Exploring mechanisms of sex differences in longevity: lifetime ovary exposure and exceptional longevity in dogs

To move closer to understanding the mechanistic underpinnings of sex differences in human longevity, we studied pet dogs to determine whether lifetime duration of ovary exposure was associated with exceptional longevity. This hypothesis was tested by collecting and analyzing lifetime medical histories, age at death, and cause of death for a cohort of canine ‘centenarians’– exceptionally long‐lived Rottweiler dogs that lived more than 30% longer than average life expectancy for the breed. Sex and lifetime ovary exposure in the oldest‐old Rottweilers (age at death, ≥ 13 years) were compared to a cohort of Rottweilers that had usual longevity (age at death, 8.0–10.8 years). Like women, female dogs were more likely than males to achieve exceptional longevity (OR, 95% CI = 2.0, 1.2–3.3; P = 0.006). However, removal of ovaries during the first 4 years of life erased the female survival advantage. In females, a strong positive association between ovaries and longevity persisted in multivariate analysis that considered other factors, such as height, body weight, and mother with exceptional longevity. A beneficial effect of ovaries on longevity in females could not be attributed to resistance against a particular disease or major cause of death. Our results document in dogs a female sex advantage for achieving exceptional longevity and show that lifetime ovary exposure, a factor not previously evaluated in women, is associated with exceptional longevity. This work introduces a conceptual framework for designing additional studies in pet dogs to define the ovary‐sensitive biological processes that promote healthy human longevity.     

Fecundity and longevity of roaming dogs in Jaipur,India

Background

Estimates of demographic parameters, such as age-specific survival and fecundity, age at first pregnancy and litter size, are required for roaming dogs (i.e. dogs that are neither confined nor restricted) to assess the likely effect of proposed methods of population control. Data resulting from individual identification of dogs spayed as part of an Animal Birth Control (ABC) programme in Jaipur, India, are used to derive such parameters for the roaming dog population of that city.

Results

The percentage of females becoming pregnant in any given year was estimated by inspection of over 25,000 females caught for spaying from 1995 to 2006. The point estimate is 47.5% with a 95% confidence interval from 44% to 51%. Adult annual survival of spayed females was estimated by recapture of 62 spayed females from 2002 to 2006. The point estimate is 0.70 (95% confidence interval from 0.62 to 0.78), corresponding to an expected total lifespan of 3.8 years for a spayed female at one year old.

Conclusion

Recording the pregnancy status of dogs collected for spaying and individual marking of dogs released following spaying can provide estimates of some of the demographic parameters essential for predicting the future effectiveness of an ABC programme. Further, we suggest that recording the number and location of spayed and unspayed dogs encountered by the catching teams could be the most effective way to monitor the size and composition of the roaming dog population.

     

Dichroism of bacteriochlorophyll in cells of the photosynthetic bacterium Rhodopseudomonas palustris

1. The dichroism was measured at varied wavelengths of polarized light in “intact” cells of Rhodopseudomonas palustris and in films of air-dried lamellar fragments of the bacterium.     

Comparison of the GnRH-stimulation test and a semiquantitative quick test for LH to diagnose presence of ovaries in the female domestic cat

It is generally recommended that female cats not intended for planned breeding are spayed to reduce the population of feral cats and also because spaying is beneficial for the long-term health of the individual. For female cats of unknown origin or with estrous symptoms after spaying there is a need for a reliable method to diagnose or rule out the presence of ovaries to avoid unnecessary surgery. Methods previously recommended include vaginal cytology, evaluation of serum estradiol concentration during suspected estrus, induction of ovulation and subsequent evaluation of progesterone, or explorative laparotomy. These methods have the disadvantages that an accurate diagnosis only can be made during estrus or that an invasive procedure is required. Previously, the use of a GnRH challenge test and a semiquantitative LH test have been reported. Our aim was to compare these two methods. We therefore divided 31 female cats in two groups: (1) intact nonestrous females (N = 16), and (2) previously ovariohysterectomized females (N = 15). A blood sample was collected (Time 0) and 0.4 μg/kg buserelin (Receptal; Intervet, Danderyd, Sweden) was injected im. A new blood sample was collected 120 min after the injection. A drop of serum from the sample collected at Time 0 was placed on the LH test (Witness LH; Synbiotics, Corp., San Diego, CA, USA) and the result was evaluated as negative or positive. The remaining serum was frozen and analyzed for estradiol in one batch. Serum estradiol before buserelin stimulation ranged between 5 and 45 pmol/L (N = 14) in intact nonestrous queens and between 2 and 6 pmol/L (N = 15) in ovariohysterectomized females. Estradiol in samples collected after 120 min ranged between 12 and 51 pmol/L (N = 16) in intact queens and between 1 and 7 pmol/L (N = 15) in spayed cats giving a sensitivity and specificity of 100% for the buserelin stimulation test at a cutoff value of 11 pmol/L. All intact queens were negative in the semiquantitative LH test while 14/15 spayed cats were positive and one was negative giving a sensitivity of 100% and a specificity of 93.8% to detect the presence of ovaries in nonestrous cats.     

