speed distribution within ±0.5%. Similarly, the degree of turbulence downstream of the nozzle when the wind speed was 25 m s−1, was 0.05–0.06, within approximately ±0.1%, so the error from the ball position was believed to have little effect on the wind speed. Furthermore, in the measuring system of this study, the dynamic pressure can be measured automatically with 0.1 kg m−1 s−2 intervals by means of the Pitot-static tube placed above the measuring portion of the soccer ball. In addition, because the position of the ball during the measurement procedure is set almost at the center of the nozzle cross section to adjust the distance between the nozzle and the ball to zero, the flow generated from the Pitot tube may not have a direct effect on the flow around the ball. Furthermore, the length of the sting used in this study was 0.8 m and its width was 0.02 m. This wind tunnel was used to perform experiments on the same orientation of six type balls. Moreover, because the effect of sting vibrations is reduced to a small value by placing the six-component force detector behind the soccer ball, the magnitude of the sting forces was ignored in this study. We performed experiments on soccer balls made using the same material (leather) in the thread (seam) between the panels. Three types of soccer balls, with 32, 12, and 6 panels, were fabricated, and in each type, balls with and without dimples  were made. The diameter of the soccer ball used in this study was uniformly 0.22 m, its weight was 0.436 ± 0.004 kg, and its internal pressure was set to 9.0 psi. In total, six types of soccer balls (−1 (approximately Re = 1.0 × 105) to 35 m s−1 (approximately Re = 5.5 × 105) at intervals of 1 m/s.Re) is a dimensionless number defined as the ratio of inertial force to viscous force, ν is wind speed (m s−1), D is ball diameter (m), and v is the kinematic viscosity (m2/s), as shown in Eq. The circulating-type low-speed low-turbulence wind tunnel located at the University of Tsukuba   was useder balls  were stuIn the present research, however, a comparative study has been performed by keeping focus on drag coefficient involving simulation of the force acting on the ball due to its surface characteristics.SD is standard deviation, ∑ means sum up, xi is a value in the data set, μ is the mean of the data set, and N is the number of data points.Also, as wind speed increased, the changes in the side and lift forces on each soccer ball and the corresponding standard deviations were shown for each wind speed and compared, as shown in Eq. Furthermore, to examine the characteristics of the surface form of soccer balls in greater detail, four types of soccer balls with different surface forms  were invThe width and depth were measured using a high-speed 2D laser scanner  To measure these parameters, all seams of the football were covered using clay with the height of the imprint representing the panel joint depth and the width representing the panel joint width . The depdC), lift coefficient (Cl), and side coefficient (Cs), as shown in Eqs. ρ is the air density (ρ = 1.2 kg m−3), U is the wind speed, and A is the projected area of the football (A = π × (0.11)2 = 0.038 m2).The force acting on the soccer ball was measured by using a sting-type 6-component force detector . The measured aerodynamic force was converted into the drag coefficient (2.2Re = 4.6 × 105) and the 32 panel dimple-type ball (32_D) and the 32 panel dimple-less ball (32_S) in the critical regime (Re = 2.3 × 105) on their flight distance and flight trajectory We conducted a simple 2D flight simulation to compare the effects of the drag coefficients of the 12 panel dimple-type ball (12_D) and the 12 panel dimple-less ball (12_S) in the super-critical regime  by selecting conditions such that the difference between the flight distance of the two balls with and without dimples is a maximum. Thus, by setting various conditions, the difference between the flight distances of various balls can be explained with more clarity.In flight simulation, by using the 33.1Cd value for balls without dimples showed a trend of being smaller than that for balls with dimples in the supercritical range ; therefore, the difference caused by practice could not be seen. This is believed to be due to the fact that in the critical Reynolds number range (Re = 1.5 × 105–3.0 × 105), the dimple-type soccer ball experiences a smaller drag (resistance) than the dimple-less ball. From the results, in the case of dimple-type balls, in the critical Reynolds number range, the shape of the dimples causes transition of the boundary layer on the ball. Therefore, the dimple-type balls are perceived to be faster than the dimple-less balls. In contrast, in the supercritical Reynolds number range (Re = 3.8 × 105–5.0 × 