Trophic state resilience to hurricane disturbance of Lake Yojoa, Honduras.

Cyclones are a poorly described disturbance in tropical lakes, with the potential to alter ecosystems and compromise the services they provide. In November 2020, Hurricanes Eta and Iota made landfall near the Nicaragua-Honduras border, inundating the region with a large amount of late-season precipitation. To understand the impact of these storms on Lake Yojoa, Honduras, we compared 2020 and 2021 conditions using continuous (every 16 days) data collected from five pelagic locations. The storms resulted in increased Secchi depth and decreased algal abundance in December 2020, and January and February 2021, and lower-than-average accumulation of hypolimnetic nutrients from the onset of stratification (April 2021) until mixus in November 2021. Despite the reduced hypolimnetic nutrient concentrations, epilimnetic nutrient concentrations returned to (and in some cases exceeded) pre-hurricane levels following annual water column turnover in 2021. This response suggests that Lake Yojoa's trophic state had only an ephemeral response to the disturbance imposed by the two hurricanes, likely due to internal input of sediment derived nutrients. These aseasonal storms acted as a large-scale experiment that resulted in nutrient dilution and demonstrated the resilience of Lake Yojoa's trophic state to temporary nutrient reductions.

Isotonitazene, a novel psychoactive substance opioid, detected in two cases following a local surge in opioid overdoses.

BACKGROUND: Isotonitazene is a novel opioid that was first reported in Europe in 2019. There have been no reports of the detection of isotonitazene in patients presenting to the emergency department with acute drug toxicity. AIM: There was an increase in presentations to our emergency department with acute opioid toxicity in August 2021. We aim to describe this outbreak and provide detail on two cases in which isotonitazene was quantified in serum samples. METHODS: Serum samples were available for comprehensive toxicological analysis for two presentations. Written consent was obtained and the samples were analysed through a Thermo XRS ultrahigh-performance liquid chromatography system, interfaced to a Thermo Q Exactive high-resolution accurate mass spectrometer, operating in heated positive ion electrospray mode. Acquired data were processed using Toxfinder software (Thermo) against a regularly updated in-house database. RESULTS: There was an increase in acute opioid presentations to our emergency department from a median of 10 per month to 36 in August 2021. Twenty were treated with naloxone, and 23 were admitted to the hospital for observation and treatment. Serum sample analysis from two patients with acute opioid toxicity responsive to naloxone detected the presence of isotonitazene (0.18 and 0.81 ng/ml). CONCLUSION: We report a cluster of acute opioid toxicity presentations to our Emergency Department with detection of isotonitazene in two cases. Analytical screening is important in determining the presence of novel psychoactive substances (NPS) and to help inform the public health of the implications of NPS use, particularly during clusters of acute recreational drug toxicity presentations.

High-affinity chromodomains engineered for improved detection of histone methylation and enhanced CRISPR-based gene repression.

Histone methylation is an important post-translational modification that plays a crucial role in regulating cellular functions, and its dysregulation is implicated in cancer and developmental defects. Therefore, systematic characterization of histone methylation is necessary to elucidate complex biological processes, identify biomarkers, and ultimately, enable drug discovery. Studying histone methylation relies on the use of antibodies, but these suffer from lot-to-lot variation, are costly, and cannot be used in live cells. Chromatin-modification reader domains are potential affinity reagents for methylated histones, but their application is limited by their modest affinities. We used phage display to identify key residues that greatly enhance the affinities of Cbx chromodomains for methylated histone marks and develop a general strategy for enhancing the affinity of chromodomains of the human Cbx protein family. Our strategy allows us to develop powerful probes for genome-wide binding analysis and live-cell imaging. Furthermore, we use optimized chromodomains to develop extremely potent CRISPR-based repressors for tailored gene silencing. Our results highlight the power of engineered chromodomains for analyzing protein interaction networks involving chromatin and represent a modular platform for efficient gene silencing.

Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models.

