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College students' supportive relationships with mentors-professors, advisors, and other caring adults to whom students turn as they develop their interests and career paths-are critical to their development and academic success. The current study sought to explore factors that promote or impede the formation of positive mentor-student relationships during college using a large, nationally representative sample of 5,684 college graduates from the Gallup-Purdue Index. Linear regression models revealed that first-generation college students, as well as students attending larger institutions, rated faculty and other college staff as less caring and supportive, and were less able to identify a supportive mentoring relationship during college. Greater engagement at college, including participation in faculty research, academic internships, long-term projects, and extracurricular clubs or activities, was associated with stronger perceptions of faculty support and mentorship while in college. Interestingly, demographic characteristics moderated the effects of some extracurricular activities on students' experiences. For example, participants with more student loans showed a stronger positive association between participation in long-term academic projects and perceptions of faculty support, relative to students with few loans. These findings have important implications for policies designed to foster sustained and meaningful faculty-student relationships for all students, including those traditionally marginalized on college campuses.

ObjectivesWell-being is a holistic, positively framed conception of health, integrating physical, emotional, social, financial, community and spiritual aspects of life. High well-being is an intrinsically worthy goal for individuals, communities and nations. Multiple measures of well-being exist, yet we lack information to identify benchmarks, geographical disparities and targets for intervention to improve population life evaluation in the USA.DesignUsing data from the Gallup National Health and Well-Being Index, we conducted retrospective analyses of a series of cross-sectional samples.Setting/participantsWe summarised select well-being outcomes nationally for each year, and by county (n=599) over two time periods, 2008–2012 and 2013–2017.Main outcome measuresWe report percentages of people thriving, struggling and suffering using the Cantril Self-Anchoring Scale, percentages reporting high or low current life satisfaction, percentages reporting high or low future life optimism, and changes in these percentages over time.ResultsNationally, the percentage of people that report thriving increased from 48.9% in 2008 to 56.3% in 2017 (pConclusionsThe percentage of the US population thriving increased from 2008 to 2017 while the percentage suffering remained unchanged. Marked geographical variation exists indicating priority areas for intervention.

INTRODUCTION Since 2001, device-assisted enteroscopy (DAE) has revolutionized the diagnostic and therapeutic capabilities for managing small bowel pathology. Though commonly performed, there have been no recent large studies to assess the use, yield, and risks of DAE and none that include all 3 DAE modalities. We hypothesized that DAE is safe with high diagnostic and therapeutic yields achieved within reasonable procedure duration and here we present a large retrospective multicenter US study evaluating the use, yield, and complications of DAE. METHODS After obtaining institutional review board approval, electronic records were used to identify all DAE's performed for luminal small bowel evaluation in adult patients at 4 US referral centers (Duke University Medical Center, New York University Langone Medical Center, Louisiana State University Health Sciences Center, and University of Massachusetts Medical Center) from January 1, 2014 to January 1, 2019. Electronic medical records were reviewed to collect and analyze a variety of procedure-related outcomes. Using the data pooled across centers, descriptive statistics were generated for the patient and procedure-related characteristics and outcomes; relationships between characteristics and outcomes were explored. RESULTS A total of 1787 DAE's were performed over this 5-year period (392 at Duke University Medical Center, 887 at Louisiana State University Health Sciences Center, 312 at New York University Langone Medical Center, and 195 at University of Massachusetts Medical Center). Of these, there were 1017 (57%) double-balloon, 391 (29%) single-balloon, and 378 (21%) spiral enteroscopies. The mean age of patients undergoing DAE was 66 years and 53% of examinations were performed on women; 18% of patients in the cohort underwent >1 DAE over this time span. A total of 53% of examinations were performed for suspected small bowel bleeding, 31% were directly guided by video capsule endoscopy findings and 8% were performed for abnormal imaging. A total of 85% of examinations used an antegrade approach and DAE took a mean of 45 minutes to complete; 76% of examinations revealed abnormal findings, with vascular, inflammatory, and neoplastic findings seen in 49%, 17%, and 15% of the cohort, respectively. Older age was significantly associated with any abnormal finding, including arteriovenous malformations (P