FSH and LH plasma levels in bitches with differences in risk for urinary incontinence

To determine whether the height of the plasma gonadotropin levels after spaying is associated with urinary incontinence, the concentrations of plasma follicle stimulating hormone (FSH) and luteinizing hormone (LH) were determined once in 191 intact and 308 spayed bitches. The bitches were grouped according to their risk for urinary incontinence and the medians of their respective gonadotropin levels were compared. For intact anestrous bitches, the FSH- and LH-plasma concentrations were 5.2 (4, 8) ng/mL (median (Q1, Q3)) and 0.5 (0.5-0.5) ng/mL, respectively. In the first year after spaying, the gonadotropin concentrations rose significantly, then stabilised at a level around 10 times those of intact bitches (FSH 62.5 (44, 91) ng/mL; LH 6.1(4, 11) ng/mL). The plasma gonadotropin concentrations of long-term spayed (>12 months) continent bitches (n=209) were higher (FSH 66.8 (46, 104) ng/mL; LH 6.5 (4, 11) ng/mL) than in spayed incontinent bitches (n=60) (FSH 51.5 (38, 74) ng/mL; LH 5.5 (3, 8) ng/mL), the latter also had a higher body weight. Multiple regression analysis showed that the FSH-plasma concentration and not the body weight was decisive for the occurrence of urinary incontinence. The results of this study suggest that levels of gonadotropins are associated, directly or indirectly in the pathophysiology of urinary incontinence after spaying.     

Expression of cyclooxygenase-2 in the canine lower urinary tract with regard to the effects of gonadal status and gender

As pituitary gonadotrophins can induce prostaglandin (PG) synthesis and receptors for LH and FSH are present in the canine lower urinary tract (LUT), the objectives of this study were to (i) investigate the expression of COX-2, a key rate-limiting enzyme in PG production, in the canine LUT and (ii) determine if COX-2 expression differs between gender, gonadal status (intact and gonadectomised) and LUT regions. Four regions (body and neck of the bladder as well as proximal and distal urethra) of the LUT were obtained from 20 clinically healthy dogs (5 intact males, 5 intact anoestrous females, 4 castrated males, 6 spayed females). In situ hybridization and immunohistochemistry were performed to determine the presence of COX-2 mRNA and protein, respectively. The mRNA and protein expression was semi-quantitatively assessed. The scoring system combined both the distribution and intensity of positive staining and was carried out separately on the three tissue layers (epithelium, sub-epithelial stroma and muscle) for each of four regions of the LUT. In comparison to intact dogs, lower expression (P < 0.001) of COX-2 and its mRNA in gonadectomised males and females was observed in all tissue layers of each region of the LUT except in the distal urethra where there was no difference in mRNA expression between gonadal statuses. Regardless of region and tissue layer, intact females expressed more (P < 0.05) COX-2 and its mRNA than intact males. However, in gonadectomised dogs, mRNA expression of COX-2 did not differ between genders; males had higher (P < 0.001) protein level of COX-2 compared to females. In conclusion, both COX-2 and its mRNA were expressed in the canine LUT and COX-2-regulated PG synthesis in the canine LUT may differ between gonadal statuses and genders. The lower expression of COX-2 in gonadectomised dogs may impair normal function of the LUT and probably implicated in the development of neutering-induced urinary incontinence in the dog.     

