Changes in disturbance regimes due to climate change are increasingly challenging the capacity of ecosystems to absorb recurrent shocks and reassemble afterwards, escalating the risk of widespread ...ecological collapse of current ecosystems and the emergence of novel assemblages
. In marine systems, the production of larvae and recruitment of functionally important species are fundamental processes for rebuilding depleted adult populations, maintaining resilience and avoiding regime shifts in the face of rising environmental pressures
. Here we document a regional-scale shift in stock-recruitment relationships of corals along the Great Barrier Reef-the world's largest coral reef system-following unprecedented back-to-back mass bleaching events caused by global warming. As a consequence of mass mortality of adult brood stock in 2016 and 2017 owing to heat stress
, the amount of larval recruitment declined in 2018 by 89% compared to historical levels. For the first time, brooding pocilloporids replaced spawning acroporids as the dominant taxon in the depleted recruitment pool. The collapse in stock-recruitment relationships indicates that the low resistance of adult brood stocks to repeated episodes of coral bleaching is inexorably tied to an impaired capacity for recovery, which highlights the multifaceted processes that underlie the global decline of coral reefs. The extent to which the Great Barrier Reef will be able to recover from the collapse in stock-recruitment relationships remains uncertain, given the projected increased frequency of extreme climate events over the next two decades
.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify ...probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recessive mutations. Whole-exome sequencing of 16 probands revealed validated homozygous, potentially pathogenic recessive mutations that segregated perfectly with disease in 4/16 families. The candidate genes (UBE3B, CLTCL1, NCKAP5L, ZNF18) encode proteins involved in proteolysis, GTPase-mediated signaling, cytoskeletal organization, and other pathways. Furthermore, neuronal depolarization regulated the transcription of these genes, suggesting potential activity-dependent roles in neurons. We present a multidimensional strategy for filtering whole-exome sequence data to find candidate recessive mutations in autism, which may have broader applicability to other complex, heterogeneous disorders.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
One Mandarin immersion programming model involves a pair of partner teachers switching cohorts of students. Many programs meet their staffing needs with international teachers that remain with the ...school district for 1–3 years. Due to transient staffing, many partner teachers find themselves as mentors to their immersion teachers and maintain the program's institutional knowledge. A national survey of 106 American teachers examined their attitudes regarding collaboration with their Chinese teacher, identification as a mentor, perceived administrative support, and school climate. Many participants worked in public elementary one‐way immersion programs classified as schools within a school; about 20% worked in full immersion schools. The partner teachers agreed that they felt connected to and supported by other staff in their building, and reported positive structures in place for student success. Respondents signaled a need for more professional development on immersion education, Chinese culture, and the partner teacher role. Some indicated administrators would promote the program without understanding it. Many reported the immersion teachers' needs for more targeted professional development about American culture and the education system because of misunderstandings at the building level. Despite concerns, partner teachers found the role challenging but professionally rewarding.
The Challenge
With the growth of dual language immersion programs across the country and the current teacher shortage, many school districts have turned to hiring international teachers to fill their immersion needs. The stability of the international teachers' positions is tenuous; visa restrictions and instability of permanent staffing in immersion positions creates an additional burden on the partner teachers to maintain the immersion program and institutional knowledge. Understanding their experiences is crucial to the success of dual language immersion programs.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The nature and anatomic location of the protective memory CD8+ T cell subset induced by intranasal vaccination remain poorly understood. We developed a vaccination model to assess the anatomic ...location of protective memory CD8+ T cells and their role in lower airway infections. Memory CD8+ T cells elicited by local intranasal, but not systemic, vaccination with an engineered non-replicative CD8+ T cell-targeted antigen confer enhanced protection to a lethal respiratory viral challenge. This protection depends on a distinct CXCR3LO resident memory CD8+ T (Trm) cell population that preferentially localizes to the pulmonary interstitium. Because they are positioned close to the mucosa, where infection occurs, interstitial Trm cells act before inflammation can recruit circulating memory CD8+ T cells into the lung tissue. This results in a local protective immune response as early as 1 day post-infection. Hence, vaccine strategies that induce lung interstitial Trm cells may confer better protection against respiratory pathogens.