The mouse is a useful preclinical species for evaluating disease etiology due to the availability of a wide variety of genetically modified strains and the ability to perform disease-modifying manipulations. In order to establish an atrial filtration (AF) model in our laboratory, we profiled several commonly used murine AF models. We initially evaluated a pharmacological model of acute carbachol (CCh) treatment plus atrial burst pacing in C57BL/6 mice. In an effort to observe micro-reentrant circuits indicative of authentic AF, we employed optical mapping imaging in isolated mouse hearts. While CCh reduced atrial refractoriness and increased atrial tachyarrhythmia vulnerability, the left atrial (LA) excitation patterns were rather regular without reentrant circuits or wavelets. Therefore, the atrial tachyarrhythmia resembled high frequency atrial flutter, not typical AF per se. We next examined both a chronic angiotensin II (Ang II) infusion model and the surgical model of transverse aortic constriction (TAC), which have both been reported to induce atrial and ventricular structural changes that serve as a substrates for micro-reentrant AF. Although we observed some extent of atrial remodeling such as fibrosis or enlarged LA diameter, burst pacing-induced atrial tachyarrhythmia vulnerability did not differ from control mice in either model. This again suggested that an AF-like pathophysiology is difficult to demonstrate in the mouse. To continue searching for a valid murine AF model, we studied mice with a cardiac-specific deficiency (KO) in liver kinase B1 (Cardiac-LKB1), which has been reported to exhibit spontaneous AF. Indeed, the electrocardiograms (ECG) of conscious Cardiac-LKB1 KO mice exhibited no P waves and had irregular RR intervals, which are characteristics of AF. Histological evaluation of Cardiac-LKB1 KO mice revealed dilated and fibrotic atria, again consistent with AF. However, atrial electrograms and optical mapping revealed that electrical activity was limited to the sino-atrial node area with no electrical conduction into the atrial myocardium beyond. Thus, Cardiac-LKB1 KO mice have severe atrial myopathy or atrial standstill, but not AF. In summary, the atrial tachyarrhythmias we observed in the four murine models were distinct from typical human AF, which often exhibits micro- or macro-reentrant atrial circuits. Our results suggest that the four murine AF models we examined may not reflect human AF well, and raise a cautionary note for use of those murine models to study AF.

A retrospective cohort study of infection risk in hospitalized patients evaluated for Sweet syndrome.

Sweet syndrome (SS) is divided into malignancy-associated, classical, and drug-induced subtypes. Features associated with SS, such as fevers, neutropenia, and cancer, are also high risk for serious infection. We aimed to describe hospitalized patients with a documented concern for SS on initial dermatologic evaluation, their risk of infection, and the impact of SS subtype on treatment and outcomes. We descriptively analyzed hospitalizations at The Ohio State University evaluated for SS by dermatology and performed a retrospective cohort analysis of malignancy-associated and non-malignancy-associated SS patients. Eighty-seven patient hospitalizations were evaluated for SS from 2012 to 2019. Thirty-one hospitalizations were complicated by neutropenia. Lesions in 12.9% (n = 4/31) of neutropenic hospitalizations were infected with Fusarium species (n = 2) or methicillin-resistant staphylococcus aureus (n = 2). One patient with fungal disease died within 30 days of hospitalization. Thirty-three patients were confirmed to have a final diagnosis of SS. In the confirmed SS cohort, malignancy was associated with greater overall dapsone use (p = .021), less initial (p = .046) and overall (p = .013) corticosteroid use, and fewer SS-related readmissions within one year (p = .020) and overall (p = .004). Corticosteroid treatment delay should be considered for a short period in neutropenic patients while excluding infection. Malignancy-associated SS patients were more frequently treated with dapsone and favorable outcomes were seen in cancer patients.

Alterations to sediment nutrient deposition and transport along a six reservoir sequence.

Reservoir presence and construction has become commonplace along rivers due to the multitude of ecosystem services they provide. Many services are well recognized, including the effectiveness of sequestering both sediments and sediment-bound nutrients such as silts and phosphorus (P). Reservoirs are also capable of transforming or sequestering significant quantities of nutrients with more complex biogeochemical pathways, like nitrogen (N). Reservoir assessments, independent of inflow-outflow models, have primarily focused on a small number of systems creating a growing need to understand how reservoirs function both individually and as reservoir sequences within large rivers and their watersheds. Models have simulated the overall efficiency and drivers of reservoir nutrient deposition, but few have considered how a sequence of reservoirs alters deposition as an interdependent watershed-sediment-transport-system. In this study, we collected sediment cores from a six-reservoir sequence along a 5th - 6th order stream receiving treated waters from a large metropolitan area in the subtropical southeastern United States. Paleolimnological studies of subtropical reservoirs are underrepresented and are needed to understand the history of reservoir development. Using paleolimnological techniques and a known 30 year flux of riverine nutrient loading from waste water treatment facilities, we compared nutrient deposition to reservoir morphological qualities and primary producer community structure during the past ~50 years. Our findings suggest phosphorus deposition is associated with reservoir order downstream of the primary nutrient source, nitrogen deposition is linked to reservoir water retention time, and N:P is most strongly linked to reservoir surface area and watershed population density. Our results were strongly influenced by a large upstream and metropolitan nutrient source, common in large rivers, but under different conditions of nutrient loading (i.e. nonpoint source), reservoirs may express other nutrient depositional patterns.

