Recent studies have shed light on how the COVID-19 pandemic changed our lives, and most of them have documented its detrimental effect on eating habits. Until now, the effects of this global crisis on negative body image and its association with disordered eating behaviors remain largely understudied. This study aimed to investigate changes in frequency of disordered eating behaviors  and negative body image  among a community sample of women during the COVID-19 pandemic (October 2020–May 2021). Furthermore, we explored the possible relation between body image-related variables and changes in the frequency of disordered eating behaviors in the context of the pandemic. A total of 161 self-identified female participants enrolled in an online-based survey. Descriptive statistics showed that women did not report clinically significant levels of weight and body shape concerns, but participants reported being dissatisfied with their body. One sample Wilcoxon Signed Rank tests revealed a tendency toward an increasing of the frequency of all disordered eating behaviors during the COVID-19 pandemic. Multinomial logistic regressions showed that weight concerns predicted an overall increase in the frequency of restrictive eating behaviors, whereas higher body dissatisfaction was associated with a moderate self-perceived increase in the frequency of emotional eating. These results shed light on a risk pattern of phenomena in a non-clinical sample of women, as they represent the key risk factors for the development of eating disorders. Findings could have implications for designing and implementing prevention programs. In December 2019, the world became aware of the development of a novel coronavirus, the coronavirus disease 2019 , but on the other hand, they may also foster overeating and binge eating episodes as consequences of the increased availability of food at home brought and stored up in response to general food insecurity and increased time spent at home . FurtherResearch conducted so far points to a marked increase of irregular eating patterns since the beginning of the pandemic . In lineThere is also preliminary evidence of increased concerns about appearance and heightened weight and shape concerns in people from the United Kingdom’s general population during the COVID-19 pandemic . SeveralNegative body image has been found to be related to disordered eating behaviors e.g.,  and to bIn consideration of the aforementioned findings and their possible preventive and therapeutic implications, we investigated self-reported changes in frequency of disordered eating behaviors  and negative body image  among a community sample of women during the COVID-19 pandemic. Furthermore, we explored the possible relationship between body image-related variables and perceived changes in the frequency of disordered eating behaviors in the context of the COVID-19 pandemic. In light of the literature on problematic eating behaviors during the COVID-19 pandemic, we expected an increase in disordered eating patterns since the beginning of the COVID-19 crisis. Regarding negative body image, since we were interested in a community sample of women, we did not expect clinical levels of body image-related issues. Nevertheless, since negative body image is considered as normative  who self-reported to be resident in a country other than Canada were excluded. To provide context for the situation during the recruitment period, Canada had reached a critical level of COVID-19 cases in the population. Between October 2020 and December 2020, most regions went into maximum alert, which involved closing non-essential businesses, restricting inter-regional travel, and banning gatherings, a curfew in effect from 8 p.m. to 5 a.m., mandatory teleworking and online school. Canada experienced several tightening of regulations until May 2021, with a slight loosening in March 2021 due to the start of vaccination  with a self-reported current or past diagnosed eating disorder were excluded from this study, yielding a sample size of n = 161.The sample consisted of 197 female self-identified participants, who accepted participating in an online-based survey exploring the impact of the COVID-19 pandemic on the self. Inclusion criteria were as: over 18 years old, self-identifying as female, never having been diagnosed with EDs, having access to the Internet, being Canadian residents, and being able to read and understand French. Almost all participants (98.2%) self-reported to be Canadian residents. Participants  months, from October 2020 to May 2021. The study was advertised on social media and participants were recruited using opportunistic and snowball sampling. Participants completed an anonymous online-based survey on LimeSurvey containing sociodemographic questions and questions around their eating habits and body image during the pandemic. Informed consent was obtained prior to completing the survey. The present study was carried out in compliance with current legislation regarding the protection of personal data  and obtained the approval from the ethical committee of Université du Québec en Outaouais  and of Université du Québec à Trois-Rivières .Participants were asked information about self-reported age, gender, country of residency, relationship status, level of education, skin color, and self-reported current height and weight . In addition, participants were asked if they ever received (in their past or present) an eating disorder diagnosis. In the present study, participants were considered to have never received a diagnosis of an eating disorder if they answered no to either question.Participants were asked, “Since the COVID-19 pandemic, please rate each of the following using this scale:,” ranging from “1 = Much less than before,” “2 = Less than before,” “3 = Somewhat less than before,” “4 = No change than before,” “5 = Somewhat more than before,” “6 = More than before,” and “7 = Much more than before.” Items included “Emotional eating (overeating in response to negative emotions such as anxiety or irritability)” , “Restriα = 0.905, McDonald’s ω = 0.906; Weight concern: Cronbach’s α = 0.808; and McDonald’s ω = 0.825).Participants were asked to answer the body shape and weight concerns subscales of the Eating Disorder Examination Questionnaire EDE-Q; . The EDEeLoriCorps Immersive Body Rating Scale  logistic regressions in order to predict several categorical outcomes (changes in the frequency of each disordered eating habit) from continuous predictors (body image-related variables). Cohen’s d effect sizes and Nagelkerkes’s R2 coefficients of determination are reported  since the COVID-19 outbreak. One sample Wilcoxon Signed Rank tests were used to compare whether sample means for each eating habit differed from a null hypothesis of “No change than before” (corresponding to a rating of 4 in the questionnaire developed for this study aims). One sample reported . The z-s2 (SD = 6.97). Three (3) participants reported that their level of education was less than high school (1.9%), 101 participants obtained a high school diploma (62.7%), 8 participants obtained a university certificate (5%), and 25 a bachelor’s degree (15.5%), whereas 24 reported a postgraduate level of education (14.9%). Regarding self-reported relationship status, 87 participants reported being married or in a common-law relationship (54.1%), 11 participants reported being divorced or separated (6.8%), 29 to be in a relationship (18%), 33 did not have a partner (20.5%), and 1 person preferred not to answer (0.6%). Concerning self-reported skin color, 38 participants self-identified their skin color as very light (38.8%), 43 as light (43.9%), 14 as intermediate (14.3%), and 3 as tan (3.1%). No participant reported having dark or very dark skin. The skin color scale used in this study is available in Mean participants age was 35.72 (SD = 13.87). Self-reported mean height was 162.91 cm (SD = 5.85), and weight was 72.89 kg (SD = 19.62), resulting in an average BMI of 27.41 kg/mWomen did not report clinically significant levels of weight  and body shape  concerns. On average participants reported being dissatisfied with their body , desiring a thinner body  than their perceived one . Since no participant self-reported to have dark or very dark skin, we did not conduct any analyses in order to explore the possible effect of the lack of representativeness of the virtual bodies.p = 0.012; overeating: p = 0.002; and emotional eating: p < 0.001). Effect sizes were small for restrictive eating and overeating, and moderate for emotional eating. Differences indicate a tendency to have increased the frequency of restrictive eating, overeating, and emotional eating. Results from parametric analyses paralleled the ones obtained with the non-parametric analyses, indicating that the median value for each eating habit was significantly different than “4”  and weight (p < 0.001) concerns. A multinomial logistic regression was performed to create a model of the relationship between the predictor variables  and six outcome categories  when compared to a baseline outcome category . Analysis of collinearity statistics shows the assumption of no multicollinearity had been met since tolerance values were above 0.1 and Variance Inflated Factor (VIF) values were less than 10  = 52.07, p < 0.001, Nagelkerkes’s R2 = 0.351. Pearson Chi-Square test indicated that the model was a good fit to the data (p = 0.975). Weight concerns had a significant main effect on self-perceived changes in the frequency of restrictive eating, χ2(6) = 17.28, p = 0.008, whereas shape concerns did not have a significant main effect, χ2(6) = 4.30, p = 0.637. Once the overall effects were broken down, results showed that higher weight concerns significantly predicted a slight (“A little more than before”) b = 1.36, Wald χ2(1) = 12.11, p = 0.001, and moderate (“More than before”) b = 1.35, Wald χ2(1) = 6.44, p = 0.011 increase in the frequency of restrictive eating behavior. In other words, women were more likely to self-perceive an increase in the frequency of restrictive eating behavior—than not change the frequency—if they experienced higher weight concerns during the COVID-19 pandemic.Non-parametric correlation analysis between eating habits and body image-related variables are reported in None of the body image-related variables  were significantly related to overeating see .p = 0.032; see χ2(6) = 18.21, p = 0.006, Nagelkerkes’s R2 = 0.184. Pearson Chi-Square test indicated that the model was a good fit for the data (p = 0.604). Once the overall effect of body dissatisfaction was broken down, results showed that higher body dissatisfaction significantly predicted a moderate (“More than before”) increase in the frequency of emotional eating, b = 2.25, Wald χ2(1) = 9.91, p = 0.002. Therefore, women were more likely to self-perceive an increase in the frequency of emotional eating—than no change in the frequency—if they experienced higher body dissatisfaction during the COVID-19 pandemic. Weight and shape concerns were not significantly correlated to self-rated changes in the frequency of emotional eating, whereas body dissatisfaction was significantly positively correlated to changes in the frequency of emotional eating . The dataset is not publicly available due to privacy and ethical restrictions.The data for this study is available upon request addressed directly to the Research Ethics Boards  and of Université du Québec à Trois-Rivières . The patients/participants provided their written informed consent to participate in this study.GC, AP, JM-B, and SB created and conceptualized the study. GC, AP, and MO collected the data. GC, AP, and SB analyzed and interpreted the data. GC and AP wrote the first draft. GC, AP, JM-B, MO, and SB critically revised the manuscript and provided constructive comments. All authors contributed to the article and approved the submitted version.This work was supported by a postdoctoral grant awarded to the first author (GC) by the Fond de Recherche du Québec— Santé ; the Canada research Chair in clinical cyberpsychology (950-210762)awarded to SB; and the RBC Royal Bank, the Lemaire family, Fond. UQTR-RBC Banque Royale-PI-Loricorps, 2017–2021, by the Fonds de Recherche du Québec- Société et culture, FRQSC-2014-NP-17646, 2013–2020, by the Social Sciences and Humanities Research Council of Canada, 2018–2023 (CRSH-SAVOIR-430-2018-00970–PIE-IC), and the settlement fund of the Centre de Recherche de l’Institut Universitaire en Santé Mentale de Montréal, awarded to JM-B.