By informing timely targeted treatments, rapid whole-genome sequencing can improve the outcomes of seriously ill children with genetic diseases, particularly infants in neonatal and pediatric ...intensive care units (ICUs). The need for highly qualified professionals to decipher results, however, precludes widespread implementation. We describe a platform for population-scale, provisional diagnosis of genetic diseases with automated phenotyping and interpretation. Genome sequencing was expedited by bead-based genome library preparation directly from blood samples and sequencing of paired 100-nt reads in 15.5 hours. Clinical natural language processing (CNLP) automatically extracted children's deep phenomes from electronic health records with 80% precision and 93% recall. In 101 children with 105 genetic diseases, a mean of 4.3 CNLP-extracted phenotypic features matched the expected phenotypic features of those diseases, compared with a match of 0.9 phenotypic features used in manual interpretation. We automated provisional diagnosis by combining the ranking of the similarity of a patient's CNLP phenome with respect to the expected phenotypic features of all genetic diseases, together with the ranking of the pathogenicity of all of the patient's genomic variants. Automated, retrospective diagnoses concurred well with expert manual interpretation (97% recall and 99% precision in 95 children with 97 genetic diseases). Prospectively, our platform correctly diagnosed three of seven seriously ill ICU infants (100% precision and recall) with a mean time saving of 22:19 hours. In each case, the diagnosis affected treatment. Genome sequencing with automated phenotyping and interpretation in a median of 20:10 hours may increase adoption in ICUs and, thereby, timely implementation of precise treatments.
To test the hypothesis that Mycoplasma ovipneumoniae is an important agent of the bighorn sheep (Ovis canadensis) pneumonia that has previously inevitably followed experimental commingling with ...domestic sheep (Ovis aries), we commingled M. ovipneumoniae–free domestic and bighorn sheep (n=4 each). One bighorn sheep died with acute pneumonia 90 days after commingling, but the other three remained healthy for >100 days. This unprecedented survival rate is significantly different (P=0.002) from that of previous bighorn-domestic sheep contact studies but similar to (P>0.05) bighorn sheep survival following commingling with other ungulates. The absence of epizootic respiratory disease in this experiment supports the hypothesized role of M. ovipneumoniae as a key pathogen of epizootic pneumonia in bighorn sheep commingled with domestic sheep.
To adhere and migrate, cells must be capable of applying cytoskeletal force to the extracellular matrix (ECM) through integrin receptors. However, it is unclear if connections between integrins and ...the ECM are immediately capable of transducing cytoskeletal contraction into migration force, or whether engagement of force transmission requires maturation of the adhesion. Here, we show that initial integrin-ECM adhesions become capable of exerting migration force with the recruitment of vinculin, a marker for focal complexes, which are precursors of focal adhesions. We are able to induce the development of focal complexes by the application of mechanical force to fibronectin receptors from inside or outside the cell, and we are able to extend focal complex formation to vitronectin receptors by the removal of c-Src. These results indicate that cells use mechanical force as a signal to strengthen initial integrin-ECM adhesions into focal complexes and regulate the amount of migration force applied to individual adhesions at localized regions of the advancing lamella.
Migrating cells extend protrusions, probing the surrounding matrix in search of permissive sites to form adhesions. We found that actin fibers polymerizing along the leading edge directed local ...protrusions and drove synchronous sideways movement of β₁ integrin adhesion receptors. These movements lead to the clustering and positioning of conformationally activated, but unligated, β₁ integrins along the leading edge of fibroblast lamellae and growth cone filopodia. Thus, rapid actin-based movement of primed integrins along the leading edge suggests a "sticky fingers" mechanism to probe for new adhesion sites and to direct migration.
Although mutations leading to a compromised nuclear envelope cause diseases such as muscular dystrophies or accelerated aging, the consequences of mechanically induced nuclear envelope ruptures are ...less known. Here, we show that nuclear envelope ruptures induce DNA damage that promotes senescence in non-transformed cells and induces an invasive phenotype in human breast cancer cells. We find that the endoplasmic reticulum (ER)-associated exonuclease TREX1 translocates into the nucleus after nuclear envelope rupture and is required to induce DNA damage. Inside the mammary duct, cellular crowding leads to nuclear envelope ruptures that generate TREX1-dependent DNA damage, thereby driving the progression of in situ carcinoma to the invasive stage. DNA damage and nuclear envelope rupture markers were also enriched at the invasive edge of human tumors. We propose that DNA damage in mechanically challenged nuclei could affect the pathophysiology of crowded tissues by modulating proliferation and extracellular matrix degradation of normal and transformed cells.
