Laurasian migration explains Gondwanan disjunctions: evidence from Malpighiaceae

Explanations for biogeographic disjunctions involving South America and Africa typically invoke vicariance of western Gondwanan biotas or long distance dispersal. These hypotheses are problematical because many groups originated and diversified well after the last known connection between Africa and South America (approximately 105 million years ago), and it is unlikely that "sweepstakes" dispersal accounts for many of these disjunctions. Phylogenetic analyses of the angiosperm clade Malpighiaceae, combined with fossil evidence and molecular divergence-time estimates, suggest an alternative hypothesis to account for such distributions. We propose that Malpighiaceae originated in northern South America, and that members of several clades repeatedly migrated into North America and subsequently moved via North Atlantic land connections into the Old World during episodes starting in the Eocene, when climates supported tropical forests. This Laurasian migration route may explain many other extant lineages that exhibit western Gondwanan distributions.     

Severity of Aortic Regurgitation Assessed by Digital Image Processing of Doppler Spectral Recordings

Visual estimates of the intensity of the regurgitant signal (RS) obtained by continuous-wave (CW) Doppler has been used as an indicator of the severity of aortic regurgitation (AR). This study was designed to test this concept quantitatively using digital image processing methods. Twenty-one patients with AR were studied, 14 of whom had concomitant mitral valve disease. Patients with aortic stenosis were excluded. By angiography, 10 patients had mild (grade 1 or 2), 5 had moderate (grade 3), and 6 severe (grade 4) AR. We digitized three well-defined AR envelopes and calculated the mean pixel intensity (MPI) of the RS and the systolic flow signal (SFS) using an offline computer analysis system developed in our laboratory. To negate the effects of different gain settings, the ratio of RS to SFS (RS/SFS ratio) was compared to angiographic grade of AR. Thus, each patient served as his own control. The mean RS/SFS ratio was 0.54 ± 0.42 SD (range 0.46-0.59) for mild AR, 0.76 ± 0.71 SD (range 0.65-0.82) for moderate AR, and 0.84 ± 0.52 (range 0.77-0.92) for severe AR. This RS/SFS ratio correlated well with angiographic severity of AR (r = 0.9). A ratio of > 0.6 identified patients with mild AR and < 0.6 correlated with moderate-to-severe. AR. We conclude that the ratio of the regurgitant to systolic flow CW Doppler signal is an accurate noninvasive indicator of AR severity.     

The effect of medroxyprogesterone acetate on gonadotropin secretion in girls with precocious puberty.

Plasma luteinizing hormone (LH) and follicle stimulating hormone (FSH) as detected by radioimmunoassay have been found to be present in prepubertal children and show a gradual rise until the onset of puberty. Children with idiopathic true precocious puberty have plasma gonadotropin levels which are appropriate for their advanced degree of sexual development. A potent progestational agent, 6-methyl-17-hydroxyprogesterone acetate or medroxyprogesterone has been used in the treatment of precocious puberty and will suppress its physical manifestations. In this study the effect of medroxyprogesterone on gonadotropin levels was investigated in seven girls with true precocious puberty. Plasma LH values were found to be significant lower in patients receiving this agent than in a group of normal prepubertal girls. FSH values did not differ from the control group. One patient was evaluated prior to treatment and showed decreasing levels of LH after therapy was begun. These data suggest that medroxyprogesterone may act on the pituitary-hypothalamic axis to suppress the pubertal levels of LH.     

