Depression and Anxiety Among English- and Spanish-Speaking Patients With Breast Cancer Receiving Radiation Therapy.

PURPOSE: An estimated 30% and 40% of patients with breast cancer experience depression and anxiety, respectively. However, distress experienced by patients with breast cancer receiving radiation therapy may vary among patients and vary at different time points. This study sought to describe the changes in levels of depression and anxiety experienced by English- and Spanish-speaking patients throughout a course of radiation therapy for breast cancer, along with the effect of different variables to better understand potential gaps. METHODS AND MATERIALS: Eligibility criteria included English- and Spanish-speaking females, aged 18 or older, undergoing radiation therapy treatment for breast cancer at 2 institutions. Pre- and posttreatment surveys were completed before and after delivery of radiation therapy. Sociodemographic characteristics collected included race, ethnicity, marital status, education level, longest residency location, religion, housing, and food insecurity. The survey ended with the standardized PHQ-4 questionnaire to assess anxiety and depression. Results were analyzed using the analysis of covariance procedure. RESULTS: A total of 160 participants completed pre- and posttreatment surveys, with an initial response rate of 100% (169 patients), though 9 were lost to follow-up. Most of the participants were nonwhite (50%), primarily married (42.5%), and had a high school or associate's level education (46.9%). The total baseline distress mean (BDM) was 2.96 and the final distress mean was 2.78. English-speaking patients comprised 82.5% (n = 132) of the sample and had a BDM of 2.91 with an adjusted change mean decrease of 0.45. Spanish-speaking patients comprised 17.5% (n = 28) of the sample, with a baseline distress mean of 3.21 and an adjusted change mean increase of 1.03 (P = .002). Housing (P = .017) and food insecurity (P = .0002) also showed increasing distress with increased insecurity at baseline. CONCLUSIONS: Patients who speak Spanish, identify as Hispanic, or are experiencing food and housing insecurity are at an increased risk for depression and anxiety, and could benefit from more support during their course of radiation therapy to minimize distress.

Disparities in Lung Cancer Clinical Trial Discussion and Enrollment at a Safety Net Hospital.

BACKGROUND: In the United States, less than 5% of all adult cancer patients enroll in clinical trials. Few studies explore participation in cancer clinical trials at safety net hospitals, which disproportionately care for minoritized, low-income, uninsured, and underinsured populations. Our study aims to investigate disparities in clinical trial discussions and enrollment among lung cancer patients at Boston Medical Center, the largest safety net hospital in New England. METHODS: We included 1121 patients diagnosed with lung cancer between January 2015 and December 2020. Electronic Medical Records (EMR) were queried, and patients were categorized into three groups: (1) clinical trial discussed and the patient enrolled, (2) clinical trial discussed but the patient not enrolled, and (3) clinical trial not discussed. Sociodemographic variables such as age, gender, race, ethnicity, city, primary language, median household income, medical insurance type, and education level were also collected. Chi-squared,t test, and multivariate regression analysis was done using SPSS version 26.0. RESULTS: Of the 1121 patients, clinical trials were discussed in 141 patients (12.6%), of which 22 (15.6%) were enrolled. Clinical trial discussions were conducted more with younger patients (68.19 vs 71.37, p = .001), but on multivariate analysis there was no significant difference (OR = 1.023; 95% CI 0.998-1.048; p = .068). There was no significant difference in clinical trial discussion or enrollment between the other sociodemographic factors. CONCLUSION: Additional study of barriers to cancer clinical trial discussion and enrollment at safety net institutions can serve as a prerequisite to ameliorating racial disparities observed on a national scale.

Are "outsiders" in? Exploring the impact of outsourced workers' perceived insider status and job value status on job performance.

Introduction: Outsourcing, one of the nonstandard employment forms, has been increasingly popular with a wide variety of industries and employers. However, much less is known about its consequences at the employee level, especially relative to standard-employed colleagues. Drawing on social categorization theory and the human resource architecture model, the study was to investigate how outsourced (vs. standard) employment form impacts employees' perceived insider status and then job performance, as well as the moderating role of job value status. Methods: To examine these effects, we collected two-wave and multi-source questionnaires from a sample of 147 outsourced employees, 279 standard employees, and their immediate supervisors. And interviews with 31 employees, their supervisors, and human resources personnel provided further support for our findings. Results: The results showed that relative to standard employees, outsourced employees were lower in perceived insider status and indirectly worse in job performance. Furthermore, both the comparative effects were stronger among core-status than peripheral-status employees. Discussion: Our study contributes to outsourcing and widely nonstandard employment literature, bringing the research focus from employers to outsourced employees' psychological and behavioral consequences. Also, we extended literature on the human resource architecture, through a deeper investigation on the issue of employment form-job value status (mis)matching as well as its impacts on employees.