Characterization of Photoactivated Singlet Oxygen Damage in Single-Molecule Optical Trap Experiments

Optical traps or “tweezers” use high-power, near-infrared laser beams to manipulate and apply forces to biological systems, ranging from individual molecules to cells. Although previous studies have established that optical tweezers induce photodamage in live cells, the effects of trap irradiation have yet to be examined in vitro, at the single-molecule level. In this study, we investigate trap-induced damage in a simple system consisting of DNA molecules tethered between optically trapped polystyrene microspheres. We show that exposure to the trapping light affects the lifetime of the tethers, the efficiency with which they can be formed, and their structure. Moreover, we establish that these irreversible effects are caused by oxidative damage from singlet oxygen. This reactive state of molecular oxygen is generated locally by the optical traps in the presence of a sensitizer, which we identify as the trapped polystyrene microspheres. Trap-induced oxidative damage can be reduced greatly by working under anaerobic conditions, using additives that quench singlet oxygen, or trapping microspheres lacking the sensitizers necessary for singlet state photoexcitation. Our findings are relevant to a broad range of trap-based single-molecule experiments—the most common biological application of optical tweezers—and may guide the development of more robust experimental protocols.     

From Fertilization to Adult Sexual Behavior

Research has established the broad mammalian developmental plan that genes on the sex chromosomes influence gonad development which determines gonadal hormone production (or its absence) leading to modification of the genitalia and simultaneously biasing the nervous system to organize adult sexual behavior. This might be considered the “gonad to hormones to behavior” model. It is clear, however, that although this model generally works well it is incomplete. The model does not account for behavioral influences attributed to the environment or to genetic but nongonadal or hormonal factors. In this essay we probe those areas of sexual development that are neither differentiated by hormones nor activated by them. The concept of the environment used for our discussion is very broad; it incorporates considerations of both the molar and the molecular levels. The general sense of the word “environment” as something exterior to the person is retained, even if that something influences intraperson processes. In addition, we focus directly on molecular events themselves. Here the “environment” involved can be that within a DNA segment. We also expand the notion of “biologically based sex differences.” Although many, and perhaps most, important sex differences arise from gonadal and hormonal development, also important are sex differences which are neither gonadal nor hormonal. All these factors affect the internal workings of the individual and intervene in structuring how the social environment might or might not modify sexual behavior. This discourse calls attention to features that are central to the so-called nature–nurture discussion.     

L’art Paléolithique est-il un « art » ?: Réflexions autour d’une question d’actualité

During the last years, an international debate about the concept of “Palaeolithic art” has taken place. On one hand, several specialists have critiqued the use of the concept of “art” in naming the images created by Homo sapiens during the Palaeolithic era. They claim that the use of this term implies the projection of a modern category to a world - that of prehistoric humans - which is completely different from our own. On the other hand, some archaeologists consider that the term “Palaeolithic art” does not imply an anachronistic interpretation of prehistoric representations. In presenting the historical context, which has made such a discussion possible, we consider the causes and effects of this controversy. Firstly, we analyze the traditional interpretation, which considered Palaeolithic images as “works of art”. Secondly, we examine the connections, which can be found between the debate about “Palaeolithic art” and certain polemics, which have arisen from the history of art and anthropological frameworks. Thirdly, we consider the arguments utilized by those who are for and those who are against the term “Palaeolithic art”. Finally, we emphasize the importance of this debate to better understand the categories and the concepts, which determine the scientific practice.     

Neutering Dogs: Effects on Joint Disorders and Cancers in Golden Retrievers

In contrast to European countries, the overwhelming majority of dogs in the U.S. are neutered (including spaying), usually done before one year of age. Given the importance of gonadal hormones in growth and development, this cultural contrast invites an analysis of the multiple organ systems that may be adversely affected by neutering. Using a single breed-specific dataset, the objective was to examine the variables of gender and age at the time of neutering versus leaving dogs gonadally intact, on all diseases occurring with sufficient frequency for statistical analyses. Given its popularity and vulnerability to various cancers and joint disorders, the Golden Retriever was chosen for this study. Veterinary hospital records of 759 client-owned, intact and neutered female and male dogs, 1–8 years old, were examined for diagnoses of hip dysplasia (HD), cranial cruciate ligament tear (CCL), lymphosarcoma (LSA), hemangiosarcoma (HSA), and mast cell tumor (MCT). Patients were classified as intact, or neutered early (<12 mo) or late (≥12 mo). Statistical analyses involved survival analyses and incidence rate comparisons. Outcomes at the 5 percent level of significance are reported. Of early-neutered males, 10 percent were diagnosed with HD, double the occurrence in intact males. There were no cases of CCL diagnosed in intact males or females, but in early-neutered males and females the occurrences were 5 percent and 8 percent, respectively. Almost 10 percent of early-neutered males were diagnosed with LSA, 3 times more than intact males. The percentage of HSA cases in late-neutered females (about 8 percent) was 4 times more than intact and early-neutered females. There were no cases of MCT in intact females, but the occurrence was nearly 6 percent in late-neutered females. The results have health implications for Golden Retriever companion and service dogs, and for oncologists using dogs as models of cancers that occur in humans.     