Assessment of rat sciatic nerve function following acute implantation of high density utah slanted electrode array (25 electrodes/mm2) based on neural recordings and evoked muscle activity

Introduction: High density Utah slanted electrode arrays (HD‐USEAs) have been developed recently for intrafascicular access to submillimeter neural structures. Insertion of such high electrode density devices may cause nerve crush injury, counteracting the intended improved selective nerve fiber access. Methods: HD‐USEAs were implanted into sciatic nerves of anesthetized rats. Nerve function was assessed before and after HD‐USEA implantation by measuring changes in evoked muscle and nerve compound action potentials and single unit neuronal recordings. Results: Neural activity was recorded with over half of all implanted electrodes. Average decreases of 38%, 36%, and 13% in nerve, medial gastrocnemius, and tibialis anterior compound action potential amplitudes, respectively, were observed following array implantation. Only 1 of 8 implantations resulted in loss of all signals. Conclusions: These studies demonstrate that HD‐USEAs provide a useful neural interface without causing a nerve crush injury that would otherwise negate their use in acute preparations (<12 h). Muscle Nerve 50 : 417–424, 2014     

Loss of glucose 6-phosphate dehydrogenase function increases oxidative stress and glutaminolysis in metastasizing melanoma cells

The pentose phosphate pathway is a major source of NADPH for oxidative stress resistance in cancer cells but there is limited insight into its role in metastasis, when some cancer cells experience high levels of oxidative stress. To address this, we mutated the substrate binding site of glucose 6-phosphate dehydrogenase (G6PD), which catalyzes the first step of the pentose phosphate pathway, in patient-derived melanomas. G6PD mutant melanomas had significantly decreased G6PD enzymatic activity and depletion of intermediates in the oxidative pentose phosphate pathway. Reduced G6PD function had little effect on the formation of primary subcutaneous tumors, but when these tumors spontaneously metastasized, the frequency of circulating melanoma cells in the blood and metastatic disease burden were significantly reduced. G6PD mutant melanomas exhibited increased levels of reactive oxygen species, decreased NADPH levels, and depleted glutathione as compared to control melanomas. G6PD mutant melanomas compensated for this increase in oxidative stress by increasing malic enzyme activity and glutamine consumption. This generated a new metabolic vulnerability as G6PD mutant melanomas were more dependent upon glutaminase than control melanomas, both for oxidative stress management and anaplerosis. The oxidative pentose phosphate pathway, malic enzyme, and glutaminolysis thus confer layered protection against oxidative stress during metastasis.

The pentose phosphate pathway is an important source of NADPH for oxidative stress resistance (1–5). The oxidative branch of the pentose phosphate pathway contains two enzymes that generate NADPH from NADP⁺, glucose 6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (PGD) (SI Appendix, Fig. S1). NADPH is an important source of reducing equivalents for oxidative stress resistance because it is used by cells to convert oxidized glutathione (GSSG) to glutathione (GSH), an abundant redox buffer. Complete deficiency for G6PD is embryonic-lethal in mice (2, 6, 7) but hypomorphic G6PD mutations are common in certain human populations, perhaps because they protect against malaria (8, 9). These partial loss-of-function G6PD mutations are well tolerated in adults, though they sensitize red blood cells to hemolysis from oxidative stress under certain circumstances (10).Several studies have reported a lower incidence and mortality for certain cancers in people with hypomorphic mutations in G6PD (11–14), suggesting that cancer cells depend upon G6PD to manage oxidative stress. Cells experience high levels of oxidative stress during certain phases of cancer development and progression, including during metastasis (15–17). Antioxidant mechanisms thus promote the survival of cells during oncogenic transformation (18, 19) as well as during metastasis (15, 16). For example, relative to primary cutaneous tumors, metastasizing melanoma cells exhibit increased dependence upon the folate pathway (15), monocarboxylate transporter-1 (MCT1) (20), and glutathione peroxidase-4 (GPX4) (21), each of which directly or indirectly attenuate oxidative stress. By better understanding the mechanisms that confer oxidative stress resistance in cancer cells, it may be possible to develop pro-oxidant therapies that inhibit cancer progression by exacerbating the oxidative stress experienced by cancer cells.G6PD (22) or PGD deficiency (23–25) reduce the growth of some cancers, including melanoma, but G6PD deficiency has little effect on primary tumor formation by K-Ras–driven epithelial cancers (26). This is at least partly because loss of G6PD in these cancers leads to compensatory increases in the function of other NADPH-generating enzymes, including malic enzyme and isocitrate dehydrogenase (1, 27). Nonetheless, pentose phosphate pathway function may increase during metastasis (20, 28–30) and higher G6PD expression is associated with worse outcomes in several cancers (31–33), raising the question of whether metastasizing cells are particularly dependent upon G6PD. G6PD is not essential for metastasis in a breast cancer cell line but it reduces their capacity to form metastatic tumors (26).Melanoma cells show little evidence of oxidative stress in established primary tumors but exhibit increased levels of reactive oxygen species (ROS) and dependence upon antioxidant mechanisms during metastasis (15, 20, 21). To test if these cells are more dependent upon the pentose phosphate pathway during metastasis, we generated three G6PD mutant melanomas, including two patient-derived xenografts and one human melanoma cell line. Reduced G6PD function had little effect on the formation or growth of primary subcutaneous tumors but significantly increased ROS levels and reduced spontaneous metastasis. G6PD mutant melanomas compensated by increasing malic enzyme activity and glutamine consumption, both to increase oxidative stress resistance and to replenish tricarboxylic acid (TCA) cycle intermediates through anaplerosis. Melanoma cells thus have redundant layers of protection against oxidative stress during metastasis, including the abilities to alter fuel consumption and antioxidant pathway utilization.     