Volcanic origin for Younger Dryas geochemical anomalies ca. 12,900 cal B.P.

The Younger Dryas (YD) abrupt cooling event ca. 12.9 ± 0.1 ka is associated with substantial meltwater input into the North Atlantic Ocean, reversing deglacial warming. One controversial and prevailing hypothesis is that a bolide impact or airburst is responsible for these environmental changes. Here, highly siderophile element (HSE; Os, Ir, Ru, Pt, Pd, and Re) abundances and 187Os/188Os ratios were obtained in a well-dated sediment section at Hall's Cave, TX, USA to test this hypothesis. In Hall's Cave, layers below, above, and in the YD have 187Os/188Os ratios consistent with incorporation of extraterrestrial or mantle-derived material. The HSE abundances indicate that these layers contain volcanic gas aerosols and not extraterrestrial materials. The most likely explanation is that episodic, distant volcanic emissions were deposited in Hall's Cave sediments. Coupled 187Os/188Os ratios and HSE concentration data at close stratigraphic intervals are required to effectively differentiate between bolide and volcanic origins.

Kikwit Ebola Virus Disease Progression in the Rhesus Monkey Animal Model.

Ongoing Ebola virus disease outbreaks in the Democratic Republic of the Congo follow the largest recorded outbreak in Western Africa (2013-2016). To combat outbreaks, testing of medical countermeasures (therapeutics or vaccines) requires a well-defined, reproducible, animal model. Here we present Ebola virus disease kinetics in 24 Chinese-origin rhesus monkeys exposed intramuscularly to a highly characterized, commercially available Kikwit Ebola virus Filovirus Animal Non-Clinical Group (FANG) stock. Until reaching predetermined clinical disease endpoint criteria, six animals underwent anesthesia for repeated clinical sampling and were compared to six that did not. Groups of three animals were euthanized and necropsied on days 3, 4, 5, and 6 post-exposure, respectively. In addition, three uninfected animals served as controls. Here, we present detailed characterization of clinical and laboratory disease kinetics and complete blood counts, serum chemistries, Ebola virus titers, and disease kinetics for future medical countermeasure (MCM) study design and control data. We measured no statistical difference in hematology, chemistry values, or time to clinical endpoint in animals that were anesthetized for clinical sampling during the acute disease compared to those that were not.

Substrate-Controlled Magnetism: Fe Nanowires on Vicinal Cu Surfaces.

Here we present a novel approach to controlling magnetic interactions between atomic-scale nanowires. Our ab initio calculations demonstrate the possibility to tune magnetic properties of Fe nanowires formed on vicinal Cu surfaces. Both intrawire and interwire magnetic exchange parameters are extracted from density functional theory (DFT) calculations. This study suggests that the effective interwire magnetic exchange parameters exhibit Ruderman-Kittel-Kasuya-Yosida-like (RKKY) oscillations as a function of Fe interwire separation. The choice of the vicinal Cu surface offers possibilities for controlling the magnetic coupling. Furthermore, an anisotropic Heisenberg model was used in Monte Carlo simulations to examine the stability of these magnetic configurations at finite temperatures. The predicted critical temperatures of the Fe nanowires on Cu(422) and Cu(533) surfaces are well above room temperature.

A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation.