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Introduction:Costs related to bone and joint infection (BJI) management are increasingworldwide, particularly due to the growing use of off-label antibiotics that are expensive treatments (ETs), in conjunction with increasing incidence of multi-drug-resistant pathogens. The aim of this study was to evaluate the whole costs related to these treatments during the patient route, including those attributed to the rehabilitation centre (RC) stay in one regional referral centre in France. The total annual cost of ETs for managing complex BJIs in France was then estimated.Material and methods:A prospective monocentric observational study was conducted from 2014 to 2019 in a referral centre for BJI management (CRIOAc – Centre de Référence des Infections OstéoArticulaires complexes). Costs related to expensive treatments  were prospectively recorded. In all cases, the use of these ETs was validated during multidisciplinary meetings.Results:Of the 3219 patients treated, 1682 (52.3 %) received at least one ET, and 21.5 % of patients who received ET were managed in RCs. The overall cost of ETs remained high but stable , despite the increase of patients treated by ETs (from 182 in 2014 to 512 in 2019) and in the cumulative days of treatment (9739 to 16 191 d).Daptomycin was the most prescribed molecule , but its cost has decreased since this molecule was genericized in 2018; the same trend was observed for linezolid. Thus, costs for old ETs decreased overall, from EUR 1 033 610 in 2014 to EUR 604 997 in 2019, but global costs remained stable due to new ET utilization accounting for 46.5 % of overall costs in 2019. Tedizolid, used as suppressive antimicrobial therapy, represented 77.5 % of total new ET costs. In our centre, dalbavancin was never used.The cost paid by RCs for ETs and the duration of ET remained stable overall between 2016 and 2019.Conclusions:A high consumption of off-label ET is required to treat patients with BJIs in a CRIOAc, and the consequence is a high cost of antimicrobial therapy for these patients, estimated to be almost EUR 10 million in France annually. Costs associated with ET utilization remained stable over the years. On the one hand, the introduction of the generic drugs of daptomycin and linezolid has significantly decreased the share of old ETs, but, on the other hand, the need for new ETs to treat infections associated with more resistant pathogens has not led to decrease in the overall costs. A drastic price reduction of generic drugs is essential to limit the costs associated with more complex BJIs. In France, the incidence is estimated at 70 per 100 000 persons per year, and in 2013, the total direct cost of treating BJIs was estimated atEUR 421 million (USD 509 million), including EUR 11 960(USD 14 460) per hospital stay .Infections involving an internal device account for up to 57.7 % ofcomplex BJIs . They are more costly than nativeBJIs. Indeed, at least one surgery is required, the prevalence ofmulti-drug-resistant bacteria is higher, and the use of expensive antibioticsis more frequent .Peri-prosthetic joint infections (PJIs) represent the vast majority of theseimplant infections, and more than one-third of all BJIs . They are increasing, with a significant morbidity and mortality rate,and high costs. In the USA, projections for 2030 estimate that the annual number of PJIs (hip and knee) could rise to more than 66 000 cases per year, with a total cost of more than EUR 1.53 billion (USD 1.85 billion).The CRIOAc (Centre de Référence des Infections OstéoArticulaires complexes) network, composed of nine regional referral centres, was implemented in France in 2008 by the General Directorate for the Provision of Healthcare  for the management of complex BJIs. The complex nature is defined by a patient who presents one or more of the following criteria: (i) relapse, (ii) host-related criteria, e.g. anaesthetic risk terrain, allergy limiting therapeutic management, and history limiting and/or modifying surgical management, (iii) surgical-related criteria, e.g. the need for bone resection or complex bone and/or soft tissue reconstruction, and (iv) pathogen-related criteria, which may be multi-drug-resistant with limited therapeutic possibilities .S. aureus infections (approximately EUR 88 755 or USD 107 264) than for methicillin-susceptible S. aureus infections . The growing incidence of resistant pathogens involved in BJIs, such as multi-drug-resistant (MDR)coagulase-negative staphylococci or MDR gram-negative pathogens , and the occurrence of sideeffects under conventional treatment are leading to the increasing use ofoff-label molecules for the treatment of BJIs.Antibiotic resistance has an impact on the cost of BJIs as it limits the useof orally adequate available drugs and may promote less active or moreexpensive drug administration. In the USA, the cost related totreatment of BJIs is significantly higher for methicillin-resistant These antibiotics have sometimes been on the market for more than 10 yearsand have only been validated for skin and soft tissue infections(anti-gram-positive antibiotics), and urinary tract or intra-abdominalinfections (anti-gram-negative antibiotics). The vast majority of them areexpensive treatments (ETs). Due to their potential high cost, their use hasto be validated during multidisciplinary meetings; therefore, they may beassociated with a significant increase in costs of treating BJIs. This couldalso be a barrier to management in rehabilitation centres (RCs).There are no precise data in France concerning the volume and cost ofprescriptions for ETs. The main objective of this study was to estimate thewhole cost of off-label ETs over time for patients treated at CRIOAcin Lyon. We included RCs and outpatient prescriptions in this descriptiveanalysis.22.1https://www.crioac-lyon.fr, last access: 14 June 2021) and included patients managed for an osteo-articular infection between 1 January 2014 and 31 December 2019. Those patients who refused to participate in the study were excluded. The clinical situation ofevery patient referred to this referral centre was discussed duringmultidisciplinary meetings, and the use of every off-label antibiotic was also validated at these meetings.A prospective monocentric cohort study was conducted at CRIOAc in Lyon, American Society of Anesthesiologists (ASA) score, presence or absence of implant, infection type , time between hardware placement and symptom onset  and osteosynthesis-associatedinfections were defined according to the MusculoSkeletal Infection Society(MSIS) 2018 criteria  and the fracture-relatedinfections (FRI) consensus group, respectively . Osteomyelitis was defined by the Infectious Diseases Society of America (IDSA) definition  and septic arthritis by modified Newman's criteria .As RCs were not equipped with the same computerized prescription program,they were asked to fill out a table with the dates of admission and exit oftheir institution. A cross-reference was made between ET dispensation datesand patient care in RCs, making it possible to calculate the exact patientlength of stay and duration of treatment (DOT) in RCs.Eventually, as we know the number of inhabitants that are referred to ourcentre, the total annual cost attributed to ETs in France was estimated,using the 2018 census for calculation.2.3Categorical variables were described by counts and percentages, while meanand standard deviation or median and interquartile range (IQR) were used tosummarize continuous variables. Charts were made with Microsoft Excel forApple Mac (version 16.48). Description analyses were done with Stata 16.1 .33.1Between 1 January 2014 and 31 December 2019, 3219 patients were managed atour referral centre with the following distribution: 410 patients in 2014,473 in 2015, 524 in 2016, 564 in 2017, 581 in 2018, and 652 in 2019. Ofthese, 1705 received one or more ET. A total of 23 were excluded from the study . Thus, 1682(52.5 %) were included in the study analysis, i.e. 182 patients(44.4 %) in 2014, 214 (45.2 %) in 2015, 220 (42.0 %) in 2016, 249(44.1 %) in 2017, 305 (52.5 %) in 2018, and 512 (78.5 %) in 2019.Patients who received ETs were predominantly male .The part of gram-positive pathogens increased during the study period(54.8 % to 65.6 %); it contrasted with decrease in gram-negative BJIs(33.2 % to 24.4 %); over the 6 years, gram-positive bacteriarepresented more than double the gram-negative bacteria , while the number of patients treated, and those for whom ETs were needed, increased. Without new ETs, the costs associated with old ETs would have almost halved between 2014 and 2019 (EUR 1 023 890 to EUR 604 997), with this being related to theappearance of generic molecules .Daptomycin represented the majority of ET costs but was decreasing since 2016 with the introduction of generic molecules.Indeed, by genericizing the molecule, the price went down from aroundEUR 150 to EUR 55. In 2019, it corresponded only to 39.2 % of thetotal costs, whereas in 2016 it was 74.9 %, while DOT had doubled .The same trend was observed for linezolid with a significant decrease inprice, from EUR 122 for 37 patients in 2014 (1236 d) to aroundEUR 5 in 2019 for 137 patients (2904 d). Despite the 2-foldincrease in the number of days, total costs related to linezolid decreased bymore than 10 times (EUR 150 975 to EUR 17 818).Ertapenem costs decreased, which is related to the use of new ETs. Indeed,ceftazidime-avibactam and ceftolozane-tazobactam have been prescribed since 2017. This use, however, remained marginal compared to treatments targetinggram-positive pathogens.Eventually, costs related to tedizolid increased drastically in 2019, representing 36.0 % of the overall