In the version of this caption initially published, the cover artwork was credited to Erin Dewalt, based on imagery from the author, rather than stating that it was created by Michael B. Battles and the design was by Erin Dewalt. The error has been corrected in the HTML and PDF versions of the caption. ERRATUM In the version of this article initially published, the genus name 'Mycoplasma' was incorrectly used in place of the correct 'Mycobacterium'. The error has been corrected in the HTML and PDF versions of the article. ERRATUM npg

Background: COVID-19 is a highly infectious respiratory disease. No therapeutics have yet been proven effective for treating severe COVID-19. Objectives: To determine whether human umbilical cord mesenchymal stem cell infusion may be effective and safe for the treatment of severe COVID-19. Methods: Patients with severe COVID-19 were randomly divided into 2 groups: the standard treatment group and the standard treatment plus hUC-MSC infusion group. The incidence of progression from severe to critical illness, 28-day mortality, clinical symptom improvement, time to clinical symptom improvement, hematologic indicators including C-reactive protein, lymphocyte number, and interleukin 6, and imaging changes were observed and compared between the two groups. Measurements and main results: The incidence of progression from severe to critical illness and the 28-day mortality rate were 0 in the hUC-MSC treatment group, while 4 patients in the control group deteriorated to critical condition and received invasive ventilation; 3 of them died, and the 28-day mortality rate was 10.34%. In the hUC-MSC treatment group, the time to clinical improvement was shorter than that in the control group. Clinical symptoms of weakness and fatigue, shortness of breath, and low oxygen saturation obviously improved beginning on the third day of stem cell infusion and reached a significant difference on day 7. CRP and IL-6 levels were significantly lower from day 3 of infusion, the time for the lymphocyte count to return to the normal range was significantly faster, and lung inflammation absorption was significantly shorter on CT imaging in the hUC-MSC group than in the control group. Conclusions: Intravenous transplantation of hUC-MSCs is a safe and effective method that can be considered a salvage and priority treatment option for severe COVID-19.

Cholera remains an important global cause of morbidity and mortality, capable of causing periodic epidemic disease. Beginning in August 2008, a major cholera epidemic occurred in Zimbabwe, with 98,585 reported cases and 4,287 deaths. The dynamics of such outbreaks, particularly in nonestuarine regions, are not well understood. We explored the utility of mathematical models in understanding transmission dynamics of cholera and in assessing the magnitude of interventions necessary to control epidemic disease. Weekly data on reported cholera cases were obtained from the Zimbabwe Ministry of Health and Child Welfare (MoHCW) for the period from November 13, 2008 to July 31, 2009. A mathematical model was formulated and fitted to cumulative cholera cases to estimate the basic reproductive numbers R 0 and the partial reproductive numbers from all 10 provinces for the 2008–2009 Zimbabwe cholera epidemic. Estimated basic reproductive numbers were highly heterogeneous, ranging from a low value of just above unity to 2.72. Partial reproductive numbers were also highly heterogeneous, suggesting that the transmission routes varied by province; human-to-human transmission accounted for 41–95% of all transmission. Our models suggest that the underlying patterns of cholera transmission varied widely from province to province, with a corresponding variation in the amenability of outbreaks in different provinces to control measures such as immunization. These data underscore the heterogeneity of cholera transmission dynamics, potentially linked to differences in environment, socio-economic conditions, and cultural practices. The lack of traditional estuarine reservoirs combined with these estimates of R 0 suggest that mass vaccination against cholera deployed strategically in Zimbabwe and surrounding regions could prevent future cholera epidemics and eventually eliminate cholera from the region.

Obesity is a severe health problem in children, afflicting several organ systems including bone. However, the role of obesity on bone homeostasis and bone cell function in children has not been studied in detail. Here we used young mice fed a high-fat diet (HFD) to model childhood obesity and investigate the effect of HFD on the phenotype of cells within the bone marrow environment. Five-week-old male mice were fed a HFD for 3, 6, and 12 weeks. Decreased bone volume was detected after 3 weeks of HFD treatment. After 6 and 12 weeks, HFD-exposed mice had less bone mass and increased osteoclast numbers. Bone marrow cells, but not spleen cells, from HFD-fed mice had increased osteoclast precursor frequency, elevated osteoclast formation and bone resorption activity, as well as increased expression of osteoclastogenic regulators including RANKL, TNF, and PPAR-gamma. Bone formation rate and osteoblast and adipocyte numbers were also increased in HFD-fed mice. Isolated bone marrow cells also had a corresponding elevation in the expression of positive regulators of osteoblast and adipocyte differentiation. Our findings indicate that in juvenile mice, HFD-induced bone loss is mainly due to increased osteoclast bone resorption by affecting the bone marrow microenvironment. Thus, targeting osteoclast formation may present a new therapeutic approach for bone complications in obese children. 5Co-corresponding author: Xing, Lianping,

Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.

