Structural basis for Retriever-SNX17 assembly and endosomal sorting.

During endosomal recycling, Sorting Nexin 17 (SNX17) facilitates the transport of numerous membrane cargo proteins by tethering them to the Retriever complex. Despite its importance, the mechanisms underlying this interaction have remained elusive. Here, we report the structure of the Retriever-SNX17 complex determined using cryogenic electron microscopy (cryo-EM). Our structure reveals that the C-terminal tail of SNX17 engages with a highly conserved interface between the VPS35L and VPS26C subunits of Retriever. Through comprehensive biochemical, cellular, and proteomic analyses, we demonstrate that disrupting this interface impairs the Retriever-SNX17 interaction, subsequently affecting the recycling of SNX17-dependent cargos and altering the composition of the plasma membrane proteome. Intriguingly, we find that the SNX17-binding pocket on Retriever can be utilized by other ligands that share a consensus acidic C-terminal tail motif. By showing how SNX17 is linked to Retriever, our findings uncover a fundamental mechanism underlying endosomal trafficking of critical cargo proteins and reveal a mechanism by which Retriever can engage with other regulatory factors.

The dampening effect of geopolitical risk and economic policy uncertainty in the linkage between economic complexity and environmental degradation in the G-20.

The question remains whether high geopolitical risk and economic policy uncertainty will have a dampening or enhancing effect on pollution factors. In this regard, the study empirically investigates the effects of economic complexity, geopolitical risk, economic policy uncertainty, renewable energy consumption and economic growth on environmental pollution for G-20 countries from 1997 to 2018. The long-term coefficient estimates, derived from the FMOLS estimator, support the inverted U-shaped EKC linkages between economic complexity and ecological footprint, carbon footprint and carbon dioxide emissions. Furthermore, over the long term, geopolitical risks, renewable energy use, and the interaction between economic complexity and policy uncertainty have a positive impact on environmental quality in the G-20 economies. Conversely, economic growth and the interaction between economic complexity and geopolitical risk are negatively associated with environmental quality. Additionally, economic policy uncertainty has a positive effect on ecological footprint carbon footprint and carbon dioxide emissions. Finally, causality results revealed that explanatory variables are the cause of environmental pollution indicators. Hence, in order to advance environmental quality in these nations, precautions must be taken to mitigate the effects of economic policy uncertainty and boost the accessibility of renewable energy sources. Additionally, while not advised as a policy measure, the feasible economic fallout of geopolitical risk should also be considered.

The dual lipid desaturase/hydroxylase DEGS2 controls phytoceramide levels necessary to counter intestinal inflammation.

Intestinal immunity is dependent on barrier function to maintain quiescence. The mechanisms for the maintenance of this barrier are not fully understood. Delta 4-desaturase, sphingolipid 2 (DEGS2) is a lipid desaturase and hydroxylase that catalyzes the synthesis of ceramide and phytoceramide from dihydroceramide. Using a forward genetic approach, we found and validated a mutation in Degs2 as causative of increasing susceptibility to colitis and altering the phytoceramide balance in the colon. DEGS2 is expressed in the intestinal epithelium, and the colitis phenotype is dependent on the non-hematopoietic compartment of the mouse. In the absence of DEGS2, the colon lacks phytoceramides and accumulates large amounts of the precursor lipid dihydroceramide. In response to dextran sodium sulfate (DSS)-induced colitis, colonic epithelial cells in DEGS2-deficient mice had increased cell death and decreased proliferation compared to those in wild-type mice. These findings demonstrate that DEGS2 is needed to maintain epithelial integrity, protect against DSS-induced colitis and maintain lipid balance in vivo.

Trans-Golgi protein TVP23B regulates host-microbe interactions via Paneth cell homeostasis and Goblet cell glycosylation.

A key feature in intestinal immunity is the dynamic intestinal barrier, which separates the host from resident and pathogenic microbiota through a mucus gel impregnated with antimicrobial peptides. Using a forward genetic screen, we have found a mutation in Tvp23b, which conferred susceptibility to chemically induced and infectious colitis. Trans-Golgi apparatus membrane protein TVP23 homolog B (TVP23B) is a transmembrane protein conserved from yeast to humans. We found that TVP23B controls the homeostasis of Paneth cells and function of goblet cells, leading to a decrease in antimicrobial peptides and more penetrable mucus layer. TVP23B binds with another Golgi protein, YIPF6, which is similarly critical for intestinal homeostasis. The Golgi proteomes of YIPF6 and TVP23B-deficient colonocytes have a common deficiency of several critical glycosylation enzymes. TVP23B is necessary for the formation of the sterile mucin layer of the intestine and its absence disturbs the balance of host and microbe in vivo.