105), the dimple-less ball had a smaller drag value. Furthermore, it can be inferred that frictional drag for dimple-less balls are lower than that for the dimple type ball in the supercritical Reynolds number range. Therefore, we found that the drag acting on the ball changes depending on the Reynolds number interval. The 32_D soccer ball had the smallest supercritical drag coefficient of approximately 0.10 (Re = 2.3 × 105), and the 12_D ball had a corresponding value of approximately 0.15 (Re = 2.1 × 105). The 6_D soccer ball had a corresponding value of approximately 0.17 (Re = 2.1 × 105). Further, in the case of the dimple-less balls, the value for the 32 panel ball was approximately 0.13 (Re = 3.5 × 105) and that for the 12 panel ball was approximately 0.12 (Re = 3.5 × 105). The 6 panel ball had a value of approximately 0.12 (Re = 3.4 × 105). In the case of the dimple-type balls, the supercritical drag coefficient increased as the number of panels reduced, but no such difference attributable to the number of panels was observed in the case of the dimple-less balls. For soccer balls with dimples, the supercritical drag coefficient was observed to increase as the number of panels decreased, so it is believed that the supercritical drag coefficient will decrease as the total length of the seams on the surface of the soccer balls with dimples increases . Furthermore, we observed the same trend as reported in prior research: that the length of the seams has a large effect on the supercritical drag coefficient The aerodynamic coefficients of the balls indicate that the aerodynamic drag  tends toal range B and C. ype ball A. This CFrom these results, the dimple shape in the soccer ball surface is also expected to have the effect of maintaining a constant boundary layer around the ball. However, because the air flow around the ball was not studied in this experiment, it is necessary to study from multiple angles how friction resistance, due to the presence or absence of dimples, affects boundary layer separation, so in the future, it will be necessary to study the ball surface air flow in further detail by using visualization methods such as PIV.−1, attack angle: 30°), we compared the flight distance of the 12_S ball , and the 12_D ball (a large one). The flight distances for the 12_S ball and 12_D ball were approximately 55.1 and 49.0 m respectively , comparing the flight distance of the 32_D ball and the flight distance of the 32_S ball, the 32_D ball distance (approximately 17.9 m) was approximately 0.5 m longer than that of 32_S ball (approximately 17.4 m)  was approximately 0.4 m higher than that of 12_D ball (approximately 1.7 m). However, in the present study, investigation of the unsteady aerodynamic force acting on the soccer ball in air has not been performed (such as knuckle effect); therefore, in future research it is necessary to investigate the difference in the knuckle effects of soccer balls in-flight by studying the vortex structure of the wake flow of the soccer ball in flight.Using a ball trajectory simulation in the supercritical regime  B. FurtheSD)) due to the increase in the flow velocity for the six types of soccer balls divided according to the presence or absence of dimples and the number of panels. First, looking at the entire graph, the lift coefficient (red line) and side coefficient (blue line) acting on the ball are seen to vary greatly depending on the types of ball. Further, although the force variation is different for the ball types, no significant difference were observed in the tendency for force variation in the lift and side coefficients in the same type of balls. In terms of the force variation (SD) in the side and lift coefficients due to the presence or absence of the dimples, the dimple-less balls (−1 (Re = 4.6 × 105), the variation is seen to exceed 2 in terms of both the lift and side coefficients, showing a greater variation than that for the other types of balls with an increase the flow velocity. However, for the 32_D ball, the magnitude of the force variation is seen to be less than 2, showing a smaller variation than that for the dimple-less ball (−1 (Re = 4.6 × 105), the variation in the lift and side coefficients of the 32_D ball was approximately 1.2 and 0.9 (respectively). However, the 32_S ball was approximately 2.0 and 1.9 (respectively). Therefore, the dimple-type balls are observed to have less force variation than the dimple-less balls. These results indicate that the shape of dimples on the surface of the soccer ball may have the effect of constantly maintaining a boundary layer around the ball. Moreover, it has been made clear that the dimple structure on the surface of the soccer ball significantly affects the force variation on the flight distance and force