costs. This expensive molecule (EUR 175) has been frequently used as a SAT, resulting in long treatment duration and high costs. In 2019, it accounted for the vast majority (77.5 %) of new ET costs and treatment days (89.8 %).3.4Between 2014 and 2019, patients under ETs in RCs increased from 50 in 2014 to87 in 2019. Nevertheless, the proportion of RC patients receiving ETscompared to the number of patients under ETs remained stable at 21.5 %(Table 3).The length of stay in RCs decreased between 2014 and 2017 and then increasedfrom 2092 d in 2014 to 2406 d in 2019.The RC global costs related to ETs decreased over this period as follows: EUR 218 836  in 2014, EUR 173 391 (13.7 %) in 2015, EUR 191 098 (19.4 %) in 2016, EUR 192 229 (17.2 %) in 2017, EUR 200 651 (17.7 %) in 2018, and EUR 113 848(10.1 %) in 2019.3.5Our referral centre is the dedicated centre for the management of complexBJIs in the Auvergne-Rhône-Alpes region located in the east of Francewith 7 994 459 inhabitants. The other part of the country is covered byeight other CRIOAcs. With a total population in France of 68 014 000inhabitants, the annual cost due to off-label antibiotics for the treatmentof BJIs within the CRIOAc network in France would be almost EUR 10 million euros (EUR 9 612 462).4Our study quantified the overall cost of off-label ETs used in BJIs over 6 consecutive years within a CRIOAc. The costs remained globally stable overthe study period despite (1) an increasing number of managed patients, (2) a larger portion of these patients requiring ETs, and (3) an increase incumulative treatment days. This is especially due to the introduction ofgeneric molecules such as daptomycin and linezolid, whose prices, unlike ertapenem, have decreased considerably.This decrease in costs related to these generic drugs is, however,counterbalanced by the appearance of multi-drug-resistant bacteria requiringthe use of more expensive, new ETs such as tedizolid. This oxazolidinoneantibiotic is similar to linezolid in terms of the spectrum of activity, and it remains active against gram-positive multi-resistant pathogens. Unlike linezolid, this antibiotic appears to be better tolerated, with less myelotoxicity and neuropathy and fewer drug–drug interactions . This makes it an excellent choice for SAT, especially for patients with MDR gram-positive PJIs for whom no oral options were available before the market launch of this drug . Yet, it remains expensive; in 2019, it accounted for one-third of ET costs and for less than 15 % of cumulative treatment days. It should be noticed that this antibiotic is not available in all countries, such as Switzerland, and that some centres use dalbavancin as a SAT; in our centre, however, it was decided to use tedizolid because it can be taken by mouth, unlike dalbavancin, which requires an injection to be administered in the hospital every 1 or 2 weeks in France .Daptomycin was the most frequently used antibiotic in our study, accountingfor almost half of the cumulative days and almost 60 % of the total costs. However, its share of costs has drastically decreased since the introduction of generic drugs in 2018, with a high drop in its price in 2019. It is worth noticing that this ET has been used more since 2018 when the combination of piperacillin-tazobactam and vancomycin was shown to increase the risk of acute renal failure .Generic drugs are defined as bio-equivalent replicas of brand name drugs,containing the same active molecules, with identical quality, safety, andefficacy profiles. Only inactive ingredients, like colouring, flavouring,and stabilizing agents can differ . Generic drugs can be approved for sale when relevant patents and legal exclusivities have expired  or when the patent owner waives their rights . Yet, generic drugs have been associated with notable monetary savings. For instance, about 90 % of all prescriptions were filled using a generic drug product in 2019 in the USA, and USD 313 billion could be saved . Unfortunately, these results do not represent what is has been achieved in other countries. In Switzerland, the proportion of prescriptions filled with generic drugs is only about 17 % to 23 %, while in France it is about 30 % to 40 % – far fromGermany and Great Britain, with 80 % to 82 % and 83 % to 85 %, respectively , 2019). Nevertheless, without the generic molecules of daptomycin and linezolid, the costs associated with ETs during the study period could not have been stable and would have increased dramatically, especially in 2019 with the use of tedizolid, ceftolozane-tazobactam, and ceftazidime-avibactam.With regard to RCs, their part of the cost was not the majority. The proportion of patients under ETs, the cost paid by RCs for ETs, and the number of cumulative days remained globally stable over the study period.This study has some other limitations. Indeed, the choice of whichantibiotic was an ET was arbitrary and could, therefore, change from onecountry to another. Moreover, it was a monocentric analysis; theprescription of any antibiotic is, therefore, linked to the practices of thecentre and is, therefore, not totally generalizable. Nevertheless, as thepatients were treated in a referral centre, it can be assumed that thesepractices are not so far from the other CRIOAcs in France. Moreover, CRIOAcs are located in hospitals that are mostly members of the same central purchasing group; therefore, they benefit from the same prices negotiated by the laboratories marketing the antibiotics.Finally, the costs related to antibiotics reflect only part of the costsgenerated by BJIs. However, in France, the costs are covered by the insurancecompanies on a fixed-price basis according to the diagnosis code of thedisease. Therefore, excess costs related to ETs are supported by thehospitals and also by the healthcare system.In conclusion, off-label ET use is common for treating BJIs in a referral centre in France, with a huge total cost (estimated to EUR 10 million per year in France), given the entire course of the patient from hospital to RCs and/or outpatient settings. With the introduction of generic molecules of daptomycin and linezolid, overall costs remained stable over the years in our study. Thus, with the rising number of multi-drug-resistant infections, the production of generic antibiotics at low cost is essential to limit the financial burden of the management of BJIs.


The online environment has had a profound sociocultural impact, and its implications pose new challenges to modern-day societies. The digital sexual and dating domains have dramatically affected sexual and romantic behavior and norms, and yet, no empirical studies have addressed the role of the sexual self-concept in driving sexual and romantic online behavior. The aim of this study is to identify reliable sexual self-configurations through a cluster analysis approach and determine whether these profiles are informative in relation to app use motives and sexual outcomes. For this purpose, a total of 244 subjects were recruited. Survey questions measured a set of demographic parameters, motives for app use, online sexual activities, attachment orientations, the sexual self-concept and sexual satisfaction. Five clusters were identified, including two with high levels of sexual drive (“Driven” and “Adventurous”), two with low levels of sexual drive (“Unassured” and “Naïve”) and one with an intermediate level of sexual drive (“Competent”). The clusters differed on gender, attachment styles, app use patterns and sexual characteristics. These findings provide insight into how the sexual self-concept relates to the interaction between individuals and the online sexual and dating scenes. Digital media has become part of our everyday lives and has had a profound impact on the way identity is formed  and on hThe sexual self-concept is considered a dynamic construct that forms by organizing perceptions of personal sexual qualities into a cohesive, internalized structure . ResearcTwo areas where sexuality is involved will be explored in this study, namely digital apps that people use for sexual and/or romantic purposes  and online sexual activities . Digital tools have dramatically impacted sexual and romantic behavior and norms, with potentially significant sociocultural consequences . Apps liOnline sexual activities (OSAs) reffers to the use of the internet for any activity that involves sexuality . Out of In brief, the present study is focused on identifying reliable sexual self-profiles and investigating differences in app use and online sexual behaviors among these groups. We expect to replicate findings in previous studies on related topics and to further expand knowledge on sexuality and the digital domain. The research was conducted based on a sample of 244 respondents consisting of 149 females and 95 males, with a mean age of 26.92 (SD = 9.32). The majority of respondents reported using Tinder and Instagram apps for romantic and sexual purposes. Recruitment for this study was done through social media platforms, such as Facebook, and participation invitations were sent via e-mail. The questionnaire application process involved the completion of an online form comprised of several sections: information regarding the confidentiality of personal data, informed consent and the measures used in the study. The ethical approval for this study was obtained from the University of Bucharest.Demographics. Demographic variables taken into consideration were age, gender, education, sexual orientation, relationship status, number of sexual partners in the previous 12 months, apps used for romantic or sexual purposes, frequency of use, partner searching online and cyber infidelity.App use motives. Motives for using apps were measured using the Tinder Motivations Scale (TMS) , developOnline sexual activities. A series of items were developed specifically for this study in order to assess the frequency of engagement in online sexual activities (OSAs) in the previous 6 months. The items were created in accordance with themes presented in previous studies ,30,31,32Attachment style. Attachment style was measured using The Revised Adult Attachment Scale (R-AAS) . The scaSexual self. The model for the sexual self-concept used in this study was proposed by Deutsch  and contSexual satisfaction. Sexual satisfaction was measured with The New Sexual Satisfaction Scale-Short Form (NSS-S) . This scn = 244. Next, in order to identify subgroups within our sample, a cluster analysis was performed based on the sexual self-model we employed . This was a two-step process in which two clustering methods were employed. First, a hierarchical cluster analysis was employed using Ward’s method (D2) and Euclidian distance measure, followed by a K-means analysis used to maximize homogeneity within clusters and maximize heterogeneity between clusters. The stability of the cluster structure obtained with the two methods was evaluated using Cramer’s V test. Cluster profiling and external correlates  were examined using analysis of variance (ANOVA) with post hoc tests (Tukey and Games–Howell). In addition, log-linear analysis was used