Carvacrol protects rat liver exposed to formaldehyde by regulating oxidative stress, and asprosin and subfatin hormones.

Toxic doses of formaldehyde (FA) can cause oxidative damage and impair energy metabolism. Asprosin (ASP) and subfatin (SUB) are adipokines produced by adipose tissue that help regulate energy metabolism. We investigated the effects of carvacrol (CAR), an antioxidant with hepatoprotective properties, on ASP and SUB in rats exposed to FA using immunohistochemistry and biochemistry. We used 42 male Wistar albino rats divided into six groups of seven: group 1, untreated control; group 2, FA (10 ppm FA by inhalation 8 h/day, 5 days/week); group 3, CAR-20 (20 mg/kg); group 4, CAR-40; group 5, FA (10 ppm FA by inhalation 8 h/day, 5 days/week) + CAR-20 (20 mg/kg); group 6, FA (10 ppm FA by inhalation 8 h/day, 5 days/week) + CAR-40 (40 mg/kg). Levels of ASP and SUB, and total oxidant status (TOS) and total antioxidant status (TAS) in blood and liver tissue were measured using ELISA. ASP and SUB immunoreactivity was assessed using immunohistochemistry. The number of apoptotic cells was determined using the TUNEL method. The number of apoptotic cells in group 2 was increased compared to group 1. TOS in group 2 was increased compared to group 1. The numbers of apoptotic cells and TOS in group 3 were decreased compared to group 1. TOS was decreased in group 6 compared to group 2, but TOS was increased compared to group 1. We found ASP and SUB immunoreactivity in the liver. All alterations were reversed by addition of CAR. It appears that FA disrupts energy metabolism and CAR ameliorates the destructive effects of FA when used at appropriate doses, although CAR might be harmful at high doses.

Self-Organization of Iron Sulfide Nanoparticles into Complex Multicompartment Supraparticles.

Self-assembled compartments from nanoscale components are found in all life forms. Their characteristic dimensions are in 50-1000 nm scale, typically assembled from a variety of bioorganic "building blocks". Among the various functions that these mesoscale compartments carry out, protection of the content from the environment is central. Finding synthetic pathways to similarly complex and functional particles from technologically friendly inorganic nanoparticles (NPs) is needed for a multitude of biomedical, biochemical, and biotechnological processes. Here, it is shown that FeS2 NPs stabilized by l-cysteine self-assemble into multicompartment supraparticles (mSPs). The NPs initially produce ≈55 nm concave assemblies that reconfigure into ≈75 nm closed mSPs with ≈340 interconnected compartments with an average size of ≈5 nm. The intercompartmental partitions and mSP surface are formed primarily from FeS2 and Fe2 O3 NPs, respectively. The intermediate formation of cup-like particles enables encapsulation of biological cargo. This capability is demonstrated by loading mSPs with DNA and subsequent transfection of mammalian cells. Also it is found that the temperature stability of the DNA cargo is enhanced compared to the traditional delivery vehicles. These findings demonstrate that biomimetic compartmentalized particles can be used to successfully encapsulate and enhance temperature stability of the nucleic acid cargo for a variety of bioapplications.

Relationship Between Prognostic Nutritional Index and Contrast-Associated Acute Kidney Injury in Patients With Non-ST Segment Elevation Myocardial Infarction Undergoing Coronary Angiography.

Prognostic nutritional index (PNI), consisting of inflammatory-nutritional parameters, has been investigated in terms of outcomes and renal function in patients with coronary artery disease. The objective of this study is to assess the predictive power of the PNI in predicting the risk for developing contrast-associated acute kidney injury (CA-AKI), an important complication following coronary angiography in patients with non-ST-elevation myocardial infarction (NSTEMI). The study population (336 patients with the diagnosis of NSTEMI) was divided into two groups: patients with CA-AKI and patients without CA-AKI. The mean age of the whole population was 62.0 ± 12.7 (21-95) years. CA-AKI was detected in 68 (20%) patients. Prognostic nutritional index values were significantly (P < .001) lower in the CA-AKI (+) group. Low PNI values (cutoff < 48.5%) were independent predictors of CA-AKI with Odds ratio (OR): .913, 95% confidence interval (CI): .866-.962, P:.001, with a sensitivity 70.6% and specificity 69.4%. Prognostic nutritional index seems to be an easily assessable and promising scoring system that can be used in clinical practice for predicting the risk of developing CA-AKI.