Both humans and mice lacking functional growth hormone (GH) receptors are known to be resistant to cancer. Further, autocrine GH has been reported to act as a cancer promoter. Here we present the first example of a variant of the GH receptor (GHR) associated with cancer promotion, in this case lung cancer. We show that the GHRP495T variant located in the receptor intracellular domain is able to prolong the GH signal in vitro using stably expressing mouse pro-B-cell and human lung cell lines. This is relevant because GH secretion is pulsatile, and extending the signal duration makes it resemble autocrine GH action. Signal duration for the activated GHR is primarily controlled by suppressor of cytokine signalling 2 (SOCS2), the substrate recognition component of the E3 protein ligase responsible for ubiquitinylation and degradation of the GHR. SOCS2 is induced by a GH pulse and we show that SOCS2 binding to the GHR is impaired by a threonine substitution at Pro 495. This results in decreased internalisation and degradation of the receptor evident in TIRF microscopy and by measurement of mature (surface) receptor expression. Mutational analysis showed that the residue at position 495 impairs SOCS2 binding only when a threonine is present, consistent with interference with the adjacent Thr494. The latter is key for SOCS2 binding, together with nearby Tyr487, which must be phosphorylated for SOCS2 binding. We also undertook nuclear magnetic resonance spectroscopy approach for structural comparison of the SOCS2 binding scaffold Ile455-Ser588, and concluded that this single substitution has altered the structure of the SOCS2 binding site. Importantly, we find that lung BEAS-2B cells expressing GHRP495T display increased expression of transcripts associated with tumour proliferation, epithelial-mesenchymal transition and metastases (TWIST1, SNAI2, EGFR, MYC and CCND1) at 2 h after a GH pulse. This is consistent with prolonged GH signalling acting to promote cancer progression in lung cancer.

Risk factors for KPC-producing Enterobacteriaceae acquisition and infection in a healthcare setting with possible local transmission: a case-control study.

BACKGROUND: Reports of Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp) in Australia were previously uncommon, with cases imported sporadically by travellers from higher prevalence countries. AIM: The study institution reported the first outbreak of KPC-Kp in Australia. The aim of this study was to identify risk factors for KPC-Kp colonization and infection using a matched case-control study. METHODS: The study included all hospitalized patients with KPC-Kp colonization or infection from January 2012 to September 2015. FINDINGS: Thirty-four cases of KPC-producing Enterobacteriaceae (including 31 KPC-Kp cases) were matched with 136 controls. Variables associated with KPC-Kp acquisition included: length of hospital stay >28 days in the past 12 months, prior vancomycin-resistant enterococci (VRE) colonization, central venous catheter (CVC), gastrointestinal disease and invasive procedures. Exposure to broad-spectrum antibiotics was also found to be a significant risk factor. In the multi-variate analysis, three factors independently associated with KPC-Kp acquisition were length of hospital stay >28 days in the past 12 months [odds ratio (OR) 23.6, 95% confidence interval (CI) 4.9-113.3], presence of a CVC (OR 15.4, 95% CI 2.7-86.9), and prior VRE colonization (OR 6.0, 95% CI 1.6-23.2). Very few patients had a history of overseas travel. CONCLUSION: This study demonstrates that patients with prolonged hospital exposure are more likely to acquire KPC-Kp in the setting of a local outbreak, and suggests that risk factors for KPC-Kp acquisition may be shared with those for VRE colonization. Local screening strategies targeting overseas travellers would likely miss many cases. The results of this study will help to inform screening policies for carbapenemase-producing Enterobacteriaceae.

Influence of surface roughness on silicone rubber voice prostheses on in vitro biofilm formation and clinical lifetime in laryngectomised patients.

OBJECTIVES: Evaluation of the influence of a smooth surface moulding technique of silicone rubber indwelling voice prostheses on in vitro biofilm formation and analysis of the clinical in situ lifetime. DESIGN: Biofilm formation on smooth and Groningen ultra low resistance (URL) prostheses was studied in an artificial throat model. The clinical lifetime of smooth voice prostheses was compared to the previous lifetime of URL by counting the number of replacements in a consecutive 6-month period in the same patient. PARTICIPANTS: Eleven laryngectomised patients in follow-up who required frequent replacement of their voice prostheses. SETTINGS: Tertiary University Medical Center. RESULTS: Use of a smoother mould and less viscous silicone rubber yielded a decrease in surface roughness from 46 to 8 nm and was accompanied by a 40% reduction in the prevalence of bacteria and yeast in in vitro formed biofilms. Clinically, the lifetime was significantly (P<.005) increased by a factor of 2.1. CONCLUSIONS: This combined in vitro and clinical study suggests that the choice of material and in particular its surface finishing may be determining factors with respect to the clinical lifetime of silicone rubber implants and devices failing due to biofilm formation.

Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNA Synthetase.

The recent development and spread of extensively drug-resistant and totally drug-resistant resistant (TDR) strains of Mycobacterium tuberculosis highlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB. Here, we show that small-molecule inhibitors of aminoacyl-tRNA synthetases (AARSs), which are known to be excellent antibacterial protein synthesis targets, are orally bioavailable and effective against M. tuberculosis in TB mouse infection models. We applied the oxaborole tRNA-trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl-tRNA synthetase (LeuRS), to M. tuberculosis LeuRS. X-ray crystallography was used to guide the design of LeuRS inhibitors that have good biochemical potency and excellent whole-cell activity against M. tuberculosis Importantly, their good oral bioavailability translates into in vivo efficacy in both the acute and chronic mouse models of TB with potency comparable to that of the frontline drug isoniazid.

A low-carbohydrate high-fat diet increases weight gain and does not improve glucose tolerance, insulin secretion or ß-cell mass in NZO mice.

BACKGROUND/OBJECTIVES: Dietary guidelines for the past 20 years have recommended that dietary fat should be minimized. In contrast, recent studies have suggested that there could be some potential benefits for reducing carbohydrate intake in favor of increased fat. It has also been suggested that low-carbohydrate diets be recommended for people with type 2 diabetes. However, whether such diets can improve glycemic control will likely depend on their ability to improve ß-cell function, which has not been studied. The objective of the study was to assess whether a low-carbohydrate and therefore high-fat diet (LCHFD) is beneficial for improving the endogenous insulin secretory response to glucose in prediabetic New Zealand Obese (NZO) mice. METHODS: NZO mice were maintained on either standard rodent chow or an LCHFD from 6 to 15 weeks of age. Body weight, food intake and blood glucose were assessed weekly. Blood glucose and insulin levels were also assessed after fasting and re-feeding and during an oral glucose tolerance test. The capacity of pancreatic ß-cells to secrete insulin was assessed in vivo with an intravenous glucose tolerance test. ß-Cell mass was assessed in histological sections of pancreata collected at the end of the study. RESULTS: In NZO mice, an LCHFD reduced plasma triglycerides (P=0.001) but increased weight gain (P<0.0001), adipose tissue mass (P=0.0015), high-density lipoprotein cholesterol (P=0.044) and exacerbated glucose intolerance (P=0.013). Although fasting insulin levels tended to be higher (P=0.08), insulin secretory function in LCHFD-fed mice was not improved (P=0.93) nor was ß-cell mass (P=0.75). CONCLUSIONS: An LCHFD is unlikely to be of benefit for preventing the decline in ß-cell function associated with the progression of hyperglycemia in type 2 diabetes.

The global economic burden of asthma and chronic obstructive pulmonary disease.

Non-communicable diseases are now the number one cause of disabilities and loss of life expectancy. Among them, chronic respiratory conditions constitute a major class. The burden of chronic respiratory diseases is generally increasing across the globe, and asthma and chronic obstructive pulmonary disease (COPD) are among the main causes of mortality and morbidity. However, the direct and indirect costs of these conditions vary across jurisdictions. This article reports on recent estimates of the costs of asthma and COPD, with a focus on comparing disease burden across different regions. Overall, there is tremendous variation in per capita annual costs of asthma and COPD. However, the methodology of the cost-of-illness studies is also vastly different, making it difficult to associate differences in reported costs to differences in the true burden of asthma and COPD. Suggestions are provided towards improving the validity and comparability of future studies.

Effect of Deletion of Ghrelin-O-Acyltransferase on the Pulsatile Release of Growth Hormone in Mice.