variation on lift force and side force according to the Reynolds number intervals. Therefore, we found that the drag acting on the ball changes depending on the Reynolds number interval. Furthermore, it is now understood that the aerodynamics of the ball varies not only because of the structure of the dimples, but also because of the shape of the surface protrusions. Also, the surface of the ball involves complicated factors such as shape or number of panels, their width and depth and therefore, a detailed study of the flow of air at the surface of the ball by using a visualization method such as PIV is essential in future studies.ss balls A–C with ss balls D, at floess ball A. For ex3.2Cd values in the four types of soccer balls with different surface shapes. Each of these four types of soccer balls consists of 32 same panels. Also, the measured ball orientation was set identically to that shown in Re = 1.5 × 105–3.0 × 105), the dimple-type balls have a smaller drag (resistance) than the balls with other types of panels. In addition, the 32_T1 ball experiences a smaller drag than the other balls in the supercritical Reynolds number range used during a long kick or a powerful shot (Re = 3.8 × 105–5.0 × 105). Further, the 32_T2 soccer balls with dimples have the smallest supercritical drag coefficient of approximately 0.11 (Re = 2.3 × 105), whereas the 32_T4 balls with hexagonal surface forms have the largest value of approximately 0.14 (Re = 2.7 × 105). Moreover, the 32_T1 balls made of square projections have a value of approximately 0.12 (Re = 2.7 × 105), whereas the 32_T3 balls with triangular projections have a value of approximately 0.12 (Re = 2.7 × 105). Further, we compared the flight distance of these four different types using a ball trajectory simulation in the supercritical regime . The flight distances for the 32_T1 ball and 32_T2 ball were approximately 27.0 and 25.9 m respectively (ectively . TherefoRe = 4.2 × 105), the 32_T4 ball has values of approximately 1.45 and 1.50 (respectively), which are smaller than the corresponding values for the other types . It is seen that dimples (surface texture) have a greater impact on the aerodynamic characteristics of the balls. Further, creating forms on the surface of the soccer ball makes it possible to control the irregular movement of the ball in the up and down and left and right directions to some extent. Thus, the fact that the aerodynamic force acting on the ball varies depending on the surface form of the soccer ball suggests that surface roughness is also one of the important factors that determine the aerodynamic characteristics of the ball in addition to the shape and number of panels.4Recent studies on the fluid dynamics of soccer balls have reported that the number of panels on the ball, their orientation, and changes in panel shapes have a major impact on the aerodynamic characteristics of the ball. The present researches also show results similar to those of previous studies. In particular, this study has established the fact that changing the texture of the ball surface changes the aerodynamic characteristics of the ball. This suggests that by considering the changes in the aerodynamic characteristics obtained in response to variations in the number and shape of the panels and modifications to the surface form, soccer balls with even more diverse aerodynamic characteristics can be developed. However, it is necessary to examine dimples of various sizes and patterns other than the ones used in this study. Therefore, in the future, we intend to study the surface roughness in more detail by examining the air flow around the dimple on the ball surface through visualization experiments such as particle image velocimetry.Sungchan Hong and Takeshi Asai: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paperThe authors declare no conflict of interest.Ministry of Education, Culture, Sports, Science and Technology of the Japanese government.This work was supported by JSPS KAKENHI Grant Number 24240084, 25750283, 15K16442 of the No additional information is available for this paper.