Power-Dependent Investigation of Photo-Response from GeSn-Based p-i-n Photodetector Operating at High Power Density

We report an investigation on the photo-response from a GeSn-based photodetector using a tunable laser with a range of incident light power. An exponential increase in photocurrent and an exponential decay of responsivity with increase in incident optical power intensity were observed at higher optical power range. Time-resolved measurement provided evidence that indicated monomolecular and bimolecular recombination mechanisms for the photo-generated carriers for different incident optical power intensities. This investigation establishes the appropriate range of optical power intensity for GeSn-based photodetector operation.     

Racial/Ethnic Differences in Emergency Department Utilization and Experience

BackgroundPrevious work has demonstrated racial/ethnic differences in emergency department (ED) utilization, but less is known about racial/ethnic differences in the experience of care received during an ED visit.ObjectiveTo examine differences in self-reported healthcare utilization and experiences with ED care by patients’ race/ethnicity.DesignAdult ED patients discharged to community (DTC) were surveyed (response rate: 20.25%) using the Emergency Department Patient Experience of Care (EDPEC) DTC Survey. Linear regression was used to estimate case-mix-adjusted differences in patient experience between racial/ethnic groups.Participants3122 survey respondents who were discharged from the EDs of 50 hospitals nationwide January–March 2016.Main MeasuresSix measures: getting timely care, doctor and nurse communication, communication about medications, receipt of sufficient information about test results, whether hospital staff discussed the patient’s ability to receive follow-up care, and willingness to recommend the ED.Key ResultsBlack and Hispanic patients were significantly more likely than White patients to report visiting the ED for an ongoing health condition (40% Black, 30% Hispanic, 28% White, p<0.001), report having visited an ED 3+ times in the last 6 months (26% Black, 25% Hispanic, 19% White, p<0.001), and report not having a usual source of care (19% Black, 19% Hispanic, 8% White, p<0.001). Compared with White patients, Hispanic patients more often reported that hospital staff talked with them about their ability to receive needed follow-up care (+7.2 percentile points, p=0.038) and recommended the ED (+7.2 points, p=0.037); Hispanic and Black patients reported better doctor and nurse communication (+6.4 points, p=0.008; +4 points, p=0.036, respectively).ConclusionsHispanic and Black ED patients reported higher ED utilization, lacked a usual source of care, and reported better experience with ED care than White patients. Results may reflect differences in care delivery by staff and/or different expectations of ED care among Hispanic and Black patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-021-06738-0.KEY WORDS: emergency department, patient experience, utilization, race, communication