Ghrelin, a gut hormone originating from the post-translational cleavage of preproghrelin, is the endogenous ligand of growth hormone secretagogue receptor 1a (GHS-R1a). Within the growth hormone (GH) axis, the biological activity of ghrelin requires octanoylation by ghrelin-O-acyltransferase (GOAT), conferring selective binding to the GHS-R1a receptor via acylated ghrelin. Complete loss of preproghrelin-derived signalling (through deletion of the Ghrl gene) contributes to a decline in peak GH release; however, the selective contribution of endogenous acyl-ghrelin to pulsatile GH release remains to be established. We assessed the pulsatile release of GH in ad lib. fed male germline goat(-/-) mice, extending measures to include mRNA for key hypothalamic regulators of GH release, and peripheral factors that are modulated relative to GH release. The amount of GH released was reduced in young goat(-/-) mice compared to age-matched wild-type mice, whereas pulse frequency and irregularity increased. Altered GH release did not coincide with alterations in hypothalamic Ghrh, Srif, Npy or Ghsr mRNA expression, or pituitary GH content, suggesting that loss of Goat does not compromise canonical mechanisms that contribute to pituitary GH production and release. Although loss of Goat resulted in an irregular pattern of GH release (characterised by an increase in the number of GH pulses observed during extended secretory events), this did not contribute to a change in the expression of sexually dimorphic GH-dependent liver genes. Of interest, circulating levels of insulin-like growth factor (IGF)-1 were elevated in goat(-/-) mice. This rise in circulating levels of IGF-1 was correlated with an increase in GH pulse frequency, suggesting that sustained or increased IGF-1 release in goat(-/-) mice may occur in response to altered GH release patterning. Our observations demonstrate that germline loss of Goat alters GH release and patterning. Although the biological relevance of altered GH secretory patterning remains unclear, we propose that this may contribute to sustained IGF-1 release and growth in goat(-/-) mice.

Managing a nosocomial outbreak of carbapenem-resistant Klebsiella pneumoniae: an early Australian hospital experience.

BACKGROUND: Carbapenems are traditionally reserved as the last line of defence for treatment of serious infections with multiresistant Gram-negative bacilli. Reports of Klebsiella pneumoniae carbapenemase (KPC)-producing organisms have been emerging globally, but rare in Australasia to date. We describe an outbreak of KPC-2 producing K. pneumoniae at an Australian hospital. METHODS: After initial detection in October 2012, a retrospective review of patients with meropenem-resistant K. pneumoniae to June 2012, and ongoing prospective surveillance, was undertaken. Included patients were admitted to the hospital after June 2012 and had meropenem-resistant K. pneumoniae isolated from any site. Available isolates underwent detection of the KPC-2 gene by polymerase chain reaction and molecular typing was performed to determine genetic relatedness between isolates. Point-prevalence screening was performed on selected wards to detect asymptomatic carriage. Infection control procedures were implemented to contain the outbreak. RESULTS: Ten cases were identified in the initial cluster. Eight were localised to a single inpatient ward. Point-prevalence screening revealed one extra case. After temporary containment, re-emergence of KPC-producing isolates was observed post October 2013 with 18 further cases identified. Four K. pneumoniae isolates in the 2012 cluster and 16 from the 2013-2014 cluster were referred for further testing. All carried the KPC-2 beta-lactamase gene. The 2012 isolates were genetically similar to the 2014 isolates. CONCLUSION: KPC-2 mediated resistance is an emerging threat in Australia. The re-emergence of KPC despite initial containment emphasises the need for constant vigilance in the microbiology laboratory and ongoing maintenance of infection control and antimicrobial stewardship activity.

Mcl-1 is a key regulator of the ovarian reserve.

A majority of ovarian follicles are lost to natural death, but the disruption of factors involved in maintenance of the oocyte pool results in a further untimely follicular depletion known as premature ovarian failure. The anti-apoptotic B-cell lymphoma 2 (Bcl-2) family member myeloid cell leukemia-1 (MCL-1) has a pro-survival role in various cell types; however, its contribution to oocyte survival is unconfirmed. We present a phenotypic characterization of oocytes deficient in Mcl-1, and establish its role in maintenance of the primordial follicle (PMF) pool, growing oocyte survival and oocyte quality. Mcl-1 depletion resulted in the premature exhaustion of the ovarian reserve, characterized by early PMF loss because of activation of apoptosis. The increasingly diminished surviving cohort of growing oocytes displayed elevated markers of autophagy and mitochondrial dysfunction. Mcl-1-deficient ovulated oocytes demonstrated an increased susceptibility to cellular fragmentation with activation of the apoptotic cascade. Concomitant deletion of the pro-apoptotic Bcl-2 member Bcl-2-associated X protein (Bax) rescued the PMF phenotype and ovulated oocyte death, but did not prevent the mitochondrial dysfunction associated with Mcl-1 deficiency and could not rescue long-term breeding performance. We thus recognize MCL-1 as the essential survival factor required for conservation of the postnatal PMF pool, growing follicle survival and effective oocyte mitochondrial function.