With the advances in next-generation sequencing (NGS) technology and significant reductions in sequencing costs, it is now possible to sequence large collections of germplasm in crops for detecting genome-scale genetic variations and to apply the knowledge towards improvements in traits. To efficiently facilitate large-scale NGS resequencing data analysis of genomic variations, we have developed “PGen”, an integrated and optimized workflow using the Extreme Science and Engineering Discovery Environment (XSEDE) high-performance computing (HPC) virtual system, iPlant cloud data storage resources and Pegasus workflow management system (Pegasus-WMS). The workflow allows users to identify single nucleotide polymorphisms (SNPs) and insertion-deletions (indels), perform SNP annotations and conduct copy number variation analyses on multiple resequencing datasets in a user-friendly and seamless way.https://github.com/pegasus-isi/PGen-GenomicVariations-Workflow) and a web-based implementation of the PGen workflow integrated within the Soybean Knowledge Base (SoyKB), (http://soykb.org/Pegasus/index.php). Using PGen, we identified 10,218,140 single-nucleotide polymorphisms (SNPs) and 1,398,982 indels from analysis of 106 soybean lines sequenced at 15X coverage. 297,245 non-synonymous SNPs and 3330 copy number variation (CNV) regions were identified from this analysis. SNPs identified using PGen from additional soybean resequencing projects adding to 500+ soybean germplasm lines in total have been integrated. These SNPs are being utilized for trait improvement using genotype to phenotype prediction approaches developed in-house. In order to browse and access NGS data easily, we have also developed an NGS resequencing data browser (http://soykb.org/NGS_Resequence/NGS_index.php) within SoyKB to provide easy access to SNP and downstream analysis results for soybean researchers.We have developed both a Linux version in GitHub  contains supplementary material, which is available to authorized users. In-depth informatics analysis of genotypic data can provide a better understanding of genotype-phenotype correlations with applications designed to assist in the work toward improvement of traits. In order to achieve this, many research institutions are generating large-scale sequencing datasets for crop germplasm , 2 for aG. Max) and wild soybean genomes (G. Soja) [http://soykb.org/NGS_Resequence/NGS_index.php. PGen workflow can also be utilized for other organisms and crops by easy customization and serves as a good template for reproducible workflow for bioinformatics analysis with different types of NGS data.Soybean is an important economic crop and is no exception to the computational barriers associated with a lack of access to advanced HPC and other NGS resources just mentioned. Soybean is a great source of dietary protein and oil for human and animal consumption. The soybean community has invested a great deal of efforts in both sequencing germplasm and creating phenotypic datasets, which has resulted in hundreds of resequencing datasets for both cultivated (G. Soja) . Here weG. Soja)  for aligG. Soja)  for SNP G. Soja)  environmG. Soja) , 8. We h500+ soybean germplasm lines were sequenced at different coverages (15X and 40X) from multiple datasets and utilized for SNP and indel identification. Table G. Max Williams 82 Wm82.a2.v1 version [ version  availabl version  was used version  workflow version . Only th version . Picard  version  is also  version . Filteri version  and the  version . CNVs am version . The SNP version  tool, deThe PGen workflow has been optimized to obtain the most efficient and large-scale analysis of the sequenced lines using iDS for cloud storage, Extreme Science and Engineering Discovery Environment (XSEDE) . XSEDE ipegasus-run, keep track of the workflows status using pegasus-status, generate statistics using pegasus-statistics, identify problems in case of failed workflows using pegasus-analyzer, resume the workflows after resolving the problems and remove them using pegasus-remove. With this optimization we can conduct analysis on all datasets that have more than hundreds of soybean lines with multiple PGen workflows submitted simultaneously on TACC resources, generating results within a 5- to 10-day timeframe. Each workflow consists of a batch of up to 50 soybean lines. This timeframe includes the associated wait times for individual tasks in queue before they can be executed on Stampede or Wrangler systems. For our datasets, we conducted analyses using multiple workflows submitted simultaneously for a subset of soybean lines, and later combined all results for datasets into the final variant calling using the merged GVCF file in GATK. This ensures that SNP and indel calls were made based on the entire datasets of sequenced lines. Further, the outputs were sent back to iDS and utilized in the downstream analysis as well as loaded into the SoyKB NGS data browser for sharing with biological users. The details for necessary accounts, supported input file formats and output files generated for every workflow are available in PGen documentation  tasks in the workflow as shown in Fig. https://github.com/pegasus-isi/PGen-GenomicVariations-Workflow) and easily customize it for conducting analysis on organisms other than soybean, uploading reference genome versions of their choice and customizing SNP filtering criteria. For soybean researchers and SoyKB users, the PGen workflow is