Human female pelvic development
Growth and development of the human pelvis from birth to 80 years of age. Image courtesy of MorphoLab (Anthropological Institute, University of Zurich, Switzerland).
The obstetrical dilemma hypothesis states that the size and shape of the human female pelvis represent a compromise between the need for a wide pelvis to give birth to large-brained offspring and the need for a narrow pelvis for efficient bipedal locomotion. This hypothesis has been recently challenged on multiple grounds. Alik Huseynov et al. (pp. 5227–5232) propose a modified obstetrical dilemma hypothesis, according to which pelvic structure changes over a female’s lifetime to accommodate changing obstetric needs. To test this hypothesis, the authors examined pelvic development using computed tomography measurements from 275 individuals from late fetal stages to 95 years of age. Beginning at approximately 10 years of age, pelvic development diverged substantially between males and females, resulting in wide, obstetrically favorable birth canals in females by approximately age 25. The period of greatest sexual dimorphism in pelvic structure coincided with the period of maximum fertility, approximately 25 to 30 years of age. Around age 40 to 45 pelvic development in females resumed a trajectory similar to that in males, with a consequent reduction in birth canal dimensions. The authors suggest that these developmental changes might be linked to hormonal changes during puberty and prior to menopause. — B.D.
Data visualization helps unravel brain tumors
The imperfect match between glioma histological diagnosis (colors) and molecular similarity (distribution).
Since the 1920s, brain tumors have been classified using histological changes that differentiate tumors from healthy cells. This approach has expanded to include molecular classification systems based on characteristics ranging from specific genomic mutations to predictors of chemotherapy success. To help integrate these strategies for clinical use, Hamid Bolouri et al. (pp. 5394–5399) developed a technique to synthesize large and disparate datasets and identify similarities across numerous patients. The authors’ approach relies on visualizing sample similarity using multidimensional scaling, a statistical tool that characterizes correlations in the data as distances in space. Analyzed in this manner, seemingly unrelated factors cluster together on plots, pointing to potentially clinically significant connections. Targeting genome-wide single nucleotide alterations, copy number alterations, DNA methylation, and RNA expression, the authors applied the technique to a combined dataset of glioblastoma and lower grade glioma genomic maps from the Cancer Genome Atlas, a repository of human cancer genome sequences. The approach revealed that the traditional histologic approach to classifying gliomas imperfectly predicts the molecular composition of these tumors. According to the authors, sample similarity plots help uncover tumor populations that are enriched in specific therapeutic molecular targets. — T.J.
Multiplex nanopore DNA sequencing by synthesis
Chip for nanopore synthesis-based DNA sequencing.
Single-molecule nanopore DNA sequencing by synthesis (SBS) involves the identification of distinctly tagged DNA nucleotides as the tags pass through the pore of an ion channel during enzyme-catalyzed template-directed DNA synthesis. To hone the nanopore SBS technique, Carl Fuller et al. (pp. 5233–5238) fashioned a nanopore array composed of α-hemolysin channels that were coupled to a DNA-synthesizing enzyme with high staying power, bound to a primed DNA template, and embedded in lipid bilayers on an electronic chip bearing multiple electrodes. The addition of distinct custom-designed polymer-tagged nucleotides to the nanopore array triggers DNA synthesis. By blocking the channel’s ionic current to different extents, the tags provide a readout of the template sequence in real time with single-base resolution; after each catalytic step, the tags exit the pore and end the current blockade, allowing continued DNA synthesis that enables sequence determination. Tethering the sequencing enzyme to nanopores and arraying nanopore sensors on the chip together enabled simultaneous, rapid, and high-resolution sequencing of long stretches of multiple DNA strands. Though the precise sequencing rate and accuracy of the improved technique remain to be established, the authors suggest that the method might represent a prototype high-throughput sequencing approach with applications in precision medicine, pending further improvements. Such advances may include improved DNA-synthesizing enzymes and integrated circuits with increased number of electrodes, according to the authors. — P.N.