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•Intranasal T cell epitope-targeted vaccination confers enhanced protection•Intranasal vaccination preferentially induces CXCR3LO lung-resident memory CD8+ T cells•Protective memory T cells localize to vulnerable sites of the lung interstitium•Interstitial memory CD8+ T cells rapidly protect the lung against infection
Mucosal surveillance ensures rapid protection when a pathogen breaches the barrier. Gilchuk et al. report that local vaccination elicits a distinct resident memory CD8+ T cell subset that localizes to the lung interstitium. These T cells protect against respiratory infections by positioning at vulnerable sites and acting quickly against infections.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Significance
By evaluating children with a malformed cerebral cortex, we identified an ATPase pump (ATP1A3) with an early role in brain development. The ATP1A3 pump maintains the physiological ...concentration of sodium and potassium ions in cells, a process critical for osmotic equilibrium and membrane potential across several developing cell populations. We employed single-cell sequencing approaches to identify key enrichments for
ATP1A3
expression during human cortex development. Unravelling this early cell-type–specific pathophysiology in the developing brain offers a potential basis for the treatment of
ATP1A3
-related diseases affecting prenatal and early childhood development.
Osmotic equilibrium and membrane potential in animal cells depend on concentration gradients of sodium (Na
+
) and potassium (K
+
) ions across the plasma membrane, a function catalyzed by the Na
+
,K
+
-ATPase α-subunit. Here, we describe
ATP1A3
variants encoding dysfunctional α3-subunits in children affected by polymicrogyria, a developmental malformation of the cerebral cortex characterized by abnormal folding and laminar organization. To gain cell-biological insights into the spatiotemporal dynamics of prenatal
ATP1A3
expression, we built an
ATP1A3
transcriptional atlas of fetal cortical development using mRNA in situ hybridization and transcriptomic profiling of ∼125,000 individual cells with single-cell RNA sequencing (Drop-seq) from 11 areas of the midgestational human neocortex. We found that fetal expression of
ATP1A3
is most abundant to a subset of excitatory neurons carrying transcriptional signatures of the developing subplate, yet also maintains expression in nonneuronal cell populations. Moving forward a year in human development, we profiled ∼52,000 nuclei from four areas of an infant neocortex and show that
ATP1A3
expression persists throughout early postnatal development, most predominantly in inhibitory neurons, including parvalbumin interneurons in the frontal cortex. Finally, we discovered the heteromeric Na
+
,K
+
-ATPase pump complex may form nonredundant cell-type–specific α-β isoform combinations, including α3-β1 in excitatory neurons and α3-β2 in inhibitory neurons. Together, the developmental malformation phenotype of affected individuals and single-cell
ATP1A3
expression patterns point to a key role for α3 in human cortex development, as well as a cell-type basis for pre- and postnatal
ATP1A3
-associated diseases.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Hemimegalencephaly (HMG) is a developmental brain disorder characterized by an enlarged, malformed cerebral hemisphere, typically causing epilepsy that requires surgical resection. We studied ...resected HMG tissue to test whether the condition might reflect somatic mutations affecting genes critical to brain development. We found that two out of eight HMG samples showed trisomy of chromosome 1q, which encompasses many genes, including AKT3, a gene known to regulate brain size. A third case showed a known activating mutation in AKT3 (c.49G→A, creating p.E17K) that was not present in the patient's blood cells. Remarkably, the E17K mutation in AKT3 is exactly paralogous to E17K mutations in AKT1 and AKT2 recently discovered in somatic overgrowth syndromes. We show that AKT3 is the most abundant AKT paralog in the brain during neurogenesis and that phosphorylated AKT is abundant in cortical progenitor cells. Our data suggest that somatic mutations limited to the brain could represent an important cause of complex neurogenetic disease.