to test the association between categorical data  and cluster membership with χ2 post hoc tests.Statistical analyses were performed using JASP (v. 0.13.1)  and IBM Cramer’s V = 0.771, ρ < 0.001), which indicated that similar clusters were obtained regardless of the method used to derive them. Additionally, the chi-square test showed strong confidence in this result (χ2 (16) = 579.85, ρ < 0.001). In order to further confirm separation among clusters, the scores for each variable included in the cluster analysis  were introduced into a discriminant function analysis, grouped by the identified clusters. The final cluster sizes exceeded 10% of the sample as recommended by Hair et al. [All variables included in the analysis were standardized to share the same metric. First, a hierarchical cluster analysis was performed using Ward’s method (D2) and the Euclidian distance measure. Visual inspection of the resulting dendrogram indicated a possible five-cluster solution. For cluster and membership validation, an additional K-means analysis was performed. Next, the agreement between the two methods was evaluated using the Chi-square test and Cramer’s V effect size measurement. Results of the analysis indicated a strong correspondence between cluster memberships as assigned by the two methods , mostly males (70%), and had the largest percentage of sexually active (90%) and committed (72.5%) individuals. It also had the highest percentage of infidelity (12.5%) . A small percentage of this group declared themselves bisexual (10%) and homosexual (2.5%), with the majority being heterosexual (87.5%).n = 73, 29.9% of the total sample), and it consisted mostly of females (79.5%). A high percentage of individuals were sexually active (75.3%), most of them being committed to a partner (58.9%). A small percentage of this group declared themselves bisexual (9.5%), with the majority being heterosexual (90.5%).The second cluster, labeled “Competent”, included individuals with high scores in the area of sexual self-esteem, reporting confidence in their physical attractiveness and feeling comfortable with their ability to perform sexually and conduct themselves in sexual situations. Additionally, they had the highest sexual self-efficacy scores, meaning that they are confident in their ability to communicate their sexual desires and refuse unwanted sex. Sexual arousal and interest in sexual exploration were moderate, with intermediate levels between the other groups. Individuals in this cluster reported feeling only somewhat anxious about sex. This was the largest group , with an even gender distribution . It had the second-largest percentage of sexually active individuals (80%) and infidelity (8.88%) , and 64.5% of members were in a committed relationship. A small percentage of this group declared themselves bisexual (8.8%) and homosexual (4.4%), with the majority being heterosexual (86.6%).The fourth cluster, labeled “Unassured”, consisted of individuals with particularly low levels of sexual self-esteem and extremely high sexual anxiety. Their sexual-self configuration indicates substantial dissatisfaction with their physical appearance, sexual performance and the way they conduct themselves in sexual situations. In addition, members of this cluster declared having serious difficulties in expressing their sexual desires, managing unwanted sexual advances or refusing to engage in sexual behaviors. Nevertheless, they exhibited a low-to-moderate level of sexual arousal and some interest in sexual exploration, although to a lesser extent than members of the other clusters. Sexual anxiety had the highest levels in this cluster, indicating that sexual matters pose significant difficulties associated with an incapacity to relax during intercourse, discomfort and feelings of shame and guilt. This group consisted of 39 individuals , mostly female (61.5%), with 64.1% being sexually active and 56.4% being in a committed relationship. A small percentage of this group declared themselves bisexual (10.2%), with the majority being heterosexual (89.7%).The final cluster, labeled “Naive”, included individuals with low levels of sexual self-esteem, indicating some dissatisfaction with their appearance and sexual performance and a lack of confidence in their ability to conduct themselves in sexual situations. Additionally, they reported feeling somewhat able to assert their sexual desires, but they were very confident in their capacity to refuse sexual advances. Members of this group had the lowest reported levels of sexual arousal and declared themselves less interested in experimenting sexually and rather more sexually inhibited. Sexual anxiety levels were high, meaning that sex was associated with tenseness, discomfort and feelings of guilt and shame. This group consisted of 47 individuals , mostly females (68%). Compared to the cluster “Driven”, the majority of individuals were not sexually active (55.3%), and only 38.3% of members were in a committed relationship. A small percentage of this group declared themselves bisexual (14.8%) and homosexual (4.2%), with the majority being heterosexual (80.8%). First, the clusters were compared based on variables relating to app use see . ResultsNext, the clusters were compared based on variables measuring certain aspects of sexuality: OSAs, satisfaction and number of sex partners in the last 12 months see . Regardi2 (12) = 52.398, ρ < 0.0001) was significant. In order to evaluate this effect, χ2 post hoc tests were performed separately for each cluster. Results indicated that subjects with secure attachment were more represented in clusters “Competent” (χ2 (1) = 15.13, ρ < 0.001) and “Adventurous” (χ2 (1) = 6.71, ρ < 0.01) and less represented in clusters “Unassured” (χ2 (1) = 9.86, ρ < 0.01) and “Naïve” (χ2 (1) = 14.59, ρ < 0.002). In contrast, subjects with fearful attachment were less represented in clusters “Competent” (χ2 (1) = 8.49, ρ < 0.01) and “Adventurous” (χ2 (1) = 8.94, ρ < 0.01) and more represented in the cluster “Unassured” (χ2 (1) = 21.07, ρ < 0.000). In regards to attachment orientation, sexually “Competent” and “Adventurous” groups exhibited the lowest mean levels of attachment anxiety and avoidance, while the sexually “Unassured” and “Naïve” groups reported the highest levels. Finally, the groups were compared based on attachment orientation see . The two2 (4) = 29.986, ρ < 0.0001), cluster by relationship status (χ2 (8) = 27.615, ρ < 0.001) and cluster by cyber infidelity (χ2 (4) = 33.74, ρ < 0.001), were statistically significant, while the interaction cluster by seek partner online (χ2 (4) = 7.557, ρ = 0.109) was not significant in the model. In order to evaluate these effects, χ2 post hoc tests were performed separately for each cluster. Results indicated that males were overrepresented in the cluster “Driven” (χ2 (1) = 19.45, ρ < 0.001) and underrepresented in the cluster “Competent” (χ2 (1) = 14.82, ρ < 0.001). Gender was not significantly associated with clusters “Adventurous”, “Unassured” and “Naïve”. Regarding relationship status, subjects in a relationship were less represented in the cluster “Naïve” (χ2 (1) = 9.06, ρ < 0.001), while sexually inactive single subjects were less represented in the cluster “Driven” (χ2 (1) = 8.47, ρ < 0.001) and overrepresented in the cluster “Naïve” (χ2 (1) = 19.36, ρ < 0.001). No other post hoc test reached statistical significance. As for cyber infidelity, subjects were more represented in clusters “Driven” (χ2 (1) = 14.29, ρ < 0.001) and “Adventurous” (χ2 (1) = 11.02, ρ < 0.001). Although the interaction cluster by seeking a partner online failed to reach significance, frequency analysis results showed a preference to seek partners online, especially in cluster “Driven”. In contrast, the cluster “Naïve” had the lowest percentage of subjects that used the online environment to look for a potential partner.The analysis of the demographic data see  showed nThe aim of this study was to examine characteristics of online app use within specific configurations of the sexual self-concept. In order to pursue this objective, we determined if reliable sexual-self subtypes can be identified among individuals. Similar to the findings of Buzwell and Rosenthal , five clThis study contributes to research regarding sexuality and the digital environment by offering an additional framework for understanding what drives people in their app use and related sexual outcomes. Consistent with previous research , we founThese results were evidenced by the cluster comparisons where sexually “Driven” and “Adventurous” individuals reported the highest frequencies of Tinder use and online sexual activities, greater variety of sex partners, more interest in using apps for sexual experiences and higher rates of cyber infidelity. Although similar in regards to their sexual outcomes, the dynamics that drive their behavior in the online romantic scene seem to be quite different. While the sexually “Adventurous” profile denotes strong agreement between the sexual self-components, the sexually “Driven” style does not seem to be fully coherent in its configuration. High sexual desire and need for sexual exploration come in conflict with their relative uneasiness about sex, doubts about their sex appeal and performance and low capacity to refuse sex. This particular combination might link sexuality to efforts in self-esteem regulation or to fear of rejection, as shown by the tendency of these individuals to use apps for social approval and because they feel more comfortable in online interactions. The high levels of attachment anxiety reported in this group supports this hypothesis, as it has been associated previously with more short-term sexual encounters, hypersexuality , high nuIn contrast, individuals not driven by their sexual urges reported significantly lower interest in using apps for sexual encounters, less Tinder use, less variety of sexual partners and engagement in online sexual activities. However, they were more likely than sexually “Driven” and “Adventurous” individuals to use apps because they felt better relatedness to others online rather than offline and for social approval. This result could be linked to lower levels of sexual self-esteem and more sexual anxiety. For these groups, particularly the sexually “Unassured” and “Naïve”, future research could be focused on the impact of the online environment, more specifically social/dating apps and online sexual interactions, on their sexual self-concept.The lowest interest in using Tinder was found among sexually “Competent” individuals, who exhibited moderate sexual preoccupations, solid awareness of their sexual needs and felt in control of their sexuality. They reported being very satisfied with their sex life while having fewer sex partners than sexually “Driven” and “Adventurous” individuals. This suggests more conservative attitudes towards promiscuity and the capacity to sustain more stable romantic relationships. Given their sexual profile and predominantly secure attachment orientation, people with this sexual style did not revolve around sexual urges in their app use and