Designing cell-targeted drugs
The hormone erythropoietin increases red blood cell (RBC) production and is used to treat anemia caused by chronic kidney disease or cancer chemotherapy. In addition to targeting receptors on RBC precursors, the hormone binds to receptors on platelets and other cell types, thereby causing side effects such as life-threatening blood clots. To address this problem, Devin Burrill et al. (pp. 5245–5250) mutated erythropoietin to weaken the molecule’s affinity for receptors on nontargeted cell types. The authors tethered the hormone to an antibody fragment that targets glycophorin A, a molecule found specifically on the surface of RBC precursors. Within 4 days of being injected into mice, the engineered protein stimulated more than a 10% increase in the number of newly formed RBCs called reticulocytes, whereas the total platelet count showed little or no change at any dose. By contrast, darbepoetin—a clinically approved synthetic form of erythropoietin—showed a similar effect on reticulocytes, but caused platelet counts to significantly increase from baseline at all tested doses. The findings demonstrate that rational drug design can improve the cell type specificity of erythropoietin, potentially allowing for safe administration of higher doses of the drug. According to the authors, this approach could reduce side effects caused by a broad range of protein therapeutics. — J.W.
Ape malaria vectors and host specificity
Many parasites related to Plasmodium falciparum, a causal agent of human malaria, have been found in African great apes. The reasons for the high host specificity of these parasites are unclear. To identify the vectors responsible for Plasmodium transmission in apes and determine their role in the parasites’ host specificity, Boris Makanga et al. (pp. 5329–5334) conducted an entomological survey over 15 months in two natural parks in Gabon. The authors collected 2,415 female anopheline mosquitoes belonging to 18 species, and found only three species infected with ape Plasmodium—Anopheles vinckei, Anopheles moucheti, and Anopheles marshallii—with A. vinckei having the highest prevalence of infection. The authors found that these vector species’ salivary glands contained parasites, confirming their role in transmission. All three mosquito species were able to transmit parasites of chimpanzees and gorillas, suggesting that the parasites’ strong host specificity is not due to a specific association between vector species and vertebrate host. Using human landing catches, where mosquitoes are collected off the exposed limbs of human collectors, the authors found that the three vector species could feed on humans. According to the authors, the three species could act as bridge vectors between apes and humans and are not responsible for Plasmodium’s host specificity. — S.R.
Cognition and sex differences in circadian rhythms
Circadian rhythms affect brain function via the sleep–wake cycle, but whether the effects differ between men and women is unknown. Nayantara Santhi et al. (pp. E2730–E2739) compared the effects of circadian phase and sleep–wake cycles on the performance of men and women in several cognitive tasks. During a 10-day sleep protocol, the sleep–wake cycles of 16 men and 18 women were rescheduled to a 28-hour day. With no external daylight or time cues, the brain’s 24-hour clock desynchronized from the sleep–wake schedule, similar to the effect observed during shiftwork. Every 3 hours when participants were awake, the authors administered three subjective assessments, such as reported sleepiness, and 13 objective cognitive performance tests, including attention and motor control. In both men and women, the effects of circadian phase and awake time were stronger for subjective assessments than for performance in objective tests. The circadian effect on cognition, however, was larger in women than in men, such that women were more impaired during the early morning hours. While many factors affect sleep and cognition, the findings provide insight into factors that may contribute to cognitive differences, and future studies should use tests designed to account for any existing baseline differences in task performance between the sexes, according to the authors. — T.H.D.
Vascular damage and retinal diabetic neuropathy
Sections of human eyes with diabetes and no retinopathy (Left) and age-matched controls (Right). Ganglion cells and nerve fiber layer are in green and nuclei are in blue.
Retinal diabetic neuropathy causes visual impairment through the degeneration of neurons in the retina. Combining evidence from patients and mouse models, Elliott Sohn et al. (pp. E2655–E2664) demonstrate that retinal diabetic neuropathy causes progressive neuronal damage before signs of vascular abnormalities appear. Using an imaging technique called optical coherence tomography, the authors found that the nerve fiber layer and ganglion cell/inner plexiform layer became progressively thinner over a 4-year period in 45 patients with type 1 diabetes. The retinal tissue layers were also thinner in six donor eyes from deceased diabetic individuals, compared with nondiabetic controls, even though retinal capillary density was not different between the two groups. Similarly, mouse models of type 1 and type 2 diabetes showed significant, progressive thinning of the two tissue layers, but no vascular abnormalities, compared with nondiabetic control mice. Taken together, the results suggest that retinal diabetic neuropathy is a progressive condition that precedes diabetes-induced vascular changes. According to the authors, the findings could aid the development of treatment options for retinal diabetic neuropathy and potentially other forms of diabetic eye disease. — J.W.