Idan Frumin, Ph.D.

A growing body of evidence suggests that humans can communicate socially relevant information, such as aggression, dominance, and readiness for competition, through chemosensory signals. Androstadienone (androsta-4,16,-dien-3-one), a testosterone-derived compound found in men’s axillary sweat, is a main candidate for a human pheromone that may convey such information. The current study aimed to investigate whether androstadienone serves as a chemosignaling threat cue to men, thus triggering… Show more

A growing body of evidence suggests that humans can communicate socially relevant information, such as aggression, dominance, and readiness for competition, through chemosensory signals. Androstadienone (androsta-4,16,-dien-3-one), a testosterone-derived compound found in men’s axillary sweat, is a main candidate for a human pheromone that may convey such information. The current study aimed to investigate whether androstadienone serves as a chemosignaling threat cue to men, thus triggering avoidance behavior during competitive interaction with another man. In a double-blind, placebo-controlled, within-subject study design, 30 healthy, normosmic, heterosexual male participants completed the social orientation paradigm (SOP), a monetary game played against a fictitious partner that allows 3 types of responses to be measured in the context of provocation: an aggressive response, an individualistic withdrawal response, and a cooperative response. Participants completed the SOP task twice, once under exposure to androstadienone and once under exposure to a control solution. The results indicate that androstadienone increased individualistic responses while it decreased cooperative responses. These findings support the role of androstadienone as a threatening signal of dominance that elicits behavioral avoidance and social withdrawal tendencies, possibly as a submissive response. Show less

• A bacterial biosensor was used to detect Pseudomonas aeruginosa in ear infections.
• Detection was based on interaction with the volatile 2-aminoacetophenone.
• The detection limit of a biosensor-based device is on par with GC-MS analyses

Improved easy-to-use diagnostic tools for infections are in strong demand worldwide. Yet, despite dramatic advances in diagnostic technologies, the gold-standard remains culturing. Here we offer an alternative tool demonstrating that a bacterial… Show more

• A bacterial biosensor was used to detect Pseudomonas aeruginosa in ear infections.
• Detection was based on interaction with the volatile 2-aminoacetophenone.
• The detection limit of a biosensor-based device is on par with GC-MS analyses

Improved easy-to-use diagnostic tools for infections are in strong demand worldwide. Yet, despite dramatic advances in diagnostic technologies, the gold-standard remains culturing. Here we offer an alternative tool demonstrating that a bacterial biosensor can efficiently detect Pseudomonas aeruginosa infections in patients suffering from otitis externa. Detection was based on specific binding between the biosensor and 2-aminoacetophenone (2-AA), a volatile produced by P. aeruginosa in high amounts. We collected pus samples from ears of 26 subjects exhibiting symptoms of otitis externa. Detection of P. aeruginosa using the biosensor was compared to detection using gold-standard culturing assay and to gas-chromatograph-mass-spectrometry (GC-MS) analyses of 2-AA. The biosensor strain test matched the culture assay in 24 samples (92%) and the GC-MS analyses in 25 samples (96%). With this result in hand, we designed a device containing a whole-cell luminescent biosensor combined with a photo-multiplier tube. This device allowed detection of 2-AA at levels as low as 2 nmol, on par with detection level of GC-MS. The results of the described study demonstrate that the volatile 2-AA serves as an effective biomarker for P. aeruginosa in ear infections, and that activation of the biosensor strain by 2-AA provides a unique opportunity to design an easy-to-use device that can specifically detect P. aeruginosa infections.

Abbreviations:
2-AA, 2-aminoacetophenone; PMT, photo multiplier tube; GC–MS, gas chromatography mass–spectrometry Show less

Objectives/Hypothesis
Electronic noses can identify diseases, including head and neck squamous cell carcinoma (SCC) by the fingerprint of volatile organic compounds (VOCs) in exhaled air. However, whether these VOCs originated from the malignant lesion itself remains unclear. The objective was to test for the presence and properties of VOCs directly over the vocal folds in malignant and benign lesions, as a potential tool for noninvasive screening.