seemed more able to balance their expectations regarding the online romantic and sexual scene. Similarly, sexually “Naïve” individuals were more inclined to use apps for romantic purposes, but, overall, they were not highly motivated in their app use and showed little interest in dating apps, like Tinder. This is hardly surprising, given that Tinder, although initially introduced as a dating app, is often associated with the “hook-up” culture and generally seen as a sex app. In their study of sexual self-profiles, Buzwell and Rosenthal  describeIn conclusion, our findings suggest that people’s perceptions of themselves as sexual beings play an important role in determining why and how they engage the online dating, social and sexual scenes. This approach could offer new directions for future research and a framework for better understanding online social interactions and their sexual outcomes by taking into consideration not only sexual self-components but also the personal meaning that people attribute to their sense of sexual self. Uncovering individual sexual dynamics and understanding how they guide the people in their online romantic and sexual endeavors could have the potential to inform app developers to better tailor their platform concepts for a better fit with the needs of specific populations and help promote more healthy environments. Additionally, in regards to attachment theory, our results suggest that the sexual self-concept could play an important role in determining sexual outcomes related to attachment orientations.A number of limitations in the present study should be noted. First, the cross-sectional approach we used in this study does not allow for conclusions regarding causality or the circular effects that the variables may induce . A longiIn summary, we replicated previous findings concerning sexual self-profiles, and we also analyzed these profiles in relation to motives for app use, in particular Tinder, which emerged as the most utilized dating app in our sample. Next, we investigated differences among these groups based on attachment orientation and sexuality-related measures. To our knowledge, this is the first study attempting to profile app users based on sexual self-characteristics.We found that sexual self-characteristics can be reliably grouped into five different sexual styles, in accordance with Buzwell and Rosenthal’s  proposed


Many birds are endowedwith a visual magnetic sense that may exploitmagnetosensitive radical recombination processes in the protein cryptochrome.In this widely accepted but unproven model, geomagnetic sensitivityis suggested to arise from variations in the recombination rate ofa pair of radicals, whose unpaired electron spins undergo coherentsinglet–triplet interconversion in the geomagnetic field bycoupling to nuclear spins via hyperfine interactions. However, simulationsof this conventional radical pair mechanism (RPM) predicted only tinymagnetosensitivities for realistic conditions because the RPM’sdirectional sensitivity is strongly suppressed by the intrinsic electron–electrondipolar (EED) interactions, casting doubt on its viability as a magneticsensor. We show how this RPM-suppression problem is overcome in athree-radical system in which a third “scavenger” radicalreacts with one member of the primary pair. We use this finding topredict substantial magnetic field effects that exceed those of theRPM in the presence of EED interactions in animal cryptochromes. These organisms include different typesof birds, as well as insects and amphibians.16 This long-standing model mechanismis known to govern various magnetic-field-sensitive kinetic effectsin spin chemistry.24 Conventionally, themodel assumes two geminate molecular radicals, “borntogether” from closed-shell reactants, possibly by photoexcitationor a light-independent reaction cascade.2 This radical pair initially comprises two physically separated,spin-correlated molecules in a shared “singlet”  spin angular momentum state if born from the diamagnetic precursor(without intersystem crossing). Starting out from this pure singletstate, the radical pair can evolve in time under local magnetic interactions,which modulate its singlet/triplet character, and thus its likelihoodof recombination. These dynamics are mediated by the Zeeman effect,in conjunction with the local magnetic field variations resultingfrom the nuclear hyperfine interactions. Thus, hyperfine interactionswith local magnetic nuclei are the main driver of singlet–tripletinterconversion in the RPM. The anisotropy of the hyperfine interactions imprints directionalityon the magnetosensitivity of this process, providing the theoreticalbasis for the RPM-based inclination compass.In the most widely accepted model of the inclination compass,sensingis actuated by the radical–pair mechanism (RPM).15 In this model, the magnetic-field dependent, coherent spindynamics modulate the proportion of radical pairs that recombine withrespect to those that “escape” recombination, wherethose that escape are assumed to generate a structurally distinctsignaling state (perhaps by adopting a different molecular conformation).25 In this way, the RPM forms the basis for a sensorthat is insensitive to field polarity, responsive to a narrow (butadjustable) range of magnetic field intensities, light-dependent , and disrupted by weak radio frequency (rf)electromagnetic fields.26 These properties are thought to distinguish it from the magneticparticle-mediated sense.27 Specifically,the prediction of rf-interference has been borne out in many experiments,for example, on birds,30 crustaceans,31 fruit flies,32 andplants.33According to theconventional RPM model of magnetoreception, chemicalsensitivities to the amplitude and direction of an ambient magneticfield arise in the photoreceptor protein cryptochrome Cry, 1.15 In t15 because it had been foundin mammalian eyes and was known to undergo the right kind of light-dependentradical reaction (as a protein in the cryptochrome/photolyase family34). Cryptochromes have since been found in birds’and other species’ eyes.36 Interestingly, forsome cryptochromes, there is strong evidence to implicate their rolein the regulation of avian seasonal migration,38 a function beyond their activity as the circadian governor.36 Furthermore, evidence has accumulated to showthat cryptochrome plays a critical role in magnetosensation in fruitflies, where gene knockout experiments have demonstrated that cryptochrome-deficientflies lose their magnetic sense.22 Yet,it remains unclear whether cryptochrome is the primary magnetoreceptor,or a downstream signal transducer.Cryptochrome was suggested as a candidate magnetic receptor byRitz et al.,A, WB, WC, WD)44 as depicted in •–/W•+], born out of the photoreduction of the fully oxidized (quinone)FAD by the surface-exposed tryptophan WC via the Trp chain relatedto this photoreduction pathway in isolated cryptochromes43 and photolyases,46 and even μT-scale MFEshave been reported in cryptochrome.47 Theisolated cryptochrome 4 of the Europen Robin has recently been foundto be more magnetosensitive to mT-magnetic fields in vitro than comparablecryptochromes of nonmigratory bird species.44 On the other hand, some studies have called the [FAD•–/W•+] scheme into question as a compass mechanismin vivo,22 hinting at an alternative explanationof axial magnetosensitivity in vivo, in terms of an ultimately light-drivenprocess that incorporates a light-independent magnetosensitive step.In vitro, the cryptochrome-cofactorflavin adenine dinucleotide(FAD), is photoreduced in a reaction involving spin-conserving sequentialelectron transfer (ET) processes along a structurally conserved triad(in plants) or tetrad  of tryptophan residues .50 However, although O2•– may be optimal in this respect, an unboundsuperoxide radical would suffer rapid decoherence while tumbling insolution, and therefore might not be practical.51 To avoid this issue, it became customary to assume a hypotheticalradical denoted Z•– that is devoid of hyperfineinteractions,10 yet bestowed with the qualityof slow spin relaxation.An alternative reaction scheme involves reoxidationof the fullyphotoreduced (hydroquinone) FADHH•/O2•–] 1b.14,49 53 to considerable . Note further that while the EED-couplingis anisotropic, it alone does not induce a directional MFE in a radicalpair.56In both these RPM models of magnetoreception1, the di55 although electronicexchange was found to be negligible in studies of related compounds.58 For example, if we assume that the magneticsensitivity arises principally from a radical pair containing thethird tryptophan (WC) of the Trp chain ,43 thenthe magnitude of the EED coupling is |D| = 14 MHz.This coupling is at least comparable to the hyperfine couplings inFAD•– and W•+ and exceedsthe Zeeman interaction with the geomagnetic field (about 50 μTor 1.4 MHz). Thus, we can anticipate a non-negligible influence ofEED coupling on the spin dynamics, which, as laid out above, is knownto diminish the nuclear hyperfine-mediated RPM.55EED interactions are unavoidably significantfor radical pairsbound to cryptochrome,61 One study to address the EED problem predicted that deleteriouseffects of the dipolar coupling D and exchange coupling J might be mitigated by meeting certain equal-but-oppositeenergy-matching conditions, which would cause D and J to partially eliminate each other. This mutual “J/D cancellation” effect would allowthe essential zero-field degeneracies to be partially restored.62 However, a subsequent analysis predicted that J/D cancellation is unlikely to enableRPM-mediated MFEs in cryptochrome or other flavin-based radical-pairsystems.55 In that study, the RPM’smagnetic sensitivity was shown to be suppressed by inter-radical interactionsat the matching conditions and, for that matter, any other plausiblevalues of the J coupling. This raises questions aboutwhether it is feasible for the RPM to rationalize crytochrome-mediatedmagnetoreception, and invites the possibility that the RPM modelsshown in This problem has been largely ignored in theoretical worksthatfocused on the preferable, if unrealistic, scenario of negligibleinter-radical interactions.56 Rather, the necessary field-dependent singlet–tripletinterconversion may be enabled by a radical pair coupling to a thirdradical via the seemingly intrusive EED interaction itself, as shownin 56 To this effect, we recently performed a theoreticalanalysis examining the influence of a third radical on the cryptochromemagnetoreceptor in the presence of all relevant EED interactions (inaddition to hyperfine interactions).55 Thatgeneralized “Radical Trio Mechanism” (R3M) did indeedpredict modest-but-significant MFEs in a cryptochrome magnetoreceptorin the presence of a third, catalytic “bystander” radicalB•. However, although the presence of a bystanderwas found to boost the MFE anisotropy of a [FAD•–/WD•+] sensor by as much as factor of 20, via the EED coupling, the MFEdid not exceed 3% for recombination parameters obtained on experimentalevidence where the bystander radical was assumed unreactive.55Speaking broadly, hyperfine coupling is not necessary to mediatethe magnetic sensitivity of a radical recombination in a weak field.