Disparities in US Lung Cancer Clinical Trial Enrollment.

BACKGROUND: Disparities within clinical trial enrollment are well-documented, reducing the generalizability of results. Although nearly 30 years have passed since Congress passed the NIH Revitalization Act to encourage the participation of minoritized populations in clinical trials, these patients continue to be underrepresented. This study aimed to investigate lung cancer clinical trial enrollment disparities for race/ethnicity, sex, and age. METHODS: We queried the National Institutes of Health: US National Library of Medicine database of clinical trials for all US-based lung cancer clinical trials completed between 2004 and 2021 and collected data on race and ethnicity, gender, and age breakdown. This data was compared to Surveillance, Epidemiology, and End Results (SEER) database data. Independent sample t-tests and Kruskal-Wallis's approach were used to analyze the data. RESULTS: Of 311 eligible trials with exclusive US enrollment, 136 (44%) reported race and ethnicity breakdown for the patient cohort representing 9869 patients. Hispanic, Non-Hispanic American Indian/Alaska Native, Non-Hispanic Black, and Non-Hispanic Unreported participants were underrepresented (p = 0.001, p = 0.005, p = 0.014, p = 0.002, respectively). Non-Hispanic White participants were overrepresented (p = 0.018). Disparities worsened from 2017 to 2021 for Hispanic patients (p = 0.03). No significant differences were found for sex or age. CONCLUSIONS: Disparities for clinical lung cancer trial enrollment have not shown statistically significant improvement since 2004, and representation remains unequal, especially for racial and ethnic minorities.

Activation of the Hedgehog signaling pathway leads to fibrosis in aortic valves.

BACKGROUND: Fibrosis is a pathological wound healing process characterized by excessive extracellular matrix deposition, which interferes with normal organ function and contributes to ~ 45% of human mortality. Fibrosis develops in response to chronic injury in nearly all organs, but the a cascade of events leading to fibrosis remains unclear. While hedgehog (Hh) signaling activation has been associated with fibrosis in the lung, kidney, and skin, it is unknown whether hedgehog signaling activation is the cause or the consequence of fibrosis. We hypothesize that activation of hedgehog signaling is sufficient to drive fibrosis in mouse models. RESULTS: In this study, we provide direct evidence to show that activation of Hh signaling via expression of activated smoothened, SmoM2, is sufficient to induce fibrosis in the vasculature and aortic valves. We showed that activated SmoM2 -induced fibrosis is associated with abnormal function of aortic valves and heart. The relevance of this mouse model to human health is reflected in our findings that elevated GLI expression is detected in 6 out of 11 aortic valves from patients with fibrotic aortic valves. CONCLUSIONS: Our data show that activating hedgehog signaling is sufficient to drive fibrosis in mice, and this mouse model is relevant to human aortic valve stenosis.

Timeliness of Lung Cancer Care From the Point of Suspicious Image at an Urban Safety Net Hospital.

BACKGROUND: Timeliness of care is an important metric for lung cancer patients, and care delays in the safety-net setting have been described. Timeliness from the point of the suspicious image is not well-studied. Herein, we evaluate time intervals in the workup of lung cancer at an urban, safety net hospital and assess for disparities by demographic and clinical factors. PATIENTS AND METHODS: We performed a retrospective analysis of lung cancer patients receiving some portion of their care at Boston Medical Center between 2015 and 2020. A total of 687 patients were included in the final analysis. Median times from suspicious image to first treatment (SIT), suspicious image to diagnosis (SID), and diagnosis to treatment (DT) were calculated. Nonparametric tests were applied to assess for intergroup differences in time intervals. RESULTS: SIT, SID, and DT for the entire cohort was 78, 34, and 32 days, respectively. SIT intervals were 87 days for females and 72 days for males (p < .01). SIT intervals were 106, 110, 81, and 41 days for stages I, II, III, and IV, respectively (p < .01). SID intervals differed between black (40.5) and Hispanic (45) patients compared to white (28) and Asian (23) patients (p < .05). CONCLUSION: Advanced stage at presentation and male gender were associated with more timely treatment from the point of suspicious imaging while white and Asian were associated with more timely lung cancer diagnosis. Future analyses should seek to elucidate drivers of timeliness differences and assess for the impact of timeliness disparities on patient outcomes in the safety net setting.