The morphology of fabella and its prevalence in Turkish society.

OBJECTIVE: Fabella is a sesamoid whose prevalence is unstable and can be found as bone or cartilage, which changes over time. This study aims to reveal the prevalence, distribution, gender differences, and morphometric characteristics of cartilage and bony fabella in the Turkish population. PATIENTS AND METHODS: The study included 2.035 individuals over 18 years of age. MR images of 121 individuals, whose MR images of both knees could be obtained by anteroposterior and lateral radiographs of the participants, were evaluated retrospectively. RESULTS: The prevalence of fabella was 39.6% in females, 38.4% in males, and 38.8% in total. The prevalence of cartilage fabella was 9.1%, whereas bone fabella incidence was 29.7% regardless of gender. The fabella's mean thickness, width, length, and distance to the epicondylus lateralis femoris were 3.84 mm, 6.04 mm, 6.23, and 31.26 mm, respectively. CONCLUSIONS: The data of this study showing the occurrence and morphometric characteristics of bony and cartilaginous fabella allow early and accurate diagnosis of various pathological conditions caused by fabella.

The prevalence and distribution of the flexor carpi radialis brevis muscle in the Turkish population.

The flexor carpi radialis brevis (FCRB) is a very rare anomalous muscle that is usually asymptomatic but may cause various pathologies, such as radial-sided wrist pain. The aim of this study was to determine the prevalence of FCRB in the Turkish population, its location, and sex differences. Forearm, wrist, and hand magnetic resonance images of 849 individuals aged 18-65 years were retrospectively evaluated in this study. The survey found an FCRB prevalence of 4%, with a prevalence of 3.6% among women and of 4.7% among men. However, the difference between the sexes was not statistically significant (p = 0.629). The origin of all 34 FCRBs identified was the distal third of the anterior aspect of the radius; the insertion site of 28 was the second metacarpal bone, whereas that of the remaining 6 was the os trapezium. In conclusion, the data of this study report the prevalence of FCRB for the first time in the Turkish population, which will contribute to radiological and surgical evaluations in the region and help in early and accurate diagnosis of various pathological conditions that may be caused by FCRB.

Prevalence and distribution of triticeal cartilage.

BACKGROUND: The triticeal cartilage can be found in the lateral thyrohyoid ligament. The triticeal cartilage may exist in different shapes and locations, may be present unilaterally or bilaterally, or absent. The study aims to determine the prevalence, distribution, level, shape, and the degree of ossification of the triticeal cartilage by using three-dimensional computed tomography angiography (CTA). MATERIALS AND METHODS: Computed tomography angiography images of 1450 patients (785 women and 665 men), obtained in the period from 1 January 2017 to 30 September 2019, were evaluated retrospectively. Any unilateral or bilateral presence or the absence of triticeal cartilage was recorded with its anatomical level, shape, and degree of ossification. RESULTS: At least one triticeal cartilage was found in the CTA images of 57.4% (833 out of 1450) patients. The prevalence was 51.3% in women (403 out of 785) and 64.7% in men (430 out of 665). Bilateral triticeal cartilages were more common compared to unilateral ones. Ossification was most commonly mild at a rate of 39.1%. A round-shaped triticeal cartilage was the most common form at a rate of 46.6%. Triticeal cartilage was detected at various intervertebral disc levels from the second and third cervical vertebrae to the level of the sixth cervical vertebra. CONCLUSIONS: Triticeal cartilage is common in the Turkish population and it should receive substantial attention from clinicians because it can be confused with calcified plaques and fractures of the superior horn of the thyroid cartilage. Therefore, for appropriate diagnoses and treatment, it is important to know the prevalence of triticeal cartilage with its distribution, intervertebral disc levels of location, shapes, and ossification degrees.

Thousands of induced germline mutations affecting immune cells identified by automated meiotic mapping coupled with machine learning.