•.64 Crucially, this scavengingmechanism lifts the requirement that the primary-pair radicals beclose enough together to enable sufficiently fast recombination. Theproblem has been debated in the context of D), which is toodistant from the flavin to recombine on the required time scale.63 On the other hand, a scavenger was predictedto effectively “immunize” spin dynamics against thedestructive effects of fast relaxation in one of the radicals, lendingcredibility to models implicating O2•–.64 However, both of those studies investigated only toy-model versionsof the RPM in the presence of a scavenger radical, without including inter-radical interactions such as the invasive EED coupling.64The introduction ofa third nearby radical presents another previouslyunexplored possibility that remains as a means to tackle the EED problem:One member of the primary pair could react with the third radicalto form a stable closed-shell product, rather than recombining withits twin to recover the ground-state protein configuration (or a newsinglet-state reaction product). Indeed, past studies predicted astrong enhancement of the anisotropic MFEs by introducing the “scavenging”of one member of the geminate pair as it reacted with a “scavenger”radical SHere, we assesses the prospect of the scavenging reactions •–/C•+],complimented by a radical scavenger S• that reactswith one of the two primary-pair radicals to yield a distinct diamagneticproduct . The EED coupling was modeledbased on the point-dipole model, whereby all pairwise interactionsof the three radicals were considered explicitly. Reaction channelsconsist of the forward reaction (rate kf) and scavenging (rate kX). The term“chemical Zeno Effect” describes the reaction dynamicsenabled by this scheme.65 Specifically,the scavenging reaction converts triplets to singlet states of theoriginal pair, even in the absence of coherent interaction terms,and thus resembles the quantum (anti-)Zeno effect.66 The directionality of the MFEs, here, results from thecombined action of the anisotropic hyperfine and EED coupling, mediatedby the incoherent recombination dynamics.We formulate the model inthe context of a generic anion–cationradical pair  primary radical pair, the geminate pair isassumed to be “born”as a singlet ρ̂(0) ∝ P̂S12. Whereas in thecase of the [FADH•/Z•–]primary pair, it is born as a triplet ρ̂(0) ∝ P̂T12 (where 63In the case of the [FADf = kf ∫0∞ Tr[ρ̂(t)] dt, and the scavenging yield ΦX = kX ∫0∞ Tr[P̂Sa3 ρ̂(t)] dt, for a ∈{1,2}. Assuming a magnetic flux density of 50 μT to representthe geomagnetic field, we simulated the reaction yield for 2562 distinctfield orientations , to estimate the maximum Γ(over orientations) of the relative MFE anisotropy in each scenarioThe formulation of this modeling frameworkenabled us to predictthe forward reaction yield ΦColumba livia  and Drosophila melanogaster .67 For each protein, we considered the twoprimary radical pairs [FAD•–/W•+] and [FADH•/Z•–]. Foreach pair, we simulated one of two possible geometric arrangements,one with the primary-pair radicals spaced relatively close together, and another with them spaced far apart . The more distant spacings were chosento satisfy the need to minimize detrimental EED interactions a priori,thus realizing conditions favorable for the spin dynamics of the RPM.Respectively, W318 and W369 correspond to WC and WD of ClCry4. Likewise, W342 and W394 correspond to WC and WD of DmCry. The Znear•– and Zfar•– positions implya radical that is either tucked within 5 Å of the FAD cofactor,or placed at a distance about 18 Å away from the FAD . These two Z•– locations were introducedin prior work.55To show how the chemical Zeno effect may generate magnetosensitivespin dynamics in cryptochrome in the presence of EED coupling, wemodeled systems of three radicals, based on structural models of cryptochromedetermined for animal species SI, along with the hyperfine parametersused and other pertinent details. For the Z•–-containing systems, we consider the neutral flavin semiquinone FADH• in the assumption that this radical pair is producedfrom the fully reduced FADH– by oxidation; for theW•+-containing radical pairs implicated with thephotoreduction we assume the anion radical, FAD•–, that is, the direct product of the electron transfer to the FADresting state, the protonation of which proceeds on a time scale slowcompared to the magnetic field-dependent spin dynamics.41 As DmCry does not undergo completephotoreduction , we will additionallyconsider the alternative [FAD•–/Z•–] radical pair.68 We note that membersof the cryptochrome family in general exhibit homology in their three-dimensionalfold and conservation of critical amino acids. While the crystal structureof the European Robin cryptochrome 4 (ErCry4), recentlyhighlighted as a magnetoreceptor in ref . Thus, for the rate constantsassumed here /W•+ stands for the singlet-born[FAD•–/W•+] scenario whereinthe FAD•– is scavenged by radical S•, whereas FADH•/(Z•–/S•) designates the triplet-born [FADH•/Z•–] with Z•– susceptibleto scavenging. See Table S1 for a comprehensivelist of the systems studied.We studiednumerous three-radical scenarios, using the four radicalpairs described above as starting points. We represent these simulationscenarios by designating the three radicals and using parenthesesto indicate the reactive pair. For example, (S•/FAD•–)/WD•+ reactionin DmCry . Applied to the other systems under investigation, the fit tothis preliminary optimization generated tremendous predictions ofΓ exceeding 100% for distantly removed scavenger radicals, whileimplicating inordinately large scavenging rates (relative to the distancesfrom cryptochrome involved) in all of the systems under consideration.For example, the (S•/FAD•–)/WC•+ model of ClCry4 yielded a relative anisotropy of158% for a distance of 100 Å from FAD•– to S• and a scavenging rate kX = 3 × 107 s–1. ForFADH•/(Zfar•–/S•), we obtainedΓ = 147% for a scavenger at a distance of 45 Å from Zfar•– and a rate kX = 3 × 107 s–1. These naïve predictions are summarizedin Table S2, and presented in detail in Figures S3–S6. What they share in commonis that they require rate constants that exceed even the most optimisticpredictions of charge-transfer rates afforded by nonadiabatic ET theory.69 These outlandish estimates revealed a need tobound our procedure to exclude inordinate ET rates and unrealisticallylarge MFEs.Initially aiming toestimate the largest anisotropic MFEs thatmight be enabled by a scavenger radical introduced to combine withone member of a radical pair, we performed an unconstrained MFE optimizationby independently varying the scavenger location and the scavengingrate for the  dynamicsof electron tunneling through the biological medium. We consideredthe fastest possible ET rates to allow for the maximum possible reactantdistances, because the spin-chemistry of the RPM model is governedby competition between the need to reduce EED coupling while sustaininga large enough charge-combination rate to produce a significant reaction-yieldMFE.55To achieve this, we, subsequently, incorporatedconsiderationsof long-range ET into our scavenger-based cryptochrome compass model.For long-range biological ET,72R is again the distancefrom the scavenger (S•) to its redox target, σ= 3.6 Å is the minimal distance of the redox partners , and β is the decay parameterassociated with the square of the ET coupling matrix element. Thetunneling parameter β is expected to vary from 0.9 to 4.0 Å–1, depending on intervening matter,73 and κ = 1013 s–1 reflects a typicalrate for reactants in van der Waals contact.74To this effect, we boundedcharge combination rates from aboveby assuming scavenging by activationless ET according to the “Moser–Dutton”(MD) rate equation:kf–1 = 3 μs,consistent with estimates of the primary pair’s lifetime.75 To choose β, we examinedfour cases: ET between one primary radical and the scavenger via acovalent bridge (β = 0.9 Å–1), a typicalprotein (β = 1.4 Å–1), a weakly coupledmedium (β = 2.8 Å–1), or an extremelyweakly coupled (vacuum-like) system (β = 4.0 Å–1).76 This rangeof β-values is comparable to that used in a previous study onEED effects on radical pair recombination.54 The strong coupling limit (β = 0.9 Å–1) provides a fixed upper bound on the activationless ET rate and,thus, provides an appropriate maximum-coupling limit from which tomodel biochemical MFEs under increasingly rate-limited circumstances.For the sake of simplicity, we have presented all rate limiting effectsin the form of the single parameter model –1, typicallyquoted for covalent bridges, reflects a best-case scenario insofaras it allows placing the radicals maximally apart. While optimisticin view of the protein environment relevant here, low beta-valuesare not uncommon in biological context: β = 1.1 Å–1 has been reported for the distance dependence of driving-force-optimizedET rate constants of Ru-modified proteins and the pathway model suggestβ = 1.0 Å–1 for coupling along β-strands.77 Further note that protein ET rate data alwaysshow substantial scatter reflecting the important features of theprotein medium in terms of bond and hydrogen bond structure, and oftenrealizing significantly stronger coupling than reflected by the averageβ.69 In fact, long-distance interproteinelectron transfer reactions  proceeding through aqueous solution with extraordinaryβ = 0.15 Å–1 over distances of up to10 nm have been described.78 Incoherenthopping through real redox intermediates at moderate driving forceand dynamically limited adiabatic ET are also associated with slowdistance–decay.77For all our simulations, we assumed the primary pair to “escape”to the signaling state on the time scale 79 and might offer a betterdescription for radical scavenging reactions associated with the formationof covalent bonds ,which are expected to proceed at contact.Likewise,we wish to emphasize that the rates chosen to reflectthe most severely rate-limited ET may effectively (or even preferably)be viewed as those of protein-coupled ET across a non-zero-free-energybarrier. In this way, our one-parameter ET decay model enables samplingof significant regions of the reaction configuration space by accountingfor distance-dependent coupling, needed to inform inferences intothe nature of scavenging reactions for biochemical magnetic sensing.While more complete models can and should be employed in subsequentstudies, the large number of parameters in such models would makea systematic exploration of multiple reaction parameters in the currentstudy more computationally costly, without actually affecting therange of possible scavenging rates under consideration here (see below).Finally note that large β-rates can also result from multipathwaysscenarios because of the destructive interference intrinsic in competingcoupling routeskX  to reasonable values, we introduced 76 This limit reflects the largest plausible rate of nonadiabatic ETthrough an organic bridge, thus providing an effective bound on thedistance from the scavenger from its target in the