also available in a web-based implementation within SoyKB (http://soykb.org/Pegasus/index.php) to conduct analysis on their lines of interest and submitting their NGS datasets online. The PGen workflow submission within SoyKB is mainly intended for biology researchers and guides them through five easy steps for workflow creation and submissions, which allows them to access the results within SoyKB as well. The steps for using PGen workflow in SoyKB as outlined in Fig. Introduction: We provide an introduction page, which presents the structure and computing environment of the PGen workflow. A user manual and public data for testing are also provided  using FUSE mount. Successfully uploaded data will be shown on the create workflow page when selecting inputs  of sequenced soybean lines as well as statistics related to raw datasets. It provides the total number of raw reads, mapping rates, SNPs and indels identified  of each soybean line in both searchable tabular and PDF format . The second resource comes from the Stampede and Wrangler high-performance computing cluster of TACC. The third resource is the XSEDE gateway allocation, which has been setup for SoyKB users utilizing the PGen online workflow. We are also building a fourth computing resource locally utilizing HPC resources at the University of Missouri-Columbia to provide PGen execution. More computing resources can be added as they become available to users in future.PGen, together with its source code, is freely available to academic users via GitHub. It outlines best practices for efficient utilization of distinct and unique cyberinfrastructure (CI) resources available through multiple providers, with an emphasis on creating extensible and scalable workflows that can be easily modified and deployed. A similar approach can be utilized for designing many other bioinformatics analysis pipelines using the Pegasus workflow management system (Pegasus-WMS).


One way of expediting materials development is to decrease the need for new experiments by making greater use of published literature. Here, we use data mining and automated image analysis to gather new insights on nanoporous gold (NPG) without conducting additional experiments or simulations. NPG is a three-dimensional porous network that has found applications in catalysis, sensing, and actuation. We assemble and analyze published images from among thousands of publications on NPG. These images allow us to infer a quantitative description of NPG coarsening as a function of time and temperature, including the coarsening exponent and activation energy. They also demonstrate that relative density and ligament size in NPG are not correlated, indicating that these microstructure features are independently tunable. Our investigation leads us to propose improved reporting guidelines that will enhance the utility of future publications in the field of dealloyed materials. However, it may be possible to accelerate materials development by systematically extracting new insights from already published literature using advanced image analysis tools. We apply this strategy to nanoporous gold (NPG): a material that has been studied extensively due its potential uses in catalysis3, sensing4, actuation5, and energy storage6. NPG consists of a network of interconnected nanometer-scale pores and ligaments, as shown in Fig. 8. By mining and analyzing published, peer-reviewed, images such as those shown in Fig. Materials research and development is often frustratingly slow due to the time and resources needed to conduct new experiments9, to extract microstructure characteristics – such as NPG ligament and pore dimensions – in a consistent and reproducible manner. Combining this information with reported processing histories, we obtain a quantitative numerical description of NPG coarsening as a function of time and temperature. Our analysis confirms that coarsening in NPG is a thermally activated process, with an Arrhenius dependence on temperature and an activation energy consistent with surface self-diffusion of Au. However, our analysis finds a coarsening exponent that is lower than classical predictions developed for idealized systems, indicating a need for revised models to capture the coarsening behavior of dealloyed materials.Our method relies on novel image-analysis software, developed and discussed in a previous publicationIn addition, we find new insights concerning the relative density of NPG, approximated as the area fraction of the solid phase in published NPG images. Relative density is found not to correlate with other physical characteristics of NPG, such as ligament diameter, parent alloy composition, or processing conditions such as dealloying time or temperature. This finding suggests the existence of