Forward genetic studies use meiotic mapping to adduce evidence that a particular mutation, normally induced by a germline mutagen, is causative of a particular phenotype. Particularly in small pedigrees, cosegregation of multiple mutations, occasional unawareness of mutations, and paucity of homozygotes may lead to erroneous declarations of cause and effect. We sought to improve the identification of mutations causing immune phenotypes in mice by creating Candidate Explorer (CE), a machine-learning software program that integrates 67 features of genetic mapping data into a single numeric score, mathematically convertible to the probability of verification of any putative mutation-phenotype association. At this time, CE has evaluated putative mutation-phenotype associations arising from screening damaging mutations in ∼55% of mouse genes for effects on flow cytometry measurements of immune cells in the blood. CE has therefore identified more than half of genes within which mutations can be causative of flow cytometric phenovariation in Mus musculus The majority of these genes were not previously known to support immune function or homeostasis. Mouse geneticists will find CE data informative in identifying causative mutations within quantitative trait loci, while clinical geneticists may use CE to help connect causative variants with rare heritable diseases of immunity, even in the absence of linkage information. CE displays integrated mutation, phenotype, and linkage data, and is freely available for query online.

Mutual inhibition between Prkd2 and Bcl6 controls T follicular helper cell differentiation.

T follicular helper cells (TFH) participate in germinal center (GC) development and are necessary for B cell production of high-affinity, isotype-switched antibodies. In a forward genetic screen, we identified a missense mutation in Prkd2, encoding the serine/threonine kinase protein kinase D2, which caused elevated titers of immunoglobulin E (IgE) in the serum. Subsequent analysis of serum antibodies in mice with a targeted null mutation of Prkd2 demonstrated polyclonal hypergammaglobulinemia of IgE, IgG1, and IgA isotypes, which was exacerbated by the T cell-dependent humoral response to immunization. GC formation and GC B cells were increased in Prkd2-/- spleens. These effects were the result of excessive cell-autonomous TFH development caused by unrestricted Bcl6 nuclear translocation in Prkd2-/- CD4+ T cells. Prkd2 directly binds to Bcl6, and Prkd2-dependent phosphorylation of Bcl6 is necessary to constrain Bcl6 to the cytoplasm, thereby limiting TFH development. In response to immunization, Bcl6 repressed Prkd2 expression in CD4+ T cells, thereby committing them to TFH development. Thus, Prkd2 and Bcl6 form a mutually inhibitory positive feedback loop that controls the stable transition from naïve CD4+ T cells to TFH during the adaptive immune response.

Enhanced susceptibility to chemically induced colitis caused by excessive endosomal TLR signaling in LRBA-deficient mice.

LPS-responsive beige-like anchor (LRBA) protein deficiency in humans causes immune dysregulation resulting in autoimmunity, inflammatory bowel disease (IBD), hypogammaglobulinemia, regulatory T (Treg) cell defects, and B cell functional defects, but the cellular and molecular mechanisms responsible are incompletely understood. In an ongoing forward genetic screen for N-ethyl-N-nitrosourea (ENU)-induced mutations that increase susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice, we identified two nonsense mutations in Lrba Although Treg cells have been a main focus in LRBA research to date, we found that dendritic cells (DCs) contribute significantly to DSS-induced intestinal inflammation in LRBA-deficient mice. Lrba-/- DCs exhibited excessive IRF3/7- and PI3K/mTORC1-dependent signaling and type I IFN production in response to the stimulation of the Toll-like receptors (TLRs) 3, TLR7, and TLR9. Substantial reductions in cytokine expression and sensitivity to DSS in LRBA-deficient mice were caused by knockout of Unc93b1, a chaperone necessary for trafficking of TLR3, TLR7, and TLR9 to endosomes. Our data support a function for LRBA in limiting endosomal TLR signaling and consequent intestinal inflammation.

Synthesis, Biological Evaluation and Ligand Based Pharmacophore Modeling of New Aromatic Thiosemicarbazones as Potential Anticancer Agents.