rich biological milieu. This is distinct from the MFE itself, which alsodepends on the scavenger position as a consequence of including boththe distance and orientation dependence of the EEDcoupling (assuming point dipoles).We performedMFE simulations, systematically sampling scavengerS positions around each primary radical pair . To constrain the scavenging ET rate –1, including onetypical of coupling in a well-optimized biological environment β= 1.4 Å–1, and two weaker couplings β= 2.8, 4.0 Å–1 .This allowed us to explore realistic ET rates spanning a wide rangeof rates. Therefore, we evaluated a maximum relative MFE anisotropyΓ as a function Γβ(R) of R for each scavenged primary pair for eachdecay parameter β. This afforded us a total of 48 distinct scenariosby considering each of two model Cry structures (DmCry and ClCry4), two primary radical-pair types([FAD•–/W•+] or [FADH•/Z•–]), two distinct scavengertargets (either FAD or its primary partner), and four values of thedecay constant β—where there is no difference betweenresults obtained from using different Cry structures for the alternative[FADH•/Z•–] primary radicalpair. These 48 mechanisms are designated in the 48 distinct Γmax entries listed for the constrained ET in To account for less-than-idealET, we also considered larger decayconstants β > 0.9 Åoptimal and robust scavenger configurations: These are “optimal” insofaras they predict the largest maxima (given constraints), and “robust”in that they predict consistently large maxima acrossthe values of β considered. For both ClCry4and DmCry structures, the FAD•–/(WD•+/S•) models predict large maximum MFE anisotropiesΓmax = maxR Γβ(R) > 20% for all ofthe decay parameters explored. Likewise, the FAD•–/(WC•+/S•) models consistently predicted MFE anisotropiesΓmax ≥ 15%. The bird cryptochrome did notpredict larger MFEs than those of the fly in the cases studied. TheFADH•/(Znear•–/S•) modelspredicted large and robust MFEs, with global maxima near 30% (or even40%) for all β considered. These provide contrast to the predictionsof the FADH•/(Zfar•–/S•) model,for which the MFE maxima were not particularly large nor robust withrespect to variations in β, increasing from the modest Γmax ≈ 5% (for β = 4.0 Å–1) to large values Γmax > 35% for activationlessprotein-mediated ET between Z•– to a distantS•. The optimal distance is determined by the valueof β and is only weakly dependent on the identity of the primaryradical pair. For the systems studied in –1, we obtained the meanoptimum distances Rmax ∈ {5.5,6.3, 10.2, 16} Å, respectively, such that kX ∈ {5.0, 5.2, 1.1, 0.1} ns–1. Thisindicates that a shorter distance between the scavenger and its target(due to faster decay of the coupling matrix element) may be compensatedby a faster reaction with the scavenger radical. Regardless of theET model employed, scavenging mechanism could enable large Γβ(R) for some plausible choice of . This is unlike the RPM, for which EED coupling is notcounteracted by increasing the charge transfer rate.R from the radical being scavenged for ClCry4 for each coefficient β ∈ {0.9, 1.4, 2.8, 4.0} Å–1 . For covalently bridged ET (β = 0.9 Å–1), the peaks in these curves correspond to fairlybroad maxima  predicted tightly localized MFE maxima that couldindicate preferential scavenger positions .•/FADH•)/Znear•– model predicted Γmax ≈ 70% using a scavengerradical placed about 5 Å away from Znear• for each of the vacuum-like decayparameters .Those results indicated a substantial prospect for directional MFEsgenerated by an FADH•-scavenged reaction in thepresence of a Z•–bystander , regardless of the positionof Z•– in space or the scavenger’sreactivity with FADH•. Furthermore, both the DmCry and ClCry4 models gave similar results,with the fly (DmCry) cryptochrome performing marginallybetter than the that of the pigeon (despite a larger primary–pairseparation) in this setting.The  with an activation barrierof 4.8 kBT  when assuming an activation barrier of 6.2 kBT. This presents the possibilitythat ET may be optimized with respect to the ET parameters describingthe solvent–protein structure. Importantly, large MFEs suchas the 35% MFE shown in –1) could be achieved for an activated ET processeswith actual decay parameter of β = 1.4 Å–1 typical of protein.Overall, we found that all of thescavenger models based on BT viz., 4a. Likewβ(R) by calculating the maximum MFE over all locations ona sphere of radius R. β(R) on the distance R from thescavenger S• to its target, for reaction modelsinitialized with the conventional [FAD•–/W•+] pair. •/Z•–] pair. As expected, these diagrams reflect the trends discussedabove. For small β in particular, the profiles are wider withmaxima occurring at large distances; whereas for large β theyare peaked at small distances. We further used these profiles to systematicallysearch for optimal scavenger locations by recursively increasing thenumber of sampling points at a given R.To explore the scavenger’s dependenceon β for eachreaction type, we have considered Γmax ≥ 20% for a scavengerlocated near Trp (or Tyr) residues in the cryptochrome structuresare particularly significant here. In DmCry, we foundthat a WD•+ scavenger, positioned in the vicinity of the residue Met506, providedMFEs of about 20%, which were robust with respect to variations inthe tunneling decay parameter between 1.4 Å–1 ≤ β ≤ 4.0 Å–1. Likewise,a Znear•– scavenger, located near Trp420  produced significantMFEs of about 10% over the same tunneling decay range, consistentwith the position of a scavenger implicated near WA in ClCry4. Simulations of protein-mediated ET (β = 1.4Å–1) predicted WD-scavenged Γmax > 20% (or WC-scavenged Γmax > 10%) for scavengers in close-contact with a Tyr residue neartheend of the Trp-tetrad in ClCry4.Predictionsof Γ•/FADH•)/Znear•– model corresponded to Γmax > 70% for a scavengerradical placed about 5 Å away from both Znear• and FADH• for β = 4.0 Å–1, or Γmax > 65% for a pair of maxima within 6 Å of Znear•– and FADH• for β = 2.8 Å–1 (butin opposite directions). The FADH•/(Znear•–/S•) model predicted Γmax >37%for a scavenger nestled near the FAD flavin and Asp387 of ClCry4. The (S•/FADH•)/Zfar•– model predicted Γmax ≈ 30% for scavengerradicals nestled near to the FAD flavin, in close contact with Ile390for both β = 2.8 and β = 4.0 Å–1. Finally, the FADH•/(Zfar•–/S•)model predicted Γmax ≈ 35% for scavengerswith β = 1.4 Å–1, placed either in contactwith the FAD phosphate or near the protein surface about 5 Åaway from both His352 and His354.The predictionsof the ,68 we have furthermoretested the alternative modelof a scavenger FAD•–/Z•– radical pair born with random spin configuration .Such a pair could conceivably result in DmCry afterthe initial photoreduction by encounter with a O2•–. As shown in Figure S9, the magnetosensnitivity of this modeleven exceeds that of the scavenger FADH•/Z•, demonstrating general applicability of the model even for initialstates that are not spin-correlated.As the triplet-born FADHDmCry was coloredby the maximal relative MFE elicited at the location of its heavyatoms. DmCry was used here as a template as its crystalstructure is complete in the surroundings of FAD. In any case, notethat for many scenarios the maximal relative anisotropy is realizedoutside of the protein envelope. Note, furthermore, that if βis increased in these plots, the optimal sites move closer to thereaction partner’s location, as expected, while the optimaldirections are roughly preserved  and the standard RPM under equivalentconditions, we estimated equivalent recombination-based MFEs usingthe same ET decay coefficients (β), relative radical locations,hyperfine, and dipolar interactions. To do so, we considered an inert“bystander” radical B•–/W•+ pairs afforded MFEs of at most 1% (for FAD•–/ WC•+) or 2% (for FAD•–/WD•+), and only in the activationless limit of recombination by assumingET directly across a covalent bridge linking FAD to TrpH in the presenceof a bystander radical B•. That assumption could be tolerable for the FAD•–/WC•+ pair with radical lifetime between 3 and 10 μs,75 which are comparable to that of long-range ET over the same distancewith a well-optimized tunneling coefficient . However, the lifetime ofthe more distantly separated FAD•–/WD•+ pair wouldcorrespond to a value of β ≈ 1.4 Å–1, typical of protein-mediated ET . Hence, the direct recombination of WD•+ with FAD can scarcelyprovide a viable mechanism in Cry, either for the R3M (with a bystandernearby), or for the RPM model alone where MFEs < 0.1% because of the suppressive EED interaction. Asits lifetime is 3 orders of magnitude longer than that of the WC•+-basedcounterpart, it would furthermore be strongly attenuated by spin relaxation,an effect which has not been taken into account here.To wit,the R3M models based on recombination between FAD•–/Zfar•– magnetoreception predicted MFEs no larger 4%, and then again onlyin the scenario with primary pair recombination governed by covalentlybridge ET (β = 0.9 Å–1) and with a catalyticbystander nearby. The RPM alone, again predicted MFEs of no more thanabout 0.1% even assuming fast ET, again because of the suppressingeffect of the EED interaction. On the other hand, models of recombinationin the FADH•–/Znear•– primary pair predictedsizable MFEs approaching 8% with a bystander radical nearby . Thisreserves the possibility for the R3M-based [FADH•–/Znear•–] sensory system, where the B• sits next to theflavin cofactor (see SI)—contingenton the existence of a slow-relaxing Z•–.Similarly,the R3M-based models of FADH51 A proof-of-principle of a RPM-based compass was engineered and synthesizedusing a covalently bridged radical-pair system in a laboratory,80 but the compelling demonstration of a biologicalradical-pair reaction, sensitive to the direction of an Earth-strength(50 μT) field, remains to be shown beyond circumstantial evidence.The demonstration of a practical cryptochrome geocompass would providestrong support for the magnetoreceptor hypothesis, but its absenceraises the question: Does the RPM provide an appropriate model ofcryptochrome-mediated magnetoreception?The absence of a robust candidate model has left a gap betweenconflicting claims in the chemical magnetoreception literature.not recombine. Therefore, radical pair recombination is not a prerequisitefor chemical magnetoreception, although it is equally not excluded.63 Whereasthe extension of the RPM by a third bystander radical can mitigate the reduction in magnetic sensitivity because of thepresence of unavoidable EED coupling,55 the scavenging mechanisms circumvents certain otherwise-insurmountableproblems. In particular, we have shown that the scavenger-based mechanismpredicts large directional magnetosensitivity in the presence of EEDcoupling , even when the ETcoupling to the scavenger radical is weak or limited by an activationfree energy barrier.The radical-scavengingmechanism proposed in this work as a modelchemical compass stands apart from the traditional RPM-based schemes,by allowing one member of the radical pair to be either taken up bya dedicated scavenger  or to escape tothe signaling state. To illustrate