unreported, “hidden” processing parameters that may enable NPG relative density and ligament size to be independently tuned. Based on our investigation, we propose new publication guidelines that will facilitate the discovery of such unanticipated, hidden parameters from data mining studies on future publications in the field of dealloyed materials.10. It is an ideal target material for a data mining study such as ours because it has inspired a large volume of literature to analyze. Indeed, keyword searches on “dealloying” and “nanoporous” using the Web of Science database yield more than 1,500 and 22,000 hits, respectively. However, only a small fraction of these publications refers to work that uses de-alloying to synthesize NPG. An even smaller fraction contains the information needed for our study, such as high-quality images and a comprehensive description of material processing conditions. Since most widely used search engines do not have the capability to sort publications according to the type of data they contain, we confine our work to manuscripts citing the seminal paper on dealloyed NPG by Erlebacher et al.11. At the time of our search (03/01/2017), there were a total of 1293 citations for this paper listed on Web of Science. Out of these, only 145 contained sufficient information for our analysis. Of these 145 manuscripts, only 28 were focused on NPG37.NPG is a prototypical dealloyed material, formed by selectively dissolving Ag or Cu out of a parent Ag/Cu-Au alloy using an acid solvent9, applies advanced algorithms to extract accurate microstructural information even with significant additions of noise, blurring, and magnification errors  to light blue at the largest (1630 ± 770 nm), where ± is not an uncertainty but instead one standard deviation. Figure λ, indicating that coarsening for long times at low temperatures may yield similar ligament diameters as short anneals at elevated temperatures. For example, room temperature coarsening for 864,000 seconds gives rise to a ligament diameter of 56 ± 20 nm, comparable to the ligament diameter produced by coarsening at 473 K for 600 sec, 63 ± 16 nm.Figure The literature used in our study reports ligament diameters for approximately 70% of the data points shown in Fig. 38 and only three manuscripts employed computer-aided software to measure the ligament diameter37. Some authors reported using fast Fourier transform (FFT) image analysis to measure the ligament diameter under the assumption that ligament and pore diameters are equivalent21. However, this assumption does not accurately represent most NPG samples. Many manuscripts, moreover, failed to report the number of manual measurements used to determine the ligament diameter and often reported values without quantifying uncertainty 37. By contrast, AQUAMI analyzes all the ligaments in each image using automated image analysis to determine λ as well as its variance.We attribute these differences to approximations made in the publications mined for our study. For example, some authors measured only a handful of representative ligament diameters to estimate the ligament diameter of their samples38. It is likely that similar choices were also made by other groups. AQUAMI avoids such approximations by determining ligament diameters over the entire ligament length, and allows us to examine the literature data in a consistent manner.In addition to random scatter, some systematic discrepancies are also evident in Fig. 39. The data we mined for our study allow us to determine quantitative descriptions of this coarsening behavior. We expect that coarsening of NPG depends on one dominant mass transport mechanism, so— following Herring’s analysis40 – we fit a general power-law expression for the ligament diameter:t is coarsening time excluding the time spent in dealloying , Ds is surface self-diffusivity, n is a coarsening exponent, and k is a proportionality constant. Ds has the usual Arrhenius form, Ea is the activation energy for rate-limiting process of coarsening. Thus, Eq. NPG is known to undergo thermally-driven coarsening, manifested as a continuous increase in ligament diameter with time at rates that rise with temperature42. Note that, according to Eq. nEa and not Ea.The data shown in Fig. nEa, we determine via free corrosion  in nitric acid. However, some of the data are obtained from NPG fabricated using electrochemical corrosion  or other electrolytes. Data from all processing conditions were included when fitting the exponent.The second data group includes ligament diameters at a single temperature (room temperature) from a wide range of times. Plotting this data in Fig. 42. It should be noted that our activation energy calculation is not for the surface self-diffusion of Au in electrolytes, which is typically