Low cost of reproduction in female stalk-eyed flies, Cyrtodiopsis dalmanni

We investigated the effect of exposure to males on female longevity and egg production in the stalk-eyed fly, Cyrtodiopsis dalmanni. In this species, females typically mate several times each morning over a lifetime that can span several months. We hypothesised that high costs of mating with males would be incompatible with the life history of this species. We predicted that 1) female longevity costs of exposure to males would be low, and 2) that the magnitude of mating-induced fecundity increases in C. dalmanni, if present, would also be low. We tested the predictions by comparing the longevity and lifetime fecundity of virgin and mated females. In line with prediction 1), the longevity difference between virgin and fully reproductive females was small and of borderline significance. In line with prediction 2), egg production was not significantly higher in females continually exposed to males than for virgin females. Our results suggest that costs of reproduction resulting from exposure to males are low in species that mate promiscuously at high rates.     

Age of ovary determines remaining life expectancy in old ovariectomized mice

We investigated the capacity of young ovaries, transplanted into old ovariectomized CBA mice, to improve remaining life expectancy of the hosts. Donor females were sexually mature 2-month-olds; recipients were prepubertally ovariectomized at 3 weeks and received transplants at 5, 8 or 11 months of age. Relative to ovariectomized control females, life expectancy at 11 months was increased by 60% in 11-month recipient females and by 40% relative to intact control females. Only 20% of the 11-month transplant females died in the 300-day period following ovarian transplantation, whereas nearly 65% of the ovariectomized control females died during this same period. The 11-month-old recipient females resumed oestrus and continued to cycle up to several months beyond the age of control female reproductive senescence. Across the three recipient age groups, transplantation of young ovaries increased life expectancy in proportion to the relative youth of the ovary. Our results relate to recent findings on the gonadal input upon aging in Caenorhabditis elegans and may suggest how the mammalian gonad, including that of humans, could regulate aging and determine longevity.     

Differences in the proportion of collagen and muscle in the canine lower urinary tract with regard to gonadal status and gender

Gonadectomy not only affects hormonal homeostasis but also alters the turnover of different components of the extracellular matrix in urogenital tissues. Collagen is an important component of the bladder and urethral walls and thus crucial for the mechanical properties of normal lower urinary tract (LUT) functions. This study aimed at investigating the possibility of differences in the proportion of collagen and muscle tissues in the LUT of intact and gonadectomised male and female dogs. Twenty clinically healthy dogs were used including 10 sexually intact dogs (5 males, 5 anoestrus females) and 10 gonadectomised dogs (4 males and 6 females). Four regions of the LUT, i.e. body and neck of the bladder as well as proximal and distal urethra were collected. The tissue sections were stained with Masson's Trichrome. Quantitative evaluation of the blue-stained area for collagen and red-counterstained area for muscle was performed using colour image analysis. The relative proportion of collagen and muscle significantly differed with the gonadal status, the gender and the region. Overall, gonadectomised dogs had a higher (P < 0.001) proportion of collagen and consequently a lower (P < 0.001) proportion of muscle than intact dogs. Regardless of gonadal statuses, females had a higher (P < 0.05) proportion of collagen and a lower (P < 0.05) proportion of muscle tissues than males. Gender differences were found in all four regions of the LUT in intact dogs but only in proximal urethra in gonadectomised dogs where spayed females had a higher (P < 0.05) proportion of collagen and less muscle (P < 0.05). Regional differences were observed in females; a higher proportion of collagen and therefore less muscle were found in the urethra compared with the bladder. Proportional differences in collagen and muscle between intact and gonadectomised animals suggest a relation of different hormonal statuses to structural changes in the canine LUT. Excessive collagen deposits and less muscular volume may impair structural and functional integrity of the LUT which may associate with the development of post-neutering urinary incontinence in the dog.     

Picasso-Hund - ein neuer Name für Lycaon pictus?

