Jason Xu, Samson Koelle, Peter Guttorp, Chuanfeng Wu, Cynthia Dunbar, Janis L. Abkowitz, Vladimir N. Minin.

Source: The Annals of Applied Statistics, Volume 13, Number 4, 2091--2119.

Abstract:
Single-cell lineage tracking strategies enabled by recent experimental technologies have produced significant insights into cell fate decisions, but lack the quantitative framework necessary for rigorous statistical analysis of mechanistic models describing cell division and differentiation. In this paper, we develop such a framework with corresponding moment-based parameter estimation techniques for continuous-time, multi-type branching processes. Such processes provide a probabilistic model of how cells divide and differentiate, and we apply our method to study hematopoiesis , the mechanism of blood cell production. We derive closed-form expressions for higher moments in a general class of such models. These analytical results allow us to efficiently estimate parameters of much richer statistical models of hematopoiesis than those used in previous statistical studies. To our knowledge, the method provides the first rate inference procedure for fitting such models to time series data generated from cellular barcoding experiments. After validating the methodology in simulation studies, we apply our estimator to hematopoietic lineage tracking data from rhesus macaques. Our analysis provides a more complete understanding of cell fate decisions during hematopoiesis in nonhuman primates, which may be more relevant to human biology and clinical strategies than previous findings from murine studies. For example, in addition to previously estimated hematopoietic stem cell self-renewal rate, we are able to estimate fate decision probabilities and to compare structurally distinct models of hematopoiesis using cross validation. These estimates of fate decision probabilities and our model selection results should help biologists compare competing hypotheses about how progenitor cells differentiate. The methodology is transferrable to a large class of stochastic compartmental and multi-type branching models, commonly used in studies of cancer progression, epidemiology and many other fields.

Jie Yen Fan, Kais Hamza, Peter Jagers, Fima Klebaner.

Source: Bernoulli, Volume 26, Number 2, 893--926.

Abstract:
We consider a family of general branching processes with reproduction parameters depending on the age of the individual as well as the population age structure and a parameter $K$, which may represent the carrying capacity. These processes are Markovian in the age structure. In a previous paper ( Proc. Steklov Inst. Math. 282 (2013) 90–105), the Law of Large Numbers as $K o infty $ was derived. Here we prove the central limit theorem, namely the weak convergence of the fluctuation processes in an appropriate Skorokhod space. We also show that the limit is driven by a stochastic partial differential equation.

The chic sneaks are part of Zappos' massive Cyber Monday sale.

They’re already going out of stock.

French translation of the BIS press release about the BIS Quarterly Review, December 2018

Mitochondrial fission catalyzed by dynamin-related protein 1 (Drp1) is necessary for mitochondrial biogenesis and maintenance of healthy mitochondria. However, excessive fission has been associated with multiple neurodegenerative disorders, and we recently reported that mice with smaller mitochondria are sensitized to ischemic stroke injury. Although pharmacological Drp1 inhibition has been put forward as neuroprotective, the specificity and mechanism of the inhibitor used is controversial. Here, we provide genetic evidence that Drp1 inhibition is neuroprotective. Drp1 is activated by dephosphorylation of an inhibitory phosphorylation site, Ser637. We identify Bβ2, a mitochondria-localized protein phosphatase 2A (PP2A) regulatory subunit, as a neuron-specific Drp1 activator in vivo. Bβ2 KO mice of both sexes display elongated mitochondria in neurons and are protected from cerebral ischemic injury. Functionally, deletion of Bβ2 and maintained Drp1 Ser637 phosphorylation improved mitochondrial respiratory capacity, Ca²⁺ homeostasis, and attenuated superoxide production in response to ischemia and excitotoxicity in vitro and ex vivo. Last, deletion of Bβ2 rescued excessive stroke damage associated with dephosphorylation of Drp1 S637 and mitochondrial fission. These results indicate that the state of mitochondrial connectivity and PP2A/Bβ2-mediated dephosphorylation of Drp1 play a critical role in determining the severity of cerebral ischemic injury. Therefore, Bβ2 may represent a target for prophylactic neuroprotective therapy in populations at high risk of stroke.