Study Design
Prospective… Show more

Objectives/Hypothesis
Electronic noses can identify diseases, including head and neck squamous cell carcinoma (SCC) by the fingerprint of volatile organic compounds (VOCs) in exhaled air. However, whether these VOCs originated from the malignant lesion itself remains unclear. The objective was to test for the presence and properties of VOCs directly over the vocal folds in malignant and benign lesions, as a potential tool for noninvasive screening.

Study Design
Prospective observational case control study.

Methods
Samples of mucus directly covering vocal fold lesions were analyzed using gas chromatography mass spectrometry for detection of VOCs, and evaluation of the properties and quantity of VOCs in the samples. Additionally, samples of oropharyngeal mucus were analyzed to exclude VOCs found also in the vicinity of the lesion. Benign and malignant lesion groups were compared using a nonparametric (Mann-Whitney) test.

Results
We studied 14 patients, six with SCC and eight with benign pathology. We found an increased number of discrete VOC types in patients with SCC both above the lesion (SCC = 4.333 ± 2.5, benign = 0.875 ± 0.6; Z=3, P < .001) and directly above the lesion with exclusion of its vicinity (SCC = 3.167 ± 1.9, benign = 0.5 ± 0.5; Z = 2.8, P < .003). VOCs detected in SCCs but not in benign samples included the straight-chain fatty acids: butyric acid, pentanoic acid, hexanoic acid, and heptanoic acid.

Conclusions
Compared with benign vocal fold lesions, the environment of vocal folds in SCC is enriched with VOCs. These preliminary findings highlight a unique pattern that may contribute to the development of a future minimally invasive technology for screening vocal fold lesions for malignancy. Show less

Each person expresses a potentially unique subset of ∼400 different olfactory receptor subtypes. Given that the receptors we express partially determine the odors we smell, it follows that each person may have a unique nose; to capture this, we devised a sensitive test of olfactory perception we termed the “olfactory fingerprint.” Olfactory fingerprints relied on matrices of perceived odorant similarity derived from descriptors applied to the odorants. We initially fingerprinted 89 individuals… Show more

Each person expresses a potentially unique subset of ∼400 different olfactory receptor subtypes. Given that the receptors we express partially determine the odors we smell, it follows that each person may have a unique nose; to capture this, we devised a sensitive test of olfactory perception we termed the “olfactory fingerprint.” Olfactory fingerprints relied on matrices of perceived odorant similarity derived from descriptors applied to the odorants. We initially fingerprinted 89 individuals using 28 odors and 54 descriptors. We found that each person had a unique olfactory fingerprint (P < 10−10), which was odor specific but descriptor independent. We could identify individuals from this pool using randomly selected sets of 7 odors and 11 descriptors alone. Extrapolating from this data, we determined that using 34 odors and 35 descriptors we could individually identify each of the 7 billion people on earth. Olfactory perception, however, fluctuates over time, calling into question our proposed perceptual readout of presumably stable genetic makeup. To test whether fingerprints remain informative despite this temporal fluctuation, building on the linkage between olfactory receptors and HLA, we hypothesized that olfactory perception may relate to HLA. We obtained olfactory fingerprints and HLA typing for 130 individuals, and found that olfactory fingerprint matching using only four odorants was significantly related to HLA matching (P < 10−4), such that olfactory fingerprints can save 32% of HLA tests in a population screen (P < 10−6). In conclusion, a precise measure of olfactory perception reveals meaningful nonolfactory genetic information. Show less

Social chemosignaling is a part of human behavior, but how chemosignals transfer from one individual to another is unknown. In turn, humans greet each other with handshakes, but the functional antecedents of this behavior remain unclear. To ask whether handshakes are used to sample conspecific social chemosignals, we covertly filmed 271 subjects within a structured greeting event either with or without a handshake. We found that humans often sniff their own hands, and selectively increase this… Show more