Nedosiran, a Candidate siRNA Drug for the Treatment of Primary Hyperoxaluria: Design, Development, and Clinical Studies.

Due to the lack of treatment options for the genetic disease primary hyperoxaluria (PH), including three subtypes PH1, PH2, and PH3, caused by accumulation of oxalate forming kidney stones, there is an urgent need for the development of a drug therapy aside from siRNA drug lumasiran for patients with PH1. After the recent success of drug therapies based on small interfering RNA (siRNA), nedosiran is currently being developed for the treatment of three types of PH as a siRNA-based modality. Through specific inhibition of lactate dehydrogenase enzyme, the key enzyme in biosynthesis of oxalate in liver, phase 1, 2, and 3 clinical trials of nedosiran have achieved the desired primary end point of reduction of urinary oxalate levels in patients with PH1. More PH2 and PH3 patients need to be tested for efficacy. It has also produced a favorable secondary end point on safety and toxicity in PH patients. In addition to common injection site reactions that resolved spontaneously, no severe nedosiran treatment-associated adverse events were reported. Based on the positive results in the clinical studies, nedosiran is a candidate siRNA drug to treat PH patients.

A Systematic Review and Meta-Analysis of the Association Between Periodontal Disease and Severe Mental Illness.

BACKGROUND: Periodontal disease represents a global public health concern, with a disproportionate burden being borne by vulnerable populations. One such group is people with severe mental illness (SMI), and this study examined whether periodontal health is poorer in people with SMI than the general population. METHODS: We conducted a systematic search for studies published before March 2021 on the periodontal health of people with SMI using the following databases: PubMed, PsycINFO, EMBASE, China National Knowledge Infrastructure, and Chongqing VIP. Outcomes were periodontitis, periodontal disease, and shallow and deep periodontal pockets. Results were compared with the general population. RESULTS: Seventeen studies had sufficient data for a random-effects meta-analysis, consisting of 4404 psychiatric patients and 95,411 controls. SMI was associated with an increased prevalence of periodontitis (odds ratio = 1.97, 95% confidence interval [CI] = 1.15-3.35) compared with the general population. People with SMI had 4.28 the odds of having periodontal disease compared with controls (95% CI = 2.54-7.21). They also had 3.65 the odds of shallow pockets (95% CI = 1.80-7.42) and 2.76 the odds of deep pockets (95% CI = 1.10-6.93). CONCLUSIONS: Our findings highlight the increased prevalence and severity of periodontal disease in people with SMI. Oral health is often considered the gateway to overall health and should be a public health priority for this population.

The potential of psychological connectedness: Mitigating the impacts of COVID-19 through sense of community and community resilience.

The purpose of this study was to identify patterns of relationships connecting sense of community (SOC) and community resilience with psychological wellbeing, via the mediation of coronavirus disease 2019 (COVID-19) impacts on life domains. Survey data were collected from an international sample of adults (n = 824) during the COVID-19 outbreak (June-September 2020). Using a structural equation model, we tested a mediation model to identify the associations between SOC and community resilience with the perceived impacts of the emergency situation and with psychological wellbeing. Results revealed that SOC mitigated the impacts of COVID-19 on multiple life domains, and it was also positively associated with wellbeing. Community resilience was correlated with SOC and wellbeing but showed no significant relationship with COVID-19 impacts. The findings support that SOC has a protective function and can contribute to mitigating the impacts of difficult life situations. SOC can also be leveraged as an intervention aimed at protecting the wellbeing of people and communities, particularly in times of crisiss.

Variation in the stearoyl-CoA desaturase gene (SCD) and its influence on milk fatty acid composition in late-lactation dairy cattle grazed on pasture.