SIGNIFICANCE STATEMENT With recent advances in clinical practice including mechanical thrombectomy up to 24 h after the ischemic event, there is resurgent interest in neuroprotective stroke therapies. In this study, we demonstrate reduced stroke damage in the brain of mice lacking the Bβ2 regulatory subunit of protein phosphatase 2A, which we have shown previously acts as a positive regulator of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). Importantly, we provide evidence that deletion of Bβ2 can rescue excessive ischemic damage in mice lacking the mitochondrial PKA scaffold AKAP1, apparently via opposing effects on Drp1 S637 phosphorylation. These results highlight reversible phosphorylation in bidirectional regulation of Drp1 activity and identify Bβ2 as a potential pharmacological target to protect the brain from stroke injury.

Microglial cells are considered as sensors of brain pathology by detecting any sign of brain lesions, infections, or dysfunction and can influence the onset and progression of neurological diseases. They are capable of sensing their neuronal environment via many different signaling molecules, such as neurotransmitters, neurohormones and neuropeptides. The neuropeptide VGF has been associated with many metabolic and neurological disorders. TLQP21 is a VGF-derived peptide and has been shown to signal via C3aR1 and C1qBP receptors. The effect of TLQP21 on microglial functions in health or disease is not known. Studying microglial cells in acute brain slices, we found that TLQP21 impaired metabotropic purinergic signaling. Specifically, it attenuated the ATP-induced activation of a K⁺ conductance, the UDP-stimulated phagocytic activity, and the ATP-dependent laser lesion-induced process outgrowth. These impairments were reversed by blocking C1qBP, but not C3aR1 receptors. While microglia in brain slices from male mice lack C3aR1 receptors, both receptors are expressed in primary cultured microglia. In addition to the negative impact on purinergic signaling, we found stimulating effects of TLQP21 in cultured microglia, which were mediated by C3aR1 receptors: it directly evoked membrane currents, stimulated basal phagocytic activity, evoked intracellular Ca²⁺ transient elevations, and served as a chemotactic signal. We conclude that TLQP21 has differential effects on microglia depending on C3aR1 activation or C1qBP-dependent attenuation of purinergic signaling. Thus, TLQP21 can modulate the functional phenotype of microglia, which may have an impact on their function in health and disease.

SIGNIFICANCE STATEMENT The neuropeptide VGF and its peptides have been associated with many metabolic and neurological disorders. TLQP21 is a VGF-derived peptide that activates C1qBP receptors, which are expressed by microglia. We show here, for the first time, that TLQP21 impairs P2Y-mediated purinergic signaling and related functions. These include modulation of phagocytic activity and responses to injury. As purinergic signaling is central for microglial actions in the brain, this TLQP21-mediated mechanism might regulate microglial activity in health and disease. We furthermore show that, in addition to C1qBP, functional C3aR1 responses contribute to TLQP21 action on microglia. However, C3aR1 responses were only present in primary cultures but not in situ, suggesting that the expression of these receptors might vary between different microglial activation states.

An independent survey finds that although NPS's annual budget is around $3 billion, Americans are willing to pay much more

A St. John's cardiologist says public health restrictions put in place under the COVID-19 pandemic, while justified, may be harming cardiac patients whose procedures have been postponed indefinitely as well as heart patients who are avoiding hospitals.

Acute myeloid leukemia is an aggressive cancer of the blood-forming system. It affects the hematopoietic stem cells, or blood stem cells, of various white blood cells and of the red blood cells and platelets.

Baltimore Orioles outfielder and first baseman Trey Mancini revealed Tuesday he is in the midst of six months of chemotherapy as he fights Stage III colon cancer.

An idea that began when a classicist went to a brewery to sip beers and ponder the history of hops has brought to life an ancient ale.

Where are they from? Why are they there? Crates full of steel-toe boots showed up at the Yellowknife dump last week. Now they're almost gone.

Hanna Jovin and Adrian Morphy say many, including themselves, have been experiencing strange and vivid dreams since the pandemic began and the pair decided to illustrate and share them on social media.

The hoarders, the deliverers and what the coronavirus says about class in America.

SOLIDWORKS Electrical Schematic has added many new features this release to make completing electrical design projects easier than ever. The new Project Preview option, accessed from the Project Manager, lets you review a projects’ contents prior to opening it.  This

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OM Guatemala distributes more than 1,000 pairs of shoes at local primary schools.