Menopausal transition accelerates an age-associated decrease in vascular function and a decline in aerobic fitness. The purpose of this study was to examine the effect of 8 weeks of interval sprinting cycle ergometer exercise on arterial stiffness, basal forearm blood flow, and aerobic fitness of post-menopausal women. Sixty overweight post-menopausal women were randomized into either exercise (Ex, n = 30) or control (C, n = 30) groups. Ex participants completed 24 interval sprinting exercise (ISE) sessions over 8 weeks. Each 20-minute ISE session comprised of alternating 8 seconds sprints and 12 seconds of light pedaling. Arterial stiffness assessed through ankle-brachial pulse wave velocity (baPWV) and augmentation index (AIx), basal forearm blood flow (FBF) assessed using venous occlusion, and aerobic fitness were assessed before and after the intervention. baPWV was significantly decreased in the Ex group by 7.2%, P = .03, whereas AIx demonstrated a 10% decrease, P = .002. No changes were found in basal FBF. Aerobic fitness was significantly increased, P = .002, in the Ex group (14%) with no change occurring in the control group.ISE training, despite minimal exercise commitment time (8 hours over 8 weeks), significantly lowered the arterial stiffness and increased the aerobic fitness of post-menopausal women. These results suggest that ISE positively influences the negative change in arterial stiffness and aerobic fitness that typically accompanies menopause.

IgG antibodies contain N-linked glycans on the Fc portion of each heavy chain. The glycan on one heavy chain can either match the glycan on the other heavy chain (symmetrical pairing) or be different (asymmetrical pairing). These Fc glycans influence effector functions and can alter clearance rates. Previous studies showing that high mannose forms result in faster mAb clearance in humans were incapable of differentiating the impact of symmetrically vs. asymmetrically paired HM forms, and, therefore, the effect of pairing on clearance was not clear. Traditional analytical methods, which are used to measure glycans in such studies, do not determine the number of HM glycans per antibody. With a sensitive method designed to measure HM pairing, we followed the levels of symmetrically and asymmetrically paired HM on antibodies in human pharmacokinetic serum samples to determine the impact of Fc HM glycan pairing on therapeutic human IgG clearance in humans. The two HM paired forms cleared at the same rate, indicating that the effect on clearance was not proportional to the degree of modification. Since both forms can exist on therapeutic antibodies and the ratio can differ between products, measuring their relative levels is necessary to properly estimate effects on clearance.

Population wellbeing, an aggregate measure of positive mental, physical, and emotional health, has previously been used as a marker of community thriving. We examined whether several community measures of wellbeing, and their change since 2012, could be used to understand electoral changes that led to the outcome of the 2016 United States presidential election. We found that areas of the US which had the largest shifts away from the incumbent party had both lower wellbeing and greater drops in wellbeing when compared with areas that did not shift. In comparison, changes in income were not related to voting shifts. Well-being may be more useful in predicting and understanding electoral outcomes than some more conventional voting determinants.

Disulfide reduction in therapeutic monoclonal antibodies can occur during cell harvest operations as a result of cell breakage. Understanding these product quality changes and manufacturers' ability to control them would likely be of concern to regulatory bodies. To study the biological impact of disulfide reduction, mAbs, including IgG2κ, IgG2λ, IgG1κ, and IgG1λ forms, were partially reduced with dithiothreitol (DTT). Samples generated had approximately 10% or 50% intact molecules as determined by nrCE-SDS. Similar to the type of partial reduction obtained during uncontrolled harvest operations, DTT reduced antibodies were free from sulfur-linked adduct, such as attached cysteine. These partially reduced materials were incubated under physiological (blood-mimicking) redox conditions in vitro to follow the fate of the interchain cysteines. Within 8h, the original disulfide bonds reformed. For mAbA, an IgG2κ, the initial re-oxidized state favored the IgG2-A disulfide isoform, which then underwent conversion over time to other isoforms. Reduced material was fully active. Results suggest that the type of disulfide reduction would have minimal impact to safety or efficacy. Antibody re-oxidation rates were found to be in the order of IgG2κ