► Two cases showing trisomy 1q in brain tissue were associated with hemimegalencephaly ► A third hemimegalencephaly case had a somatic mosaic-activating mutation in AKT3 ► AKT3 is the most prevalent of the three AKT paralogues during human neurogenesis ► Phosphorylated AKT is expressed in apical progenitors of the developing cortex
Poduri et al. identify trisomy on chromosome 1q, which encompasses AKT3, and a separate activating AKT3 somatic mutation in patients with the developmental brain disorder hemimegalencephaly. Results suggest that somatic mutations limited to the brain may contribute to neurodevelopmental disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Maintenance of DNA integrity is crucial for all cell types, but neurons are particularly sensitive to mutations in DNA repair genes, which lead to both abnormal development and neurodegeneration. We ...describe a previously unknown autosomal recessive disease characterized by microcephaly, early-onset, intractable seizures and developmental delay (denoted MCSZ). Using genome-wide linkage analysis in consanguineous families, we mapped the disease locus to chromosome 19q13.33 and identified multiple mutations in PNKP (polynucleotide kinase 3′-phosphatase) that result in severe neurological disease; in contrast, a splicing mutation is associated with more moderate symptoms. Unexpectedly, although the cells of individuals carrying this mutation are sensitive to radiation and other DNA-damaging agents, no such individual has yet developed cancer or immunodeficiency. Unlike other DNA repair defects that affect humans, PNKP mutations universally cause severe seizures. The neurological abnormalities in individuals with MCSZ may reflect a role for PNKP in several DNA repair pathways.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Genes disrupted in human microcephaly (meaning “small brain”) define key regulators of neural progenitor proliferation and cell-fate specification. In comparison, genes mutated in human lissencephaly ...(lissos means smooth and cephalos means brain) highlight critical regulators of neuronal migration. Here, we report two families with extreme microcephaly and grossly simplified cortical gyral structure, a condition referred to as microlissencephaly, and show that they carry homozygous frameshift mutations in NDE1, which encodes a multidomain protein that localizes to the centrosome and mitotic spindle poles. Both human mutations in NDE1 truncate the C-terminal NDE1domains, which are essential for interactions with cytoplasmic dynein and thus for regulation of cytoskeletal dynamics in mitosis and for cell-cycle-dependent phosphorylation of NDE1 by Cdk1. We show that the patient NDE1 proteins are unstable, cannot bind cytoplasmic dynein, and do not localize properly to the centrosome. Additionally, we show that CDK1 phosphorylation at T246, which is within the C-terminal region disrupted by the mutations, is required for cell-cycle progression from the G2 to the M phase. The role of NDE1 in cell-cycle progression probably contributes to the profound neuronal proliferation defects evident in Nde1-null mice and patients with NDE1 mutations, demonstrating the essential role of NDE1 in human cerebral cortical neurogenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Charged multivesicular body protein 1A (CHMP1A; also known as chromatin-modifying protein 1A) is a member of the ESCRT-III (endosomal sorting complex required for transport-III) complex but is also ...suggested to localize to the nuclear matrix and regulate chromatin structure. Here, we show that loss-of-function mutations in human CHMP1A cause reduced cerebellar size (pontocerebellar hypoplasia) and reduced cerebral cortical size (microcephaly). CHMP1A-mutant cells show impaired proliferation, with increased expression of INK4A, a negative regulator of stem cell proliferation. Chromatin immunoprecipitation suggests loss of the normal INK4A repression by BMI in these cells. Morpholino-based knockdown of zebrafish chmp1a resulted in brain defects resembling those seen after bmi1a and bmi1b knockdown, which were partially rescued by INK4A ortholog knockdown, further supporting links between CHMP1A and BMI1-mediated regulation of INK4A. Our results suggest that CHMP1A serves as a critical link between cytoplasmic signals and BMI1-mediated chromatin modifications that regulate proliferation of central nervous system progenitor cells.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
•High levels of transgender-related discrimination are associated with substance use.•Experiencing transgender-related discrimination yields higher odds of SUD.•Substance use treatment is associated ...with transgender-related discrimination.
Substantial research gaps exist regarding the relationship between transgender-related discrimination and substance use outcomes for transgender adults, with few studies accounting for other experiences of victimization.
Transgender adults (N = 600) from Massachusetts and Rhode Island completed a survey online or in-person. Multivariable linear and logistic regression models examined the association between lifetime experiences of transgender-related discrimination using the validated 11-item Everyday Discrimination Scale (theoretical range = 0–44) and substance use outcomes: past 12-month substance use frequency, lifetime substance use disorder (SUD) diagnosis, and substance use treatment (SUTx) history. All models were adjusted for age, gender identity, race, survey modality, childhood physical/sexual abuse, intimate partner violence, and discrimination attributable to other reasons than being transgender.
The mean transgender-related discrimination score was 20.8 (SD = 9.6, range = 0–44). Overall, 11.8 % of the sample had a SUD diagnosis and 11.0 % had received SUTx. In separate multivariable models adjusted for sociodemographic and victimization experiences, the highest quartile of transgender-related discrimination was significantly associated with higher past 12-month substance use (B = 1.44; aR2 = 0.13; p = .009), SUD diagnosis (aOR = 3.64; 95 % CI = 1.46−9.07; p = .006), and lifetime treatment history (aOR = 3.93; 95 % CI = 1.50−10.21; p = .005).
There was a significant positive association between experiencing high levels of transgender-related discrimination and substance use outcomes among the transgender adults sampled. Longitudinal research is needed to understand the specific mediators driving these relationships and to address the implications of transgender-related discrimination on SUD treatment utilization.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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