Display omitted
•Deformed nuclei and DNA damage are enriched at micro-invasive foci of breast cancer•TREX1 causes DNA damage in deformed nuclei upon nuclear envelope rupture events•TREX1 drives senescence in normal cells and an invasive phenotype in cancer cells•Nuclear envelope rupture events and DNA damage are observed in human tumors
Extreme nuclear deformations in dense microenvironments lead to repeated nuclear envelope rupture followed by TREX1-dependent chronic DNA damage. This triggers a partial EMT in malignant cells which might underlie tumor progression.
A lifetime of change
Measurements of total and basal energy in a large cohort of subjects at ages spanning from before birth to old age document distinct changes that occur during a human lifetime. ...Pontzer
et al
. report that energy expenditure (adjusted for weight) in neonates was like that of adults but increased substantially in the first year of life (see the Perspective by Rhoads and Anderson). It then gradually declined until young individuals reached adult characteristics, which were maintained from age 20 to 60 years. Older individuals showed reduced energy expenditure. Tissue metabolism thus appears not to be constant but rather to undergo transitions at critical junctures. —LBR
How metabolism and energy expenditure change over the human life span.
Total daily energy expenditure (“total expenditure”) reflects daily energy needs and is a critical variable in human health and physiology, but its trajectory over the life course is poorly studied. We analyzed a large, diverse database of total expenditure measured by the doubly labeled water method for males and females aged 8 days to 95 years. Total expenditure increased with fat-free mass in a power-law manner, with four distinct life stages. Fat-free mass–adjusted expenditure accelerates rapidly in neonates to ~50% above adult values at ~1 year; declines slowly to adult levels by ~20 years; remains stable in adulthood (20 to 60 years), even during pregnancy; then declines in older adults. These changes shed light on human development and aging and should help shape nutrition and health strategies across the life span.
The Western Pacific Region has one of the fastest-growing populations of older adults (≥ 65 years) globally, among whom tuberculosis (TB) poses a particular concern. This study reports country case ...studies from China, Japan, the Republic of Korea, and Singapore reflecting on their experiences in managing TB among older adults.
Across all four countries, TB case notification and incidence rates were highest among older adults, but clinical and public health guidance focused on this population was limited. Individual country reports illustrated a range of practices and challenges. Passive case finding remains the norm, with limited active case finding (ACF) programs implemented in China, Japan, and the Republic of Korea. Different approaches have been trialled to assist older adults in securing an early diagnosis, as well as adhering to their TB treatment. All countries emphasised the need for person-centred approaches that include the creative application of new technology and tailored incentive programs, as well as reconceptualisation of how we provide treatment support. The use of traditional medicines was found to be culturally entrenched among older adults, with a need for careful consideration of their complementary use. TB infection testing and the provision of TB preventive treatment (TPT) were underutilised with highly variable practice.
Older adults require specific consideration in TB response policies, given the burgeoning aging population and their high TB risk. Policymakers, TB programs and funders must invest in and develop locally contextualised practice guidelines to inform evidence-based TB prevention and care practices for older adults.