Human IgG2 antibodies contain three types of disulfide isoforms, classified by the number of Fab arms having disulfide links to the heavy chain hinge region. In the IgG2-B form, both Fab arms have interchain disulfide bonds to the hinge region, and in IgG2-A, neither Fab arm are disulfide linked to the hinge. The IgG2-A/B is a hybrid between these two forms, with only one Fab arm disulfide linked to the hinge. Changes in the relative levels of these forms over time are observed while IgG2 circulates in humans, suggesting IgG2-A→IgG2-A/B→IgG2-B conversion. Using a flow-through dialysis system, we studied the conversion kinetics of these forms in vitro under physiological conditions. For two IgG2κ antibodies, in vivo results closely matched the kinetics observed in vitro, indicating that the changes observed in vivo were solely conversions between isoforms, not differential clearance of specific forms. Moreover, the combined results validate the accuracy of the physiological model for the study of blood redox reactions. Further exploration of the conversion kinetics using material enriched in the IgG2-A forms revealed that the IgG2-A→IgG2-A/B rate was similar between IgG2κ and IgG2λ antibodies. In IgG2κ antibodies, conversion of IgG2-A/B→IgG2-B was slower than the IgG2-A→IgG2-A/B reaction. However, in IgG2λ antibodies, little IgG2-A/B→IgG2-B conversion was detected under physiological conditions. Thus, small differences in the C-terminus of the light chain sequences affect the disulfide conversion kinetics and impact the IgG2 disulfide isoforms produced in vivo.

Glycation of immunoglobulin G (IgG) can result from incubation with a reducing sugar in vitro or during circulation in vivo. Upon injection of a recombinantly produced human therapeutic IgG into humans, changes in the glycation levels could be observed as a function of circulation time. Mass changes on the individual IgG polypeptide chains as the results of glycation were determined using reversed-phase liquid chromatography/mass spectrometry. Changes to the light and heavy chains were low but easily detectable at 0.00092 and 0.0021 glucose (Glc) additions per chain per day, respectively. Levels of glycation found on the Fc portion of IgG isolated from healthy subjects, using a similar analytical approach, were on average 0.045 Glc molecules per fragment. In vivo glycation rates could be approximated in vitro by modeling the physiological glycation reaction with a simplified incubation containing physiological Glc concentrations, pH and temperature but with a high concentration of a single purified IgG. To test the impact of glycation on IgG function, highly glycated IgG1 and IgG2 were prepared containing on average 42-49 Glc molecules per IgG. Binding to FcγIIIa receptors, neonatal Fc receptor or protein A was similar or identical to the non-glycated IgG controls. Although the modifications were well distributed throughout the protein sequence, and at high enough levels to affect the elution position by size-exclusion chromatography, no changes in the tested Fc functions were observed.

Therapeutic proteins contain a large number of post-translational modifications, some of which could potentially impact their safety or efficacy. In one of these changes, pyroglutamate can form on the N terminus of the polypeptide chain. Both glutamine and glutamate at the N termini of recombinant monoclonal antibodies can cyclize spontaneously to pyroglutamate (pE) in vitro. Glutamate conversion to pyroglutamate occurs more slowly than from glutamine but has been observed under near physiological conditions. Here we investigated to what extent human IgG2 N-terminal glutamate converts to pE in vivo. Pyroglutamate levels increased over time after injection into humans, with the rate of formation differing between polypeptide chains. These changes were replicated for the same antibodies in vitro under physiological pH and temperature conditions, indicating that the changes observed in vivo were due to chemical conversion not differential clearance. Differences in the conversion rates between the light chain and heavy chain on an antibody were eliminated by denaturing the protein, revealing that structural elements affect pE formation rates. By enzymatically releasing pE from endogenous antibodies isolated from human serum, we could estimate the naturally occurring levels of this post-translational modification. Together, these techniques and results can be used to predict the exposure of pE for therapeutic antibodies and to guide criticality assessments for this attribute.

Human IgG2 exists as a mixture of disulfide-linked structural isoforms that can show different activities. To probe the contribution of specific cysteine residues to the formation of structural isoforms, we characterized a series of Cys-->Ser mutant IgG2 recombinant monoclonal antibodies, focused on the first C(H)1 cysteine and the first two hinge cysteines. These residues participate in the formation of structural isoforms that have been noted by nonreduced capillary sodium dodecyl sulfate polyacrylamide gel electrophoresis, reversed-phase high-performance liquid chromatography, and cation exchange chromatography. We show that single Cys-->Ser mutants can greatly reduce heterogeneous disulfide bonding in human IgG2 and maintain in vitro activity. The data demonstrate the feasibility of applying site-directed mutagenesis to reduce disulfide bond heterogeneity in human IgG2 while preserving the activity of this therapeutically important class of human antibodies.