the distinction between this scavenger-basedmodel and recombination-based ones (such as the RPM or R3M), here,we have assumed that the primary radical pair does 55 but it does not solve it. Rather, bystander-enhanced schemes remaintied to the essential recombination-based design of the RPM whichemploys the difference between separation and recombination reactionyields. Furthermore, although the introduction of a catalytic bystanderradical might induce a larger MFE than the RPM alone, it does notrationalize the effects of weak magnetic fields on the biologicalproduction of reactive oxygen species.86 The accumulation of nuclear spin polarization realized via three-spinmixing, has also been suggested to deliver large MFEs in the presenceof EED coupling.87 However, the necessityto retain nonequilibrium nuclear spin populations between subsequentphotoexcitations questions the relevance of this proposal in vivo.87 A scavenger mechanism overcomes these issues,so a larger magnetosensitivity prevails as the primary-pair EED interactionmay be compensated by that of a suitably placed scavenger radical.Scavenging also accommodates larger radical–radical distances(separating the primary pair) by obviating the need for significantrecombination. From the RPM the mechanism inherits a comparable sensitivityto RF electromagnetic fields, as we demonstrated for a chosen systemin the SI . These advantages may be offset by the extra reaction complexityintroduced by radical scavenging, but the additional flexibility ofthis scenario nonetheless may generate sufficiently large MFEs tofoster magnetoreception in vivo .The requirement of an anisotropic MFE sensitiveto fractional variationsin an Earth-strength (50 μT) magnetic field suggests the needfor substantial chemical amplification of the ambient magnetic field.A radical bystander-based enhancement of the RPM might mitigate theproblem of marginal anisotropic sensitivity,Although the additional complexity of ascavenger-mediated theoryof magnetoreception could be considered detrimental, it is conceivablethat natural selection may have provided the necessary structuraland physiological optimizations to allow such a complex-but-efficientmechanism to emerge from existing design principles found in, forexample, less-sensitive, RPM-based reactions evidenced in studiesof the magnetosensitivity of cryptochromes in vitro. Our model predictsmuch larger MFEs than those of the RPM for immobilized radicals likecryptochrome’s. Significant scavenger-mediated MFEs of Γ≫ 5% may arise naturally in cryptochrome in the geomagneticfield—while accounting for EED interactions even with the scavenger.Such a radical could be produced by reactions of reactive oxygen species(ROS) which are a well-known byproduct of cryptochrome reoxidation,or produced directly via photoreduction. Given that radical productionhas been linked to cryptochrome’s reactivity, it is plausiblethat evolutionary pressures have harnessed these secondary radicalprocesses, exploiting scavenger-based MFEs for sensing and ultimatelyeven navigation.D•+-scavenged model of ClCry4, for which the Trp-tetradwas proposed to be extendedby an additional tyrosine (Tyr) residue implicated during photoreduction.57 In a recent experiment, it was found that site-directedmutagenesis of Tyr319 (YE) to Asp319 resulted in a significantdecrease in the of FAD-photoreduction quantum yield, attributed tothe elimination of FAD-Tyr radical-pair formation, suggesting itsrelevance as extended electron transfer pathway. Conspicuously, we,here, identify an adjacent Tyr site  and their efficientreduction by external reductants on the time scale of milliseconds.88 Alternatively, the direct scavenging of theFAD-radical from these remote tyrosine sites could sustain sizableMFEs in the [FADH•/Z•–]models, as previously suggested, provided that the electronic couplingwas very efficient, that is, β small.64 In view of the reductive cellular environment, this would requireshielding of the tyrosine radicals from premature reduction, possiblythrough conformational changes or protein–protein interactionsand association with appropriate signaling partners.Here, we have predicted large maximum MFEsin a W•–/W•+] and [FADH•/Z•–] modelmechanisms could designate distinct steps in the same overall process.The oxidation products generated in the light-driven reduction processcould then be used to generate stable radical scavengers poised tointeract with a radical pair generated in the reoxidation processof FADH– by molecular oxygen (forming FADH• and superoxide). However, given that many chemical details are asyet unknown—not to mention the question of the structure ofthe protein when interacting with binding partners in vivo—thecrucial issue at hand is not the actual site, but the principles neededto realize such exquisite sensitivities to weak magnetic fields inthe presence of EED interactions. To this end, we emphasize that theradical pairs and scavenger molecules considered here are meant toinform and suggest future lines of inquiry while proposing likelycandidate models for more detailed investigations, and these resultsshould not yet be considered conclusive.Althoughwe shall not speculate further as to the radical scavengerand site identities, the prospect of a scavenger located somewherenear the terminus of the Trp-tetrad is particularly promising, asit could be generated in well-controlled manner, that is, the photoreductionprocess, and could furthermore return the spare electron via a long-distanceET-process, again possibly involving the Trp-tetrad. It is temptingto speculate that [FAD•–-decoherence in the primary pair,63 thus providing a plausible basis for discussingthe role of superoxide in the avian chemical compass despite its fastspin relaxation. Recognition that the rapid decoherence of a nearbyZnear•– can sometimes enhance MFEs lends credence to the notion that a fast-relaxingradical (such as O2•–) may be integrated in the reaction schemeconsistently via a scavenging-mediated MFE.64 While large effects appear feasible, this also implicates the needfor a novel three-radical reoxidation process, as a topic for futurework.The tremendous MFEs> 70% predicted for the FAD-scavenged systemsupport an idea that superoxide  could play a role in a chemical magnetoreceptivesystem. This highlights the question of the identity of the scavengeritself. We note that the scavenging reaction is known to be robustagainst Z– and the scavenger radical) over time,poising it for discharge when triggered later. Such a scheme couldaddress problems that are inherent to a stochastic quantum read-out,needed to infer the compass orientation, by allowing the swift accumulationof a large number of reaction events depending only on the MFE size.In contrast, the absence of electronic preloading could preclude useof a conventional RPM-based sensor during the night or other low-lightingconditions, discussed elsewhere.89 We overcomethe faint-signal problem by introducing much larger-scale MFEs toallow for an accurate, low-latency sensor—poised for rapidchemical magnetoreception. In any case, it is critical that the outcomeof the magnetosensitive chemical step should trigger the moleculefor signaling. Therefore, establishing details of the sensor’sresting and activated states could be helpful to infer the characteristicsof any subsequent chemical steps or structural rearrangements thatare involved in sensing.In vivo, the indiscriminate production of free radicalsas “signalling”(escape) products could influence homeostasis both via signaling moleculesand through oxidative stress, indicating that radicals produced bya chemical compass mechanism need to be controlled, preferably travelingalong designated ET pathways to be taken up by dedicated redox partners.Likewise, the magneto-sensor could be charged  scavenger radicals, which would abolish the MFEs.92 Thus, a certain degree of compartmentalization, association ,or reduction of translational mobility will be required. These experimentswould need to be accompanied by theoretical predictions of the generalform realized here, being specifically adapted to the exact radicalspecies under experimental consideration in cryptochrome or otherbiological macromolecules of interest for the practical applicationof chemical magnetoreception.We suggest that tractable experiments could be built around thecyclic photoreduction and dark reoxidation of a cryptochrome in vitro.Weak magnetic fields could be applied selectively during the photoreductionor the dark reoxidation. The fluorescence during the photoreductioncycle could be used to readout the oxidation yield,J/D cancellation schemes—castsdoubt on its significance as the chemical basis for precise magneticnavigation in vivo.Analysis of EED couplingin physically realistic RPM models revealeda “Catch-22” scenario: MFEs are suppressed by the intrusionof EED interactions if the primary radical pair is close enough togetherto allow adequate recombination, but become negligible if the primarypair is separated far enough apart to sufficiently reduce EED coupling(via the inverse-cube separation law of the EED interaction energy)due to the reduced recombination likelihood. An RPM mechanism mightstill provide a plausible scheme for low-field MFEs in the biologicalcontext . However,its lack of resilience to EED interactions—facing the inefficiencyof 55). These mechanisms seem unlikely to produce MFEs of more than afew percent, even under the best imaginable biochemical conditions,when physically realistic models that include EED interactions areconsidered. Although we have focused on the protein cryptochrome inour study, prototype radical reactions of the form considered hereinmay be encountered throughout a wide range of biological processes,which typically incorporate numerous hyperfine interactions, dipolarcouplings between electrons, and potentially fast spin relaxation.Reactive oxygen species, frequently implicated in reactions of thiskind, are particularly prone to rapid spin relaxation. Consequently,these characteristics cannot be summarily neglected, and must be considered(if not explicitly included) in studies of spin-biochemical reactions.Here, we have revisited predictions of anisotropicbiochemicalMFEs in the Earth’s magentic field, based on the RPM and itsvariants . In particular, we suggest a novel role for radical scavenger-enabledmagnetic sensing, and suggest a possible scavenger site near the CryC-terminal tail. We recommend the inclusion of all relevant physics,with explicit treatments of EED interactions and ET beyond the primarypair to investigate the possible involvement of a third radical. Futurework may be aimed at developing experimentally testable predictionsof conformational protein signaling states and identifying ET pathwaysmost critical to cryptochrome signaling. Thus, scavenger-mediatedmodels of cryptochrome-based magnetoreceptors are currently the onlyones that are able to predict the substantial MFEs anticipated toenable the precision of the avian inclination compass. Models neglectingEED interactions may not be considered predictive of radical MFE-basedsensors in vivo.