Gene markers have become useful tools for improving animal genetics and breeding since they improve the accuracy of selection for superior breeding stock. In this study, the stearoyl-CoA desaturase ( Δ -9-desaturase) gene (SCD) was investigated in New Zealand pasture-grazed Holstein-Friesian  × â€¯Jersey cows. Three nucleotide substitutions were identified in exon 5 of the gene (c.702A/G, c.762T/C and c.878C/T), and a single nucleotide substitution was identified in intron 5 (c.880 + 105A/G). The c.878C/T substitution would, if expressed, result in the amino acid substitution p.A293V. Four nucleotide substitutions (c.*1783A/G, c.*1883C/T, c.*1984G/A and c.*2066T/C/G) were identified in the 3 ' -untranslated region (3 ' -UTR), and these resulted in three nucleotide sequence variants (named a , b and c ) . The sequence that would encode valine (V) at position 293 of SCD was linked to 3 ' -UTR variant a , and the sequence that would encode alanine (A) was linked to variants b and c . The frequency of the genotypes was as follows: VV (equivalent to aa: 15.1 %), VA (equivalent to ab + ac : 50.0 %) and AA (equivalent to bb + cc + bc : 34.9 %). The cows with the V variant produced less C10:1, C12:1 and C14:1 fatty acid (FA) but more C10:0, C11:0, C14:0, C16:1 and C18:2 FA than the A variant cows ( P < 0.001 ). Effects of c.*1783A/G and c.*2066T/C/G on milk fat composition were also found for the AA cows. The presence of c was associated with decreased levels of C16:1 ( P < 0.001 ), C17:1 ( P = 0.001 ), C18:2 cis-9, trans-13 ( P = 0.045 ), C18:2 cis-9, trans-12 ( P = 0.018 ) FA and C16:1 FA index ( P < 0.001 ). The presence of b was associated with increased levels of C13:0 iso FAs ( P < 0.001 ), monounsaturated FA (MUFA; P = 0.002 ) and C12:1 ( P < 0.001 ).

Effects of FABP4 variation on milk fatty-acid composition for dairy cattle grazed on pasture in late lactation.

This research communication describes associations between variation in the fatty acid binding protein 4 gene (FABP4) and milk fat composition in New Zealand Holstein-Friesian × Jersey cross dairy cows. After correcting for the effect of the amino acid substitution p.K232A in diacylglycerol O-acyltransferase 1 (DGAT1), which is associated with variation in many milk fatty acid (FA) component levels, the effect of FABP4 c.328A/G on milk FA levels was typically small. For the five genotypes analysed, the AB cows produced more medium-chain fatty acids than CC cows (P < 0.05), and more C14:0 FA than AA and AC cows (P < 0.05). The AA and AC cows produced less C22:0 FA (P < 0.01) than the BC cows, and the AC cows produced more C24:0 FA (P < 0.05) than was produced by the BC cows. Cows of genotype CC produce more long-chain fatty acids than cows of genotype BC (P < 0.05).

Promoter and Terminator Optimization for DNA Methylation Targeting in Arabidopsis.

DNA methylation is an important epigenetic mark involved in gene regulation and silencing of transposable elements. The presence or absence of DNA methylation at specific sites can influence nearby gene expression and cause phenotypic changes that remain stable over generations. Recently, development of new technologies has enabled the targeted addition or removal of DNA methylation at specific sites of the genome. Of these new technologies, the targeting of the catalytic domain of Nicotiana tabacum DOMAINS REARRANGED METHYLTRANSFERASE 2 (ntDRM2cd) offers a promising tool for the addition of DNA methylation as it can directly methylate DNA. However, the methylation targeting efficiency of constructs using ntDRM2cd thus far has been relatively low. Previous studies have shown that the use of different promoters or terminators can greatly improve genome-editing efficiencies. In this study, we systematically survey a variety of promoter and terminator combinations to identify optimal combinations to use when targeting the addition of DNA methylation in Arabidopsis thaliana.

Co-targeting RNA Polymerases IV and V Promotes Efficient De Novo DNA Methylation in Arabidopsis.