Several studies using a variety of approaches have investigated the impact of the Fc glycan structure on IgG clearance rates. Most, but not all, of these studies have concluded that glycan structural differences do not affect clearance. Here we investigated the impact of glycan on the clearance of a human antibody in humans. To monitor glycan-dependent changes, a human IgG2 was affinity purified in a single step from serum samples from a human pharmacokinetic study. The glycan profile from the purified antibody samples was determined by RP-HPLC/MS analysis of the 2-aminobenzamide-labeled glycans. Relative levels of high-mannose species (M6-M9) decreased over circulation time. Differences in the individual high-mannose structural isoform clearance rates were measured from extracted ion current profiles. Similar changes to the glycan profile could be achieved through incubation of the antibody in serum in vitro, suggesting that the changes observed in vivo were the result of glycan cleavage, not differential antibody clearance. These results confirm that antibody clearance is not significantly affected by the Fc glycan structure and provide evidence for the presence of circulating mannosidase activity in humans.

In 2003, physicians in China were unprepared to care for people with AIDS. Project HOPE partnered with Hubei Province health authorities to train and mentor doctors and build capacity for HIV care. From 2004 to 2006, seventy-eight Chinese "master trainers" were trained, who then trained and mentored 8,759 health workers. During this period, as the free antiretroviral therapy period began, measures of physician competence in HIV care improved significantly, and annual mortality from AIDS fell from 49 percent to 8.8 percent. This international partnership created a sustainable capacity for effective HIV prevention and care that could be replicable in other settings.

In the accompanying report ( Wypych, J., Li, M., Guo, A., Zhang, Z., Martinez, T., Allen, M. J., Fodor, S., Kelner, D. N., Flynn, G. C., Liu, Y. D., Bondarenko, P. V., Ricci, M. S., Dillon, T. M., and Balland, A. (2008) J. Biol. Chem. 283, 16194-16205 ), we have identified that the human IgG2 subclass exists as an ensemble of distinct isoforms, designated IgG2-A, -B, and -A/B, which differ by the disulfide connectivity at the hinge region. In this report, we studied the structural and functional properties of the IgG2 disulfide isoforms and compared them to IgG1. Human monoclonal IgG1 and IgG2 antibodies were designed with identical antigen binding regions, specific to interleukin-1 cell surface receptor type 1. In vitro biological activity measurements showed an increased activity of the IgG1 relative to the IgG2 in blocking interleukin-1beta ligand from binding to the receptor, suggesting that some of the IgG2 isoforms had lower activity. Under reduction-oxidation conditions, the IgG2 disulfide isoforms converted to IgG2-A when 1 m guanidine was used, whereas IgG2-B was enriched in the absence of guanidine. The relative potency of the antibodies in cell-based assays was: IgG1 > IgG2-A > IgG2 >> IgG2-B. This difference correlated with an increased hydrodynamic radius of IgG2-A relative to IgG2-B, as shown by biophysical characterization. The enrichment of disulfide isoforms and activity studies were extended to additional IgG2 monoclonal antibodies with various antigen targets. All IgG2 antibodies displayed the same disulfide conversion, but only a subset showed activity differences between IgG2-A and IgG2-B. Additionally, the distribution of isoforms was influenced by the light chain type, with IgG2lambda composed mostly of IgG2-A. Based on crystal structure analysis, we propose that IgG2 disulfide exchange is caused by the close proximity of several cysteine residues at the hinge and the reactivity of tandem cysteines within the hinge. Furthermore, the IgG2 isoforms were shown to interconvert in whole blood or a "blood-like" environment, thereby suggesting that the in vivo activity of human IgG2 may be dependent on the distribution of isoforms.