Social chemosignaling is a part of human behavior, but how chemosignals transfer from one individual to another is unknown. In turn, humans greet each other with handshakes, but the functional antecedents of this behavior remain unclear. To ask whether handshakes are used to sample conspecific social chemosignals, we covertly filmed 271 subjects within a structured greeting event either with or without a handshake. We found that humans often sniff their own hands, and selectively increase this behavior after handshake. After handshakes within gender, subjects increased sniffing of their own right shaking hand by more than 100%. In contrast, after handshakes across gender, subjects increased sniffing of their own left non-shaking hand by more than 100%. Tainting participants with unnoticed odors significantly altered the effects, thus verifying their olfactory nature. Thus, handshaking may functionally serve active yet subliminal social chemosignaling, which likely plays a large role in ongoing human behavior. Show less

In this study we identify a volatile compound produced by Pseudomonas aeruginosa, which can specifically activate the LuxR quorum-sensing response regulator of Vibrio fischeri. Comparative gas-chromatography analysis between P. aeruginosa wild type and a ΔlasR mutant strain implied that the active volatile is 2-aminoacetophenone. The use of synthetic 2-aminoacetophenone and in silico docking analyses verified the activity of the molecule and provided putative interacting residues within the… Show more

In this study we identify a volatile compound produced by Pseudomonas aeruginosa, which can specifically activate the LuxR quorum-sensing response regulator of Vibrio fischeri. Comparative gas-chromatography analysis between P. aeruginosa wild type and a ΔlasR mutant strain implied that the active volatile is 2-aminoacetophenone. The use of synthetic 2-aminoacetophenone and in silico docking analyses verified the activity of the molecule and provided putative interacting residues within the binding site. Show less

While effectively doubling the number of known odorant-to-receptor pairings in human olfaction, researchers explain a portion of perceptual variability that stems from genetic variability.

Like all mammals, humans use chemosignals. Nevertheless, only few such chemosignals have been identified. Here we describe an experimental arrangement that casts a wide net for the possible chemosignaling functions of target molecules. This experimental arrangement can be used in concert with various methods for measuring the human behavioral and brain responses, including psychophysiology and brain imaging. Moreover, many of the methodological issues we describe are relevant to any study with… Show more

Like all mammals, humans use chemosignals. Nevertheless, only few such chemosignals have been identified. Here we describe an experimental arrangement that casts a wide net for the possible chemosignaling functions of target molecules. This experimental arrangement can be used in concert with various methods for measuring the human behavioral and brain responses, including psychophysiology and brain imaging. Moreover, many of the methodological issues we describe are relevant to any study with human chemosignals. Show less

To understand the brain mechanisms of olfaction we must understand the rules that govern the link between odorant structure and odorant perception. Natural odors are in fact mixtures made of many molecules, and there is currently no method to look at the molecular structure of such odorant-mixtures and predict their smell. In three separate experiments, we asked 139 subjects to rate the pairwise perceptual similarity of 64 odorant-mixtures ranging in size from 4 to 43 mono-molecular components.… Show more

To understand the brain mechanisms of olfaction we must understand the rules that govern the link between odorant structure and odorant perception. Natural odors are in fact mixtures made of many molecules, and there is currently no method to look at the molecular structure of such odorant-mixtures and predict their smell. In three separate experiments, we asked 139 subjects to rate the pairwise perceptual similarity of 64 odorant-mixtures ranging in size from 4 to 43 mono-molecular components. We then tested alternative models to link odorant-mixture structure to odorant-mixture perceptual similarity. Whereas a model that considered each mono-molecular component of a mixture separately provided a poor prediction of mixture similarity, a model that represented the mixture as a single structural vector provided consistent correlations between predicted and actual perceptual similarity (r≥0.49, p<0.001). An optimized version of this model yielded a correlation of r = 0.85 (p<0.001) between predicted and actual mixture similarity. In other words, we developed an algorithm that can look at the molecular structure of two novel odorant-mixtures, and predict their ensuing perceptual similarity. That this goal was attained using a model that considers the mixtures as a single vector is consistent with a synthetic rather than analytical brain processing mechanism in olfaction. Show less