The RNA-directed DNA methylation (RdDM) pathway in plants controls gene expression via cytosine DNA methylation. The ability to manipulate RdDM would shed light on the mechanisms and applications of DNA methylation to control gene expression. Here, we identified diverse RdDM proteins that are capable of targeting methylation and silencing in Arabidopsis when tethered to an artificial zinc finger (ZF-RdDM). We studied their order of action within the RdDM pathway by testing their ability to target methylation in different mutants. We also evaluated ectopic siRNA biogenesis, RNA polymerase V (Pol V) recruitment, targeted DNA methylation, and gene-expression changes at thousands of ZF-RdDM targets. We found that co-targeting both arms of the RdDM pathway, siRNA biogenesis and Pol V recruitment, dramatically enhanced targeted methylation. This work defines how RdDM components establish DNA methylation and enables new strategies for epigenetic gene regulation via targeted DNA methylation.

Targeted DNA demethylation of the Arabidopsis genome using the human TET1 catalytic domain.

DNA methylation is an important epigenetic modification involved in gene regulation and transposable element silencing. Changes in DNA methylation can be heritable and, thus, can lead to the formation of stable epialleles. A well-characterized example of a stable epiallele in plants is fwa, which consists of the loss of DNA cytosine methylation (5mC) in the promoter of the FLOWERING WAGENINGEN (FWA) gene, causing up-regulation of FWA and a heritable late-flowering phenotype. Here we demonstrate that a fusion between the catalytic domain of the human demethylase TEN-ELEVEN TRANSLOCATION1 (TET1cd) and an artificial zinc finger (ZF) designed to target the FWA promoter can cause highly efficient targeted demethylation, FWA up-regulation, and a heritable late-flowering phenotype. Additional ZF-TET1cd fusions designed to target methylated regions of the CACTA1 transposon also caused targeted demethylation and changes in expression. Finally, we have developed a CRISPR/dCas9-based targeted demethylation system using the TET1cd and a modified SunTag system. Similar to the ZF-TET1cd fusions, the SunTag-TET1cd system is able to target demethylation and activate gene expression when directed to the FWA or CACTA1 loci. Our study provides tools for targeted removal of 5mC at specific loci in the genome with high specificity and minimal off-target effects. These tools provide the opportunity to develop new epialleles for traits of interest, and to reactivate expression of previously silenced genes, transgenes, or transposons.

Antioxidant and functional properties of protein hydrolysates obtained from squid pen chitosan extraction effluent.

Squid pens were subjected to alkali hydrolysis to extract chitin and chitosan. Proteins present in the alkaline extraction wastewater were recovered at pH 3, 4, 5 and 6, and were subjected to hydrolysis by trypsin, pepsin and a bacterial protease called HT for 1, 2, 4 and 24h. Hydrolysis of the extracted proteins with either trypsin or HT generated more antioxidant activity than hydrolysis with pepsin. Higher ACE-inhibitory activity was generated in the trypsin and pepsin hydrolysates than in the HT hydrolysate. Squid pen protein recovered from chitosan processing waste alkaline solution can be a potential source of bioactive peptides for addition to foods. The antioxidant and ACE-inhibitory activities of the extracted proteins were initially low and increased upon incubation with the proteases. Pepsin generated significantly lower (P<0.05) antioxidant activities compared to trypsin and HT, while trypsin and pepsin hydrolysates exhibited higher ACE-inhibitory activity than HT (P<0.05).

Collaborative prescribing: a qualitative exploration of a role for pharmacists in mental health.

BACKGROUND: Collaborative prescribing has been proposed as an extension of practice for advanced pharmacist practitioners. A lack of research investigating how pharmacists might be most effective as prescribers in mental health was identified. OBJECTIVE: To explore health professionals' and consumers' attitudes and beliefs that relate to the role of specialist mental health pharmacists working as collaborative prescribers within their advanced scope of practice in secondary care. METHODS: Semistructured interviews were conducted with key informants in the New Zealand mental health sector. Participants were selected via a purposive sampling method, including health professionals (n=9) and consumers (n=3). NVivo software was used to analyze data, using a thematic analysis approach to develop a series of key themes from the interviews. Common themes were extracted, which were used to gather results and draw conclusions. RESULTS: The key findings include a widespread acknowledgment of the role of specialist pharmacists as collaborative prescribers in mental health and as integral members of the multidisciplinary team; however, consumers were unaware of pharmacists' role in secondary care. The role was seen to extend current practice particularly in medication management after assessment and diagnosis by a medical practitioner. Concerns regarding demonstrating competence, practitioner role/boundary confusion, insufficient training and workforce development, hesitancy by pharmacists to extend role, consumer awareness, and public perception of the traditional pharmacist role were identified. Solutions discussed included education by the profession; relationship building, training, and robust competency assessments; and a structured framework for implementing a collaborative prescribing model. CONCLUSIONS: This study suggests there was recognition and acceptance of the role that specialist pharmacist practitioners could play in contributing to the care of mental health consumers as collaborative prescribers; their medication expertise being regarded highly. Further research is necessary to investigate how current resource constraints will allow for collaborative prescribing to be implemented within the context of mental health practice.