E7389, a macrocyclic ketone analog of the marine natural product halichondrin B, currently is undergoing clinical trials for cancer. This fully synthetic agent exerts its highly potent in vitro and in vivo anticancer effects via tubulin-based antimitotic mechanisms, which are similar or identical to those of parental halichondrin B. In an attempt to understand the impressive potency of E7389 in animal models of human cancer, its ability to induce apoptosis following prolonged mitotic blockage was evaluated. Treatment of U937 human histiocytic lymphoma cells with E7389 led to time-dependent collection of cells in the G2-M phase of the cell cycle, beginning as early as 2 h and becoming maximal by 12 h. Increased numbers of hypodiploid events were seen beginning at 12 h, suggesting initiation of apoptosis after prolonged E7389-induced mitotic blockage. The identity of hypodiploid events as apoptotic cells under these conditions was confirmed by two additional morphologic criteria: green to orange/yellow shifts on acridine orange/ethidium bromide staining, and cell surface annexin V binding as assessed by flow cytometry. Several biochemical correlates of apoptosis also were seen following E7389 treatment, including phosphorylation of the antiapoptotic protein Bcl-2, cytochrome c release from mitochondria, proteolytic activation of caspase-3 and -9, and cleavage of the caspase-3 substrate poly(ADP-ribose) polymerase (PARP). In LNCaP human prostate cancer cells, treatment with E7389 also led to generation of hypodiploid cells, activation of caspase-3 and -9, and appearance of cleaved PARP, indicating that E7389 can activate cellular apoptosis pathways under anchorage-independent and -dependent cell culture conditions. These results show that prolonged mitotic blockage by E7389 can lead to apoptotic cell death of human cancer cells in vitro and can provide a mechanistic basis for the significant in vivo anticancer efficacy of E7389.

Borrelidin, an antibiotic with anti-angiogenic activity, not only suppresses new capillary tube formation, but also collapses formed capillary tubes in a rat aorta culture model. Since it selectively inhibits threonyl-tRNA synthetase, we examined the effect of threonine on its anti-angiogenic activity. We found that a high concentration of threonine (1 mM) attenuated the ability of borrelidin to inhibit both capillary tube formation in the rat aorta culture model and human umbilical vein endothelial cells (HUVEC) proliferation, yet did not affect the ability of borrelidin to collapse formed capillary tubes or to induce apoptosis in HUVEC. Borrelidin activated caspase-3 and -8, and inhibitors of both caspase-3 and -8 suppressed borrelidin-induced apoptosis in HUVEC. Taken together, these data suggest that the anti-angiogenic effects of borrelidin are mediated through at least two mechanisms, i.e. one threonine-dependent and the other threonine-independent, and borrelidin induces apoptosis in endothelial cells via the caspase-8/-3 pathway.

Manufacturing-induced disulfide reduction has recently been reported for monoclonal human immunoglobulin gamma (IgG) antibodies, a widely used modality in the biopharmaceutical industry. This effect has been tied to components of the intracellular thioredoxin reduction system that are released upon cell breakage. Here, we describe the effect of process parameters and intrinsic molecule properties on the extent of reduction. Material taken from cell cultures at the end of production displayed large variations in the extent of antibody reduction between different products, including no reduction, when subjected to the same reduction-promoting harvest conditions. Additionally, in a reconstituted model in which process variables could be isolated from product properties, we found that antibody reduction was dependent on the cell line (clone) and cell culture process. A bench-scale model using a thioredoxin/thioredoxin reductase regeneration system revealed that reduction susceptibility depended on not only antibody class but also light chain type; the model further demonstrates that the trend in reducibility was identical to DTT reduction sensitivity following the order IgG1λ > IgG1κ > IgG2λ > IgG2κ. Thus, both product attributes and process parameters contribute to the extent of antibody reduction during production.

Glycan structures attached to the C(H)2 domain of the Fc region of immunoglobulin G (IgG) are essential for specific effector functions but their role in modulating clearance is less clear. Clearance is of obvious importance for therapeutic monoclonal antibodies (Mabs) as it directly impacts efficacy. Here, we study the impact of Fc glycan structure on the clearance of four therapeutic human IgGs (one IgG1 and three IgG2s) in humans. The therapeutic IgGs were affinity purified from serum samples from human pharmacokinetic studies, and changes to the glycan profile over time were determined by peptide mapping employing high-resolution mass spectrometry. Relative levels of high-mannose 5 (M5) glycan decreased as a function of circulation time, whereas other glycans remained constant. These results demonstrate that therapeutic IgGs containing Fc high-mannose glycans are cleared more rapidly in humans than other glycan forms. The quantitative effect of this on pharmacokinetic area under the curve was calculated and shown to be relatively minor for three of the four molecules studied, but, depending on the dosing regimen and the relative level of the high-mannose glycan, this can also have significant impact. High-mannose content of therapeutic Mabs should be considered an important product quality attribute which may affect pharmacokinetic properties of therapeutic antibodies.