The smiles of children are a great motivation to keep on working for the team members of OM Guatemala.

A Fin24 user looks to an expert for help in improving his credit score by paying off his debt.

We visit the KNVB to learn about UEFA's technical exchange initiative.

We see how fair play and the integration of players from different backgrounds is reaping success in Schleswig-Holstein.

IRAQ’S prime ministerial merry-go-round continues to spin apace. Spy chief Mustafa al-Kadhimi, director of the country’s National Intelligence Service, is now the third prime minister designate this year, following the withdrawal of the two previous prospective candidates.

In a village in Serbia, OM workers see Roma believers reaching Roma, encouraging them to let God put a new song in their mouths.

Strimmers, bonfires and netting are among garden hazards that can harm hedgehogs, so take precautions during Hedgehog Awareness Week and beyond.

The only way an ed-tech company can have a meaningful impact in schools is by addressing a specific problem and offering a real solution.

It’s not that I would be without the pyramids. Nor do I think that the Taj Mahal is a waste of good stone. These tombs, monuments to the departed are treasures beyond price. But can you name the pharaohs or the Mughal empress whose death they mark? No, nor can I without the help of Google.

The contemporary art space Cample Line has been set up amongst the fields and agricultural vistas of Dumfriesshire for three years now. Occupying what was once a set of three single-storey mill workers cottages, before it was knocked through and given a second storey in the Victorian period, it will open for the 2020 season later this month with a somewhat aptly themed exhibition – “Acts for placing woollen and linen” - by the American conceptual artist Helen Mirra, whose strong socio-envi

The new Netflix series "House of Cards" features a ruthless congressman as he spearheads the renewal of a fantasy Elementary and Secondary Education Act.

The UEFA Study Group Scheme - through which Europe's national associations exchange technical know-how for European football's well-being - has completed a successful fourth season.

Delayed umbilical cord clamping in premature infants has been associated with decreased rates of intraventricular hemorrhage; however, the mechanisms that explain this finding have not been described.

Premature infants with delayed umbilical cord clamping have improved superior vena cava blood flow over the first days of life. This may provide one of the mechanism(s) by which this technique reduces the incidence in intraventricular hemorrhage in this at-risk population. (Read the full article)

The association of retinal hemorrhages (RHs) with abusive head trauma (AHT) is robust; 46% to 100% RHs are reported in AHT. There is potential selection bias with risk of circular reasoning because the majority of studies describing RH focus on AHT.

This is the first prospective observational study defining prevalence and distribution of RH in critically ill children excluding those with AHT. Severe multilayered RH were rare and observed in children with accidental fatal head injury, severe coagulopathy, severe sepsis, or a combination of these factors. (Read the full article)

Infantile hemangiomas have a period of rapid growth in early infancy. Most hemangioma growth is completed by 5 months of age, but the majority of patients are not seen by a specialist until after the growth phase is complete.

The most rapid hemangioma growth is between 1 and 2 months of life, much earlier than previously believed. Patients with high-risk hemangiomas should be followed closely, and treatment initiation should be considered before or during the most rapid growth phase. (Read the full article)

Although previous studies indicate that perinatal factors are associated with altered neurodevelopment, data on the association between ischemic-hypoxic conditions and attention-deficit/hyperactivity disorder in children are sparse.

This study demonstrates that preeclampsia, birth asphyxia, and respiratory distress syndrome are independently associated with increased risk of attention-deficit/hyperactivity disorder in a large population-based study. (Read the full article)

Although the metabolic syndrome is associated with obesity, not all obese children have insulin resistance and metabolic syndrome, and nonobese children may develop these abnormalities. Associated factors have not been well described.

There was a 6.6% prevalence of nonobese children who were insulin-resistant, associated with a family history of hypertension. There was a 21.3% prevalence of obese who were not insulin-resistant, associated with a low waist circumference. (Read the full article)

The systemic nonselective β-blocker propranolol hydrochloride is increasingly used as first-line management for infantile hemangiomas. Superficial nonulcerating lesions do not require systemic medications. Case series have suggested the efficacy of timolol; however, its safety has been questioned.