Lycaon pictus has been named by a variety of common names, such as “African Wild Dog”, “African Hunting Dog” and their adequates in other languages. The article summarizes the history of naming in that species concluding with a new recommendation by the SSP as well as the EEP for that species to rename it as Painted Dog. As the translation of that name into German is an unhandy term it is suggested to name it “Picasso-Hund” in that language.     

Lack of effect of vaginal lavages and aliphatic acids on ejaculatory responses in rhesus monkeys: Behavioral and chemical analyses

Four behavioral experiments involving a total of 19 adult male and 27 adult spayed female rhesus monkeys failed to reveal significant sexual stimulatory properties of vaginal lavages obtained from estrogen-treated donor females when the material was applied to spayed nonestrogenized recipient females. However, all but one of the males copulated to ejaculation when paired with estrogenized females. Two of three males showed moderate increases in sexual behavior with recipients when the vaginal lavage tested was contaminated with 24-hr-old ejaculate. When purified aliphatic acids were applied to spayed nonestrogenized recepients, one of two males showed increased frequencies of mounting behavior, but intromissions and ejaculations were not displayed.Quantitative analyses of short chain aliphatic acids in vaginal lavages, the hypothesized active component, revealed that (a) spayed females had nondetectable levels of aliphatic acids; (b) daily estradiol benzoate treatment for 6–10 days (25 μg/day i.m.) induced detectable levels of acetic, propionic, and butyric acids; (c) exposure to estradiol for six months resulted in a fairly constant plateau of aliphatic acid concentrations; and (d) ejaculate from the male caused up to fivefold elevations in the aliphatic acid concentrations.Three intact females were studied throughout a menstrual cycle, and the peak values of aliphatic acids occurred in the luteal phase, several days after presumed ovulation. Three spayed females treated chronically with estradiol were given four daily injections of 5 mg progesterone, and the mean concentrations of aliphatic acids increased from 199.7 to 801.0 μg/ml. However, the endocrine conditions associated with maximum concentrations of aliphatic acids in either intact or spayed females are known from other studies to be associated with decreased likelihood of copulation.We conclude that for the majority of males studied, the application of vaginal lavages obtained from estrogenized donors did not significantly increase copulatory behavior with spayed, nonestrogenized recipient females. Moreover, the data from aliphatic acid determinations suggest that increases in concentrations of these substances are not always associated with facilitation of copulation, since the largest increases were found either (1) following copulation to ejaculation, (2) during the luteal phase in cycles free of copulation, or (3) following progesterone treatment of spayed, estrogenized females. Finally, comparison of our results with those from other laboratories suggests that the mechanism involved in positive effects may depend upon associative learning or upon extinction and disinhibition of sexual interest.     

Long-Term Health Effects of Neutering Dogs: Comparison of Labrador Retrievers with Golden Retrievers

Our recent study on the effects of neutering (including spaying) in Golden Retrievers in markedly increasing the incidence of two joint disorders and three cancers prompted this study and a comparison of Golden and Labrador Retrievers. Veterinary hospital records were examined over a 13-year period for the effects of neutering during specified age ranges: before 6 mo., and during 6–11 mo., year 1 or years 2 through 8. The joint disorders examined were hip dysplasia, cranial cruciate ligament tear and elbow dysplasia. The cancers examined were lymphosarcoma, hemangiosarcoma, mast cell tumor, and mammary cancer. The results for the Golden Retriever were similar to the previous study, but there were notable differences between breeds. In Labrador Retrievers, where about 5 percent of gonadally intact males and females had one or more joint disorders, neutering at <6 mo. doubled the incidence of one or more joint disorders in both sexes. In male and female Golden Retrievers, with the same 5 percent rate of joint disorders in intact dogs, neutering at <6 mo. increased the incidence of a joint disorder to 4–5 times that of intact dogs. The incidence of one or more cancers in female Labrador Retrievers increased slightly above the 3 percent level of intact females with neutering. In contrast, in female Golden Retrievers, with the same 3 percent rate of one or more cancers in intact females, neutering at all periods through 8 years of age increased the rate of at least one of the cancers by 3–4 times. In male Golden and Labrador Retrievers neutering had relatively minor effects in increasing the occurrence of cancers. Comparisons of cancers in the two breeds suggest that the occurrence of cancers in female Golden Retrievers is a reflection of particular vulnerability to gonadal hormone removal.     