We studied onshore sediment cores obtained from a coastal marsh on the south coast of Beppu Bay, northern Kyushu Island, Japan, to ascertain whether prehistoric intraplate earthquakes in the bay had ...generated tsunamis, and to establish a chronology and recurrence intervals for these earthquakes. The latter had been inferred from investigations on shallow offshore faults, but the timing of the fault movements has large uncertainties. We identified five sand layers in the up to 8.8 m long sedimentary sequence, which is mainly composed of non-marine organic-rich mud and marine organic-poor mud. Most sand layers, 1–20 cm thick, exhibit sharp upper and lower contacts with the surrounding muds, implying that they were deposited by sudden events. The sand layers are geochemically distinct, with peaks in Si, K, Ca, Ti, Mn, Fe, and Sr, and diatom assemblages dominated by brackish–marine and marine species. This suggests that the sand came from the sea bottom and/or shore rather than from the freshwater marsh. Based on radiocarbon age modeling, the depositional ages of these sand layers are: 3270–3450 cal yr BP, 4250–4510 cal yr BP, 4970–5280 cal yr BP, 5750–6750 cal yr BP, and 6430–7070 cal yr BP. The oldest deposit is inferred to record a tsunami associated with the 7.3 ka caldera-forming eruption of the Kikai volcano, southern Japan. Thus, we exclude it from the calculation of the recurrence interval of tsunamigenic intraplate earthquakes in the bay. Recurrence is approximately 460–1850 years, including the 1596 CE Keicho Bungo earthquake and a fault rupture 1700–2200 years ago, which have been reported in studies on ruptures of shallow offshore strike-slip and normal faults. Brackish–marine and marine species dominate the fossil diatom assemblages in the upper muddy sand layer (younger than 2750–2870 cal yr BP) above the non-marine organic-rich mud, implying that the muddy sand was deposited in an inner bay or tidal flat environment. The facies change from non-marine to marine sediments after 2750–2870 cal yr BP cannot be explained by a change in the regional sea level because the latter has fallen in the last 6000 years. Therefore, the most likely interpretation for this environmental change is a local coseismic subsidence of the marsh, probably attributed to a rupture of the active fault located south of the marsh. This study is the first to report on recurrent tsunamigenic intraplate earthquakes based on research of onshore tsunami deposits, and suggests that investigating tsunami deposits can contribute to an assessment of tsunami risks for intraplate earthquakes elsewhere.
•Five tsunami layers were identified in ca. 8000 years old sedimentary sequences.•Four of them are linked with prehistoric intraplate earthquakes in Beppu Bay.•One of them was due to a tsunami generated by the 7.3 ka Kikai Volcano eruption.•Interval of tsunamigenic intraplate earthquakes in Beppu Bay is 460–1850 years.•Local coseismic subsidence probably occurred about 2750–2870 yr BP.
External-beam radiation therapy (RT) is standard of care (SOC) for pain relief of symptomatic bone metastases. We aimed to evaluate the efficacy of radiation to asymptomatic bone metastases in ...preventing skeletal-related events (SRE).
In a multicenter randomized controlled trial, adult patients with widely metastatic solid tumor malignancies were stratified by histology and planned SOC (systemic therapy or observation) and randomly assigned in a 1:1 ratio to receive RT to asymptomatic high-risk bone metastases or SOC alone. The primary outcome of the trial was SRE. Secondary outcomes included hospitalizations for SRE and overall survival (OS).
A total of 78 patients with 122 high-risk bone metastases were enrolled between May 8, 2018, and August 9, 2021, at three institutions across an affiliated cancer network in the United States. Seventy-three patients were evaluable for the primary end point. The most common primary cancer types were lung (27%), breast (24%), and prostate (22%). At 1 year, SRE occurred in one of 62 bone metastases (1.6%) in the RT arm and 14 of 49 bone metastases (29%) in the SOC arm (
< .001). There were significantly fewer patients hospitalized for SRE in the RT arm compared with the SOC arm (0
4,
= .045). At a median follow-up of 2.5 years, OS was significantly longer in the RT arm (hazard ratio HR, 0.49; 95% CI, 0.27 to 0.89;
= .018), which persisted on multivariable Cox regression analysis (HR, 0.46; 95% CI, 0.23 to 0.85;
= .01).
Radiation delivered prophylactically to asymptomatic, high-risk bone metastases reduced SRE and hospitalizations. We also observed an improvement in OS with prophylactic radiation, although a confirmatory phase III trial is warranted.
Cell interactions with the extracellular matrix (ECM) can regulate multiple cellular activities and the matrix itself in dynamic, bidirectional processes. One such process is local proteolytic ...modification of the ECM. Invadopodia of tumor cells are actin-rich proteolytic protrusions that locally degrade matrix molecules and mediate invasion. We report that a novel high-density fibrillar collagen (HDFC) matrix is a potent inducer of invadopodia, both in carcinoma cell lines and in primary human fibroblasts. In carcinoma cells, HDFC matrix induced formation of invadopodia via a specific integrin signaling pathway that did not require growth factors or even altered gene and protein expression. In contrast, phosphoproteomics identified major changes in a complex phosphosignaling network with kindlin2 serine phosphorylation as a key regulatory element. This kindlin2-dependent signal transduction network was required for efficient induction of invadopodia on dense fibrillar collagen and for local degradation of collagen. This novel phosphosignaling mechanism regulates cell surface invadopodia via kindlin2 for local proteolytic remodeling of the ECM.
PDF