This randomized controlled trial indicates that timolol maleate 0.5% gel is a well-tolerated, safe, and effective treatment of superficial infantile hemangiomas. (Read the full article)

Retinal hemorrhage (RH) is an important sign of pediatric abusive head trauma. Raised intracranial pressure (ICP) is sometimes proposed as an alternate cause of RH in children being evaluated for possible child abuse.

Nontraumatic, markedly elevated ICP rarely causes RH in children. When it does, RH are superficial intraretinal and located adjacent to a swollen optic nerve head. This pattern does not match the widespread pattern seen in abusive head trauma. (Read the full article)

Etiology and timing of onset of neonatal hypoxic-ischemic encephalopathy continue to be controversial. Previous studies suggest antepartum events are the main contributing factors, but have used a broad definition of encephalopathy and included infants with genetic, congenital, and developmental abnormalities.

Our study suggests that when strict criteria defining hypoxic-ischemic encephalopathy are applied with supporting neuroimaging evidence of an acute hypoxic-ischemic insult, intrapartum events are the final and necessary pathway leading to this condition. (Read the full article)

Cranial ultrasound is routinely used in identifying cerebral abnormalities in premature infants. Grade III and IV intraventricular hemorrhages, cystic periventricular leukomalacia, and late ventriculomegaly are all known predictors of adverse neurodevelopmental sequelae in these infants.

We reviewed neurodevelopmental outcomes among 2414 extreme preterm infants. Infants with grades I and II intraventricular hemorrhage had increased rates of neurosensory impairment, developmental delay, cerebral palsy, and deafness at 2 to 3 years’ corrected age. (Read the full article)

Systematic health disparities in adults with systemic lupus erythematosus are well documented and are likely driven by biologic as well as modifiable factors. Sociodemographic factors and health care delivery characteristics have been associated with poor outcomes.

In hospitalized children with systemic lupus erythematosus, race and ethnicity were associated with increased risk for ICU admissions, end-stage renal disease, and death. Identification of sociodemographic factors associated with outcomes is important to address the needs of these vulnerable patients. (Read the full article)

Noonan syndrome is associated with a bleeding diathesis and abnormal coagulation tests.

Bleeding diathesis in Noonan syndrome was evaluated by using a validated bleeding score. For the first time, platelet function was fully investigated, and a significant prevalence of platelet abnormalities likely to contribute to the bleeding diathesis was found. (Read the full article)

Asymptomatic neonatal subdural hemorrhage (SDH) is common, resolves within 4 weeks, and is typically infratentorial or posterior when supratentorial. Subdural hemorrhages may occur after cardiac surgery in infancy. Some hypothesize a causal relationship between hypoxia and SDH in infancy.

Asymptomatic neonatal SDH is often supratentorial and over the convexities. Small infratentorial SDHs may persist for ≤90 days. In young infants with congenital heart disease, an association between hypoxia and SDH could not be demonstrated. (Read the full article)

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an important risk factor for neonatal jaundice in Nigeria. It is associated with severe hyperbilirubinemia among infants exposed to icterogenic agents. Elevated bilirubin levels have occasionally been demonstrated in G6PD-deficient infants without exposure to icterogenic agents.

Even without exposure to known icterogens, G6PD-deficient infants have a more rapid hematocrit decline and higher bilirubin levels than their G6PD-intermediate and G6PD-normal counterparts throughout the first week of life. (Read the full article)

Neonatal arterial ischemic stroke is associated with later cerebral palsy and cognitive impairment. Many studies on neonatal ischemic stroke are limited by modest sample sizes, and prospective studies that include outcomes assessments are scarce.

Results from this prospective, nationwide, population-based study provide information on the epidemiology, associated clinical variables, clinical manifestation, vascular distribution, and treatment of neonatal arterial ischemic stroke. The study also provides outcomes regarding motor function and cognition. (Read the full article)

Studies on the consequences of abnormal prenatal hemoglobin (Hb) concentration have focused on maternal morbidities and adverse birth outcomes. To date, very little is known about the association between prenatal Hb concentration and infant cognitive and motor functions.

There is an inverted U-shaped relationship between maternal Hb concentration and infant gross motor function. Hb concentration between 90 and 110 g/L appears to be optimal for early gross motor function of children. (Read the full article)