High resolution glycan mapping was performed on human immunoglobulin G (IgG) obtained from individual healthy subjects and from a combined sample of healthy subjects. In addition to the commonly known complex glycans, a variety of minor glycans are described and quantified, including high mannose forms and several previously unreported hybrid forms. Fc specific glycan analysis was also performed through peptide mapping with LC/MS/MS. Differences in the glycan linked Fc peptide masses allowed glycan profiles to be analyzed and quantified from IgG1 and IgG2 simultaneously for each subject within the same sample. Glycan profiles differed between subtypes, with greater levels of more fully galactosylated species found on IgG1 (e.g. G2F, SG2F) than IgG2. These results also show that Gal attachment on G1F is biased to the Man (alpha1--6) arm for IgG1 and on the Man (alpha1--3) arm for IgG2 from individual healthy subjects.

Protein and peptide deamidation occurs spontaneously in vitro under relatively mild conditions. For antibodies and other therapeutic proteins, great effort is placed in manufacturing and storage to minimize this form of degradation. Concern has been especially great in cases where deamidation has been shown to impact protein activity. Here we monitored asparagine deamidation from a recombinant human antibody in humans and found that among the conserved sites, only Asn 384 deamidated at an appreciable rate. Under physiological temperature and pH conditions, in vitro antibody deamidation followed similar kinetics, indicating that simple incubation reactions may be used to model in vivo behavior. Endogenous IgG isolated from human serum possessed 23% deamidation at this site, further demonstrating that this modification is naturally occurring. Thus, deamidation generated in manufacturing and storage does not fully determine the patient exposure to the attribute. Instead, pharmacokinetic data along with the deamidation kinetics are combined to predict patient exposure. The deamidation rate can also be used to estimate the serum lifetime of antibodies. This approach could potentially be used to estimate turnover for other cellular or extracellular proteins.

Proteins destined to circulate in the blood are first folded and assembled in the endoplasmic reticulum of secretory cells. For antibodies, like many other serum proteins, the folding and assembly steps involve the formation of disulfide bonds. Such bonds have been thought to be static features of proteins, stabilizing domains, and linking polypeptide chains, although some cases of extracellular disulfide bond cleavage have been noted. Recently, the human IgG2 antibody subclass was found to possess multiple structures differing in specific disulfide linkages. These structures are naturally occurring and can, in some cases, affect the activity of the antibody. Here we show that these IgG2 disulfide linkages interconvert while circulating in humans. Secretory cells initially produce primarily one form (IgG2-A), which is rapidly converted to a second form (IgG2-A/B) while circulating in the blood, followed by a slower conversion to a third form (IgG2-B). This work demonstrates that the disulfide structure of the IgG2 antibody is dynamic in vivo, on a time scale similar to that of the protein's lifetime. Thus, changes to the IgG2 disulfide structure provide a marker of the protein's age and may alter its activity over its lifetime.

In this work, we present studies of the covalent structure of human IgG2 molecules. Detailed analysis showed that recombinant human IgG2 monoclonal antibody could be partially resolved into structurally distinct forms caused by multiple disulfide bond structures. In addition to the presently accepted structure for the human IgG2 subclass, we also found major structures that differ from those documented in the current literature. These novel structural isoforms are defined by the light chain constant domain (CL) and the heavy chain CH1 domain covalently linked via disulfide bonds to the hinge region of the molecule. Our results demonstrate the presence of three main types of structures within the human IgG2 subclass, and we have named these structures IgG2-A, -B, and -A/B. IgG2-A is the known classic structure for the IgG2 subclass defined by structurally independent Fab domains and hinge region. IgG2-B is a structure defined by a symmetrical arrangement of a (CH1-CL-hinge)2 complex with both Fab regions covalently linked to the hinge. IgG2-A/B represents an intermediate form, defined by an asymmetrical arrangement involving one Fab arm covalently linked to the hinge through disulfide bonds. The newly discovered structural isoforms are present in native human IgG2 antibodies isolated from myeloma plasma and from normal serum. Furthermore, the isoforms are present in native human IgG2 with either κ or λ light chains, although the ratios differ between the light chain classes. These findings indicate that disulfide structural heterogeneity is a naturally occurring feature of antibodies belonging to the human IgG2 subclass.