lower at ~0.6 eV43. Finally, using the average coarsening time of the samples in Fig. Combining the power-law exponent obtained from Fig. 44. Although analysis of 2D images cannot give a direct measurement of relative density, we may nevertheless use the area fraction of the solid (gold) phase in NPG images as a convenient proxy for relative density. To determine the factors that control relative density, we sought to correlate solid phase area fractions for all the images mined in our study with NPG processing parameters, such as coarsening time and temperature, free vs. potentiostatic dealloying conditions, dilute  vs. concentrated acid solvent (greater than 0.1 M), as well as the composition of the parent alloy. As shown in Fig. via data mining.Relative density is a key characteristic for predicting the properties of porous materials47.To gain further insight into the factors controlling NPG relative density, we search for correlations between solid phase area fractions and other descriptors of NPG morphology, as shown in Fig. In this study, we demonstrated that mining and analysis of published images is an effective way to gain new insight into processing-structure-property relations in materials. Applying this approach to NPG, we confirmed that coarsening is thermally activated in this material and calculated activation energies consistent with surface self-diffusion of Au being the rate-limiting process for coarsening. We also determined the coarsening exponent to be ~1/8. The strong correlation of ligament diameter with time and temperature demonstrates that they are the primary factors influencing coarsening, but our analysis may become more precise if we are able to include secondary and tertiary factors such as average grain size and defect densities. In addition, we find that NPG relative density, represented by solid phase area fraction, is not correlated with any of the processing conditions reported in the literature mined for our study. Furthermore, while solid area fraction is not correlated to ligament length or diameter, it shows a distinct correlation with ligament aspect ratio, supporting the notion that all the NPG images we investigated are topologically equivalent.48 and there has been one in-depth study regarding the dealloying potential, volume shrinkage, and remaining Ag content49. Unfortunately, we were unable to extract data from ref.48 due to poor image contrast while ref.49 provided no images corresponding to the 36 reported processing conditions.Our findings have important consequences for future investigations of NPG. First, Fig. 50. However, several key assumptions – particularly that surface diffusion is isotropic and the surface profile remains sinusoidal as it decays – are not expected to hold during coarsening in nanoporous gold. Departures from classical behavior have been observed in materials with finite terrace widths below the roughening transition temperature52. In addition, kinetic Monte Carlo coarsening studies of NPG by Erlebacher showed that a power-law exponent of n = 1/4 is only observed at long times, when the morphology approaches that of a sphere. Our findings indicate that the NPG samples investigated in the literature mined for our study are still far from this limiting condition. Had we used an exponent of n = 1/4 in our analysis, we would have obtained estimates of 0.64 ± 0.04 eV for the activation energy of Au surface self-diffusion, which is out of the range, 0.73–1.73 eV, of reported activation energies in the literature42.The coarsening exponent of n ≈ 1/8 obtained in our study stands in contrast with the classical surface diffusion exponent of 1/4, which was derived for the idealized case of a sinusoidal surface profile decaying by surface diffusion56. Reported coarsening power-law exponents have ranged from 0.1354 to 0.3256. One coarsening study55 did not directly report a coarsening relationship, but showed that their data was poorly captured by power-law exponents of 1/3 and 1/4. Only ref.54 measured ligament diameters directly from images, yielding a value close to that determined in our present study. The other manuscripts estimated the ligament diameter from scattering peaks corresponding to a characteristic length scale in the material under the assumption that ligament and pore diameters are identical. This assumption does not always hold, and there are appreciable differences in our calculated values and those reported in ref.12. Regarding the activation energy for coarsening, ref.12 reported a value of ~0.65 eV in an electrolyte, and is thus not comparable to our study, while ref.53 reported an unphysically low value of ~0.35 eV in air. Ref.56 did not directly report an activation energy, but showed that the data was better fit by a value of 0.64 