Two series of new aromatic thiosemicarbazone derivatives were synthesized by condensation of N-(4-cyanophenyl)hydrazine carbothioamide (I) and N-(4-methylsulfanylphenyl)hydrazine carbothioamide (II) with appropriate aromatic aldehydes in order to investigate their antiviral and cytostatic potency. The chemical structures of all compounds were fully characterized by elemental analysis and spectroscopic techniques. The results of the bioassays indicated that compounds Id, Ie, If and IIf proved inhibitory against influenza virus A (EC50 = 13 - 27 µg/mL for strain H1N1 and 9.3 - 18 µg/mL for strain H3N2). Compounds Ig and IIg were the most cytostatic compounds with inhibition of HeLa cell proliferation at an IC50 = 0.3 µg/mL for Ig and 1.9 µg/mL for IIg. Especially, compound Ig showed the highest cytostatic activity with IC50 of 0.30, 0.70 and 2.50 µg/mL against HeLa, CEM and L1210 cell lines, respectively. This inhibition range was within the same order of magnitude as that for cisplatin. Furthermore, molecular modeling was carried out to examine the cytostatic activity and determine the best pharmacophore model as a guide for the design and development of potential prodrugs in future studies.

A viable hypomorphic Arnt2 mutation causes hyperphagic obesity, diabetes and hepatic steatosis.

Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) is a member of the basic helix-loop-helix/PER-ARNT-SIM (bHLH/PAS) transcription factor family. ARNT2 heterodimerizes with several members of the family, including single-minded homolog-1 (SIM1) and neuronal PAS domain protein 4 (NPAS4), primarily in neurons of the central nervous system. We screened 64,424 third-generation germline mutant mice derived from N-ethyl-N-nitrosourea (ENU)-mutagenized great-grandsires for weight abnormalities. Among 17 elevated body weight phenotypes identified and mapped, one strongly correlated with an induced missense mutation in Arnt2 using a semidominant model of inheritance. Causation was confirmed by CRISPR/Cas9 gene targeting to recapitulate the original ENU allele, specifying Arg74Cys (R74C). The CRISPR/Cas9-targeted (Arnt2R74C/R74C) mice demonstrated hyperphagia and increased adiposity as well as hepatic steatosis and abnormalities in glucose homeostasis. The mutant ARNT2 protein showed decreased transcriptional activity when coexpressed with SIM1. These findings establish a requirement for ARNT2-dependent genes in the maintenance of the homeostatic feeding response, necessary for prevention of obesity and obesity-related diseases.

The class I myosin MYO1D binds to lipid and protects against colitis.

Myosin ID (MYO1D) is a member of the class I myosin family. We screened 48,649 third generation (G3) germline mutant mice derived from N-ethyl-N-nitrosourea-mutagenized grandsires for intestinal homeostasis abnormalities after oral administration of dextran sodium sulfate (DSS). We found and validated mutations in Myo1d as a cause of increased susceptibility to DSS-induced colitis. MYO1D is produced in the intestinal epithelium, and the colitis phenotype is dependent on the nonhematopoietic compartment of the mouse. Moreover, MYO1D appears to couple cytoskeletal elements to lipid in an ATP-dependent manner. These findings demonstrate that MYO1D is needed to maintain epithelial integrity and protect against DSS-induced colitis.

Coexisting Primary Ovarian and Omental Hydatid Disease Mimicking an Ovarian Neoplasm: A Case Report.

Hydatid disease is a parasitic infection that most commonly affects the liver and lungs, although the disease can arise in any part of the body. Cysts may mimic many benign and malignant conditions. The diagnosis cannot be confirmed preoperatively in all cases. A 44-yr-old menopausal woman was admitted to the department of gynecology with complaints of abdominal distention. A fixed abdominopelvic mass was identified. Radiology revealed a 20-cm mass with branched septations and solid components. CA-125 level was 55 kU/L, and Risk of Malignancy Index-2 score was 880. These findings suggested the presence of an ovarian neoplasm, and laparotomy was performed. Cystic masses measuring 22 cm and 4 cm, originating from the omentum majus and left ovary, respectively, were found during surgery. Frozen-section analysis revealed hydatid disease. Infracolic omentectomy and total abdominal hysterectomy with bilateral salpingo-oopherectomy were performed. Results of a serum Echinococcus hemagglutination test performed immediately after surgery were negative. The patient was prescribed albendazole for 6 mo and discharged on the third postoperative day with no complaints. The incidence of hydatid disease in the female reproductive system is very rare; however, clinicians must be aware of this disease and take necessary precautions while operating because any spillage may lead to anaphylactic shock and increased risk of recurrence.