Abstract. Ozone pollution in China is influenced by meteorological processes on multiple scales. Using regression analysis and weather classification, we statistically assess the impacts of local and synoptic meteorology on daily variability in surface ozone in eastern China in summer during 2013–2018. In this period, summertime surface ozone in eastern China (20–42∘ N, 110–130∘ E) is among the highest in the world, with regional means of 73.1 and 114.7 µg m−3, respectively, in daily mean and daily maximum 8 h average. Through developing a multiple linear regression (MLR) model driven by local and synoptic weather factors, we establish a quantitative linkage between the daily mean ozone concentrations and meteorology in the study region. The meteorology described by the MLR can explain ∼43 % of the daily variability in summertime surface ozone across eastern China. Among local meteorological factors, relative humidity is the most influential variable in the center and south of eastern China, including the Yangtze River Delta and the Pearl River Delta regions, while temperature is the most influential variable in the north, covering the Beijing–Tianjin–Hebei region. To further examine the synoptic influence of weather conditions explicitly, six predominant synoptic weather patterns (SWPs) over eastern China in summer are objectively identified using the self-organizing map clustering technique. The six SWPs are formed under the integral influence of the East Asian summer monsoon, the western Pacific subtropical high, the Meiyu front, and the typhoon activities. On average, regionally, two SWPs bring about positive ozone anomalies (1.1 µg m−3 or 1.7 % and 2.7 µg m−3 or 4.6 %), when eastern China is under a weak cyclone system or under the prevailing southerly wind. The impact of SWPs on the daily variability in surface ozone varies largely within eastern China. The maximum impact can reach ±8 µg m−3 or ±16 % of the daily mean in some areas. A combination of the regression and the clustering approaches suggests a strong performance of the MLR in predicting the sensitivity of surface ozone in eastern China to the variation of synoptic weather. Our assessment highlights the importance of meteorology in modulating ozone pollution over China.

Abstract. Severe high ozone (O 3 ) episodes usually have close relations to synoptic systems. A regional continuous O 3 pollution episode was detected over the Yangtze River Delta (YRD) region in China during 7-12 August 2013, in which the O 3 concentrations in more than half of the cities exceeded the national air quality standard. The maximum hourly concentration of O 3 reached 167.1 ppb. By means of the observational analysis and the numerical simulation, the characteristics and the essential impact factors of the typical regional O 3 pollution are comprehensively investigated. The observational analysis shows that the atmospheric subsidence dominated by the western Pacific subtropical high plays a crucial role in the formation of high-level O 3 . The favorable weather conditions, such as extremely high temperature, low relative humidity and weak wind speed, caused by the abnormally strong subtropical high are responsible for the trapping and the chemical production of O 3 in the boundary layer. In addition, when the YRD cities are at the front of Typhoon Utor, the periphery circulation of typhoon system can enhance the downward airflows and cause worse air quality. However, when the typhoon system weakens the subtropical high, the prevailing southeasterly surface wind leads to the mitigation of the O 3 pollution. The integrated process rate (IPR) analysis incorporated in the Community Multi-scale Air Quality (CMAQ) model is applied to further illustrate the combined influence of subtropical high and typhoon system in this O 3 episode. The results show that the vertical diffusion (VDIF) and the gas-phase chemistry (CHEM) are two major contributors to O 3 formation. During the episode, the contributions of VDIF and CHEM to O 3 maintain the high values over the YRD region. On 10-12 August, the cities close to the sea are apparently affected by the typhoon system, with the contribution of VDIF increasing to 28.45 ppb h −1 in Shanghai and 19.76 ppb h −1 in Hangzhou. In contrast, the cities far away from the sea can hardly be affected by the periphery circulation of typhoon system. When the typhoon system significantly weakens the subtropical high, the contribution values of all individual processes decrease to a low level in all YRD cities. These results provide an insight for the O 3 pollution synthetically impacted by the western Pacific subtropical high and the tropical cyclone system.

With the increasing prevalence of obesity among children and adolescents, it is imperative to understand the implications of early diet-induced obesity on bone health. We hypothesized that cancellous bone of skeletally immature mice is more susceptible to the detrimental effects of a high fat diet (HFD) than mature mice, and that removing excess dietary fat will reverse these adverse effects. Skeletally immature (5 weeks old) and mature (20 weeks old) male C57BL/6J mice were fed either a HFD (60% kcal fat) or low fat diet (LFD; 10% kcal fat) for 12 weeks, at which point, the trabecular bone structure in the distal femoral metaphysis and third lumbar vertebrae were evaluated by micro-computed tomography. The compressive strength of the vertebrae was also measured. In general, the HFD led to deteriorations in cancellous bone structure and compressive biomechanical properties in both age groups. The HFD-fed immature mice had a greater decrease in trabecular bone volume fraction (BVF) in the femoral metaphysis, compared to mature mice (p=0.017 by 2-way ANOVA). In the vertebrae, however, the HFD led to similar reductions in BVF and compressive strength in the two age groups. When mice on the HFD were switched to a LFD (HFD:LFD) for an additional 12 weeks, the femoral metaphyseal BVF in immature mice showed no improvements, whereas the mature mice recovered their femoral metaphyseal BVF to that of age-matched lean controls. The vertebral BVF and compressive strength of HFD:LFD mouse bones, following diet correction, were equivalent to those of LFD:LFD mice in both age groups. These data suggest that femoral cancellous metaphyseal bone is more susceptible to the detrimental effects of HFD before skeletal maturity and is less able to recover after correcting the diet. Negative effects of HFD on vertebrae are less severe and can renormalize with LFD:LFD mice after diet correction, in both skeletally immature and mature animals.