Effect of gonadectomy and gonadal hormones on singly established Hymenolepis diminuta in rats

The effects of gonadectomy and gonadal hormones on singly-established H. diminuta in rats on “complete” and “deficient” diets have been studied by means of estimations of the number of eggs eliminated by the parasite per 24-hour periods over varying intervals of time.     

Expression of prostaglandin E2 receptor subtypes in the canine lower urinary tract varies according to the gonadal status and gender

Locally-synthesised prostaglandin E₂ (PGE₂) is pivotal for the function of the lower urinary tract (LUT). This study aimed at investigating the expression and distribution pattern of the four PGE₂ receptor (EP) subtypes in the LUT of intact and gonadectomised male and female dogs. Expression for EP1, EP2, EP3, and EP4 and their mRNA (EP2, EP3, and EP4) was investigated. Twenty clinically healthy dogs were allotted into 4 groups based on their gonadal status and gender including 5 intact males, 5 anoestrous females, 4 castrated males, and 6 spayed females. In situ hybridization and immunohistochemistry showed variation in the expression of mRNA and protein for the EP subtypes among tissue layers (epithelium, sub-epithelial stroma, and muscle), regions (body and neck of the bladder as well as proximal and distal urethra) and between gonadal statuses and genders. The expression for the four EPs was intense in the luminal epithelium, intermediate to low in the muscle and the sub-epithelial stroma regardless of gonadal status or gender. Higher expression of all EPs and their mRNAs was observed in the proximal urethra compared to other regions in intact dogs. However, in gonadectomised dogs, the expression did not differ among different regions and was generally lower than in intact dogs particularly in the proximal urethra. Differences in the expression between genders were found and depended on EP subtypes. In conclusion, the results have shown that four subtypes of EP receptors and their mRNAs are present in the canine LUT and their expression was affected by the gonadal status and the gender. The results lead to suggest that an impaired LUT function post-neutering may partly be associated with differences in PGE₂ receptor expression between intact and gonadectomised dogs.     

Relevance of ovarian signaling for the early behavioral transition from estrus to pregnancy in the female rabbit

During estrus, the female domestic rabbit (Oryctolagus cuniculus) displays scent marking behavior (chinning), which is immediately inhibited after mating, temporarily recovers, and then declines and remains inhibited across pregnancy. Chinning is inhibited by progesterone (P) and the activation of the progesterone receptor (PR), but it is unlikely that P participates in the “acute” (immediate) or “early” inhibition of chinning (24 to 96 h post-mating, before plasma P levels rise). Since PR is activated in a ligand-independent manner by a variety of signaling molecules, some of which (e.g., GnRH) are also associated with reflexive ovulation in this species, we hypothesized that neurochemical/neuroendocrine signals associated with mating activate PR, resulting in the inhibition of chinning. In Experiment 1, we tested whether the PR antagonist, RU486 (20 mg, injected s.c. at − 1 h, or at − 7 h and + 3 h relative to mating) prevented the post-mating inhibition of chinning in intact females. RU486 did not prevent the post-mating decline in chinning, indicating that PR activation associated with mating is not necessary for this effect. In Experiment 2, we used ovariectomized (OVX), estradiol benzoate (EB)-treated females to test the hypothesis that ovarian signaling is necessary for the post-mating inhibition of chinning. The acute inhibition of chinning occurred in OVX females, but the early inhibition was absent. We conclude that ovarian signaling is necessary for the early, but not acute, post-mating inhibition of chinning. The PR seems not to participate in either of these phases.     

D2N: Distance to the native

Root-mean-square-deviation (RMSD), of computationally-derived protein structures from experimentally determined structures, is a critical index to assessing protein-structure-prediction-algorithms (PSPAs). The development of PSPAs to obtain 0 Å RMSD from native structures is considered central to computational biology. However, till date it has been quite challenging to measure how far a predicted protein structure is from its native — in the absence of a known experimental/native structure. In this work, we report the development of a metric “D2N” (distance to the native) — that predicts the “RMSD” of any structure without actually knowing the native structure. By combining physico-chemical properties and known universalities in spatial organization of soluble proteins to develop D2N, we demonstrate the ability to predict the distance of a proposed structure to within ± 1.5 ? error with a remarkable average accuracy of 93.6% for structures below 5 ? from the native. We believe that this work opens up a completely new avenue towards assigning reliable structures to whole proteomes even in the absence of experimentally determined native structures. The D2N tool is freely available at http://www.scfbio-iitd.res.in/software/d2n.jsp.