The prognostic significance of preoperative serum cancer antigen 15-3 levels in endometrial carcinomas.

OBJECTIVES: To determine the associations between serum cancer antigen 15-3 levels and prognostic factors in patients with endometrial carcinomas. Additionally, we investigated the clinical utility of serum cancer antigen 15-3 levels in the selection of low-risk patients with endometrioid type, tumor size less than 2 cm, myometrial invasion ≤50%, and histological grade 1-2. Methods: Ninety-six patients, who were surgically staged at  Ankara Yildirim Beyazit University, Ankara, Turkey, between 2007 and 2016, were retrospectively analyzed. Demographic, clinical, and surgical characteristics were retrieved from the patients' hospital records. A p less than 0.05 was considered significant. Results: Fifteen patients had advanced (≥Stage II) disease, 14 patients had Type 2 histology, 20 patients had Grade 3 tumors, 23 patients had lymphovascular space invasion, and 10 patients had positive lymph node involvement. Serum cancer antigen 15-3 levels were significantly higher in patients with advanced (≥Stage II) disease, Type 2 histology, Grade 3 tumors, lymphovascular space invasion, and positive lymph node involvement (p less than 0.05). Serum cancer antigen 15-3 levels were also significantly correlated with tumor size (p=0.006). Serum cancer antigen 15-3 levels were significantly lower (95% confidence interval: 0.57-0.79; p=0.03) in low-risk patients compared to other endometrial carcinoma patients. A cutoff of 25.0 IU/mL was used to identify high-risk patients with a specificity of 100%. Conclusion: Serum cancer antigen 15-3 levels significantly correlated with prognostic factors and were a useful diagnostic tool for endometrial carcinomas.

Impaired systolic blood pressure recovery and heart rate recovery after graded exercise in patients with metabolic syndrome.

The aim of this study was to evaluate and compare systolic blood pressure recovery and heart rate recovery (HRR) values obtained at various time intervals after maximal graded exercise treadmill testing between patients with metabolic syndrome (MS) and the controls without MS. To our knowledge, this is the first study indicating systolic blood pressure recovery (SBPR) impairment and its relations to HRR and other variables in this group of patients. The study population included 110 patients with MS (67 men, 43 women; mean age: 46 ±â€Š9 years) and 110 control subjects who did not meet the criteria for MS (58 men, 52 women; mean age: 44 ± 10 years). All patients were selected from nonobese, apparently healthy sedentary individuals who had the ability to perform maximum exercise testing. SBPR was assessed by calculating the ratio of systolic blood pressure (SBP) obtained in the third minute of the recovery period to either the peak-exercise SBP or the SBP in the first minute of the recovery period after graded exercise testing. HRR values were calculated by subtracting the HR at the first, second, third, fourth, and fifth minutes of the recovery period from the HR reached at peak exercise. There was no significant difference found between the 2 groups with respect to age and sex distribution. As expected, patients with MS had higher waist circumference, fasting plasma glucose and serum triglyceride, and lower high-density lipoprotein cholesterol compared with control subjects. All HRR values calculated in the first, second, third, fourth, and fifth minutes were significantly detected lower in the MS group compared with the control group (HRR 1st: 32 ± 10 vs 36 ± 11; P = 0.009; HRR 2nd: 47 ± 10 vs 51 ± 11; P = 0.02; HRR 3rd: 53 ± 11 vs 58 ± 12; P = 0.001; HRR 4th: 57 ± 11 vs 64 ± 12; P < 0.001; HRR 5th: 60 ± 16 vs 69 ± 15; P < 0.001). In addition, calculated mean values for SBPR1 and SBPR2 were >1 in patients with MS (1.01 ±â€Š0.2 vs 0.91 ± 0.1 and 1.01 ± 0.1 vs 0.94 ± 0.1) and these were statistically significant compared with the control group (P < 0.001 and P = 0.002, respectively). The existence of MS was found to be the only parameter that was independently and positively related to SBPR values in the study population. Our findings suggest that only the existence of MS itself, not the presence of any MS components, is independently associated with SBPRs. We are of the opinion that significantly impaired SBPR values, in addition to the decreased HRR values observed in this group of patients, such as those with MS, may especially help identify patients with potentially increased cardiovascular risk despite normal exercise stress testing findings.