Emotional tearing is a poorly understood behavior that is considered uniquely human. In mice, tears serve as a chemosignal. We therefore hypothesized that human tears may similarly serve a chemosignaling function. We found that merely sniffing negative-emotion-related odorless tears obtained from women donors induced reductions in sexual appeal attributed by men to pictures of women's faces. Moreover, after sniffing such tears, men experienced reduced self-rated sexual arousal, reduced… Show more

Emotional tearing is a poorly understood behavior that is considered uniquely human. In mice, tears serve as a chemosignal. We therefore hypothesized that human tears may similarly serve a chemosignaling function. We found that merely sniffing negative-emotion-related odorless tears obtained from women donors induced reductions in sexual appeal attributed by men to pictures of women's faces. Moreover, after sniffing such tears, men experienced reduced self-rated sexual arousal, reduced physiological measures of arousal, and reduced levels of testosterone. Finally, functional magnetic resonance imaging revealed that sniffing women's tears selectively reduced activity in brain substrates of sexual arousal in men. Show less

The circadian clock in peripheral tissues can be entrained by restricted feeding (RF), a regimen that restricts the duration of food availability with no calorie restriction (CR). However, it is not known whether RF can delay the occurrence of age-associated changes similar to CR. We measured circadian expression of clock genes, disease marker genes, metabolic factors and inflammatory and allergy markers in mouse serum, liver, jejunum and white adipose tissue (WAT) after long-term RF of 4… Show more

The circadian clock in peripheral tissues can be entrained by restricted feeding (RF), a regimen that restricts the duration of food availability with no calorie restriction (CR). However, it is not known whether RF can delay the occurrence of age-associated changes similar to CR. We measured circadian expression of clock genes, disease marker genes, metabolic factors and inflammatory and allergy markers in mouse serum, liver, jejunum and white adipose tissue (WAT) after long-term RF of 4 months. We found that circadian rhythmicity is more robust and is phase advanced in most of the genes and proteins tested under RF. In addition, average daily levels of some disease and inflammatory markers were reduced under RF, including liver Il-6 mRNA, tumour necrosis factor (TNF)-α and nuclear factor κB (NF-κB) protein; jejunum Arginase, Afp, Gadd45β, Il-1α and Il-1β mRNA, and interleukin (IL)-6 and TNF-α protein and WAT Il-6, Il-1β, Tnfα and Nfκb mRNA. In contrast, the anti-inflammatory cytokine Il-10 mRNA increased in the liver and jejunum. Our results suggest that RF may share some benefits with those of CR. As RF is a less harsh regimen to follow than CR, the data suggest it could be proposed for individuals seeking to improve their health. Show less

With the increasing incidence of drug-induced liver disease, attempts are being made to better understand the mechanisms behind these frequently life-endangering reactions. Analgesics and anti-inflammatory drugs are a major group exhibiting hepatotoxicity. We review research relating to these reactions, focusing on ultrastructural findings, which may contribute to the comprehension and possible avoidance of drug-induced liver disease. We also present some original observations on clinical… Show more

With the increasing incidence of drug-induced liver disease, attempts are being made to better understand the mechanisms behind these frequently life-endangering reactions. Analgesics and anti-inflammatory drugs are a major group exhibiting hepatotoxicity. We review research relating to these reactions, focusing on ultrastructural findings, which may contribute to the comprehension and possible avoidance of drug-induced liver disease. We also present some original observations on clinical material and cultured cells exposed to acetaminophen alone or in combination with the antioxidant N-acetylcysteine or the P-glycoprotein inhibitor verapamil. Show less