eV than 2.2 eV. Of these three studies, we can only draw direct comparison with ref.53, but the value reported in that study corresponds to nEa and not Ea.There are a few studies on coarsening of NPG reported in the literature, but the results are inconclusiveA in the coarsening law for NPG  the remaining Ag content in the parent alloy upon completion of dealloying and b) the extent of sample shrinkage (and consequently reduction in number of lattice sites) during dealloying. Unfortunately, neither Ag dissolution rate, nor final Ag content, nor sample shrinkage are consistently reported in the literature, even though individual studies show volume shrinkage may be as large as 30%, in some casesThe conclusions of the study presented here depend on the availability of data in the open literature, and our investigation reveals serious challenges in extracting this data. A surprisingly large number of the manuscripts we considered, ~89%, did not meet the minimum criteria to be used in our study due to poor image contrast, low image resolution, or lack of detailed processing history. Even if a manuscript met the minimum criteria, reported ligament diameters frequently had no corresponding images: a significant concern in light of the discrepancies between the reported and calculated ligament diameters shown in Fig. 58. It would be useful to quantify this relationship in nanoporous metals and other complex structures due to the popularity of 2D analysis in metallic foams and other cellular materials59.To enhance the utility of future publications, we propose that the following data be included in every publication on NPG : high quality images with minimum resolution of 300 DPI and at least 10 pixels per ligament diameter; representative cross-section images ; dealloying and coarsening times; dealloying and coarsening temperatures; electrolyte solution and concentration; applied potential and current relative density; composition of the parent and final dealloyed material  and percent volume change of the sample ; and finally, include all images as supplemental material whenever possible. Meeting these criteria does not require significant additional effort, given access to standard materials research equipment, such as a scanning electron microscope with elemental analysis capabilities. Although we are unaware of published data in the field of nanoporous metals demonstrating significant inaccuracies in using 2D over 3D images to gather quantitative structural information, there is evidence that 2D measurements are accurate in comparison to 3D measurements in metallic foamsThe data mining approach used in this manuscript is not confined to NPG. As noted in the Data Mining section, 116 additional manuscripts contained sufficient information for image analysis, but were not used in our study because they focused on dealloyed materials other than Au, such as Cu or Pt. Our approach is directly applicable to those materials, given sufficient data. More broadly, data mining and image analysis may be applied to study numerous materials-related phenomena, such as solidification, precipitation, and grain growth. To accelerate investigations such as ours, it would be helpful to develop techniques for the automatic acquisition and screening of images and data from the published literature.9. The segmentation procedure consists of two steps: first, bilateral filtering to remove noise from the micrographs while preserving edges; second, Local Otsu’s Method to assign pixels to the solid or void phase, generating a binary image. The measurement procedure consists of three steps: first, a distance map is generated where pixels belonging to the solid phase are replaced with a value equal to the pixel’s Euclidean distance to the nearest pixel belonging to the void phase; next, a binary array is generated comprised of one pixel-thick lines along the center of the solid phase in the distance map; finally, a radius map is generated by element-wise multiplication of the distance map and binary array. This procedure is able to output the area fraction and full ligament diameter distribution. A similar approach was used to measure the ligament length, where nodes were removed from the binary array and a connected-components labelling algorithm was used to determine the number of pixels in each ligament. Image analysis details may be found in ref.9.The NPG images used in this study were exported in TIFF format from manuscripts using Adobe Illustrator without any reduction in image resolution. The images were analyzed using a custom segmentation and measurement procedure implemented in the AQUAMI softwareAll data generated or analyzed during this study are included in Supplementary Information files.Supplementary InformationSupplementary Dataset 1