Mutant KRAS promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool.

BACKGROUND & AIMS: Adenomatous polyps are precursors to colorectal cancer (CRC), whereas hyperplastic polyps (HPPs) have low risk of progression to CRC. Mutations in KRAS are found in ∼40% of CRCs and large adenomas and a subset of HPPs. We investigated the reasons why HPPs with KRAS mutations lack malignant potential and compared the effects of Kras/KRAS activation with those of Apc/APC inactivation, which promotes adenoma formation. METHODS: We activated a KrasG12D mutant allele or inactivated Apc alleles in mouse colon epithelium and analyzed phenotypes and expression of selected genes and proteins. The mouse data were validated using samples of human HPPs and adenomas. Signaling pathways and factors contributing to Kras/KRAS-induced phenotypes were studied in intestinal epithelial cells. RESULTS: Activation of Kras led to hyperplasia and serrated crypt architecture akin to that observed in human HPPs. We also observed loss of Paneth cells and increases in goblet cell numbers. Abnormalities in Kras-mediated differentiation and proliferation required mitogen-activated protein kinase signaling and were linked to activation of the Hes1 transcription factor. Human HPPs also had activation of HES1. In contrast to Apc/APC inactivation, Kras/KRAS activation did not increase expression of crypt stem cell markers in colon epithelium or colony formation in vitro. Kras/KRAS activation was not associated with substantial induction of p16(INK4a) protein expression in mouse colon epithelium or human HPPs. CONCLUSIONS: Although Kras/KRAS mutation promotes serrated and hyperplastic morphologic features in colon epithelium, it is not able to initiate adenoma development, perhaps in part because activated Kras/KRAS signaling does not increase the number of presumptive stem cells in affected crypts.

Antioxidant activities, sensory and anti-influenza activity of grape skin tea infusion.

Grape skin extracts from pinot noir and pinot gris exhibited significant in vitro antiviral (influenza virus) activity. Five tea infusions from grape skins (Vitis vinifera var. pinot noir and pinot gris) without any additives (control pinot noir and control pinot gris) or by adding variable amounts of green tea and hibiscus were investigated as a means to utilise wine wastes. The antioxidant activities (DPPH scavenging capacity and superoxide anion radical scavenging capacity), total phenolics, the polyphenolics profile and objective colour measurements (CIELab) were determined on freeze-dried water extracts of all five tea infusions, hibiscus and green tea. The colour parameters, L(∗) and a(∗) values, varied widely (P<0.05) for all the infusions as a result of having different levels and variety of pigments. The tea infusions exhibited weak antioxidant activity and the antiviral activity in grape skin appears not related to phenolics contents.

Osteopotentia regulates osteoblast maturation, bone formation, and skeletal integrity in mice.

During skeletal development and regeneration, bone-forming osteoblasts respond to high metabolic demand by active expansion of their rough endoplasmic reticulum (rER) and increased synthesis of type I collagen, the predominant bone matrix protein. However, the molecular mechanisms that orchestrate this response are not well understood. We show that insertional mutagenesis of the previously uncharacterized osteopotentia (Opt) gene disrupts osteoblast function and causes catastrophic defects in postnatal skeletal development. Opt encodes a widely expressed rER-localized integral membrane protein containing a conserved SUN (Sad1/Unc-84 homology) domain. Mice lacking Opt develop acute onset skeletal defects that include impaired bone formation and spontaneous fractures. These defects result in part from a cell-autonomous failure of osteoblast maturation and a posttranscriptional decline in type I collagen synthesis, which is concordant with minimal rER expansion. By identifying Opt as a crucial regulator of bone formation in the mouse, our results uncover a novel rER-mediated control point in osteoblast function and implicate human Opt as a candidate gene for brittle bone disorders.