Polar Positioning of Phase-Separated Liquid Compartments in Cells Regulated by an mRNA Competition Mechanism.

P granules are non-membrane-bound RNA-protein compartments that are involved in germline development in C. elegans. They are liquids that condense at one end of the embryo by localized phase separation, driven by gradients of polarity proteins such as the mRNA-binding protein MEX-5. To probe how polarity proteins regulate phase separation, we combined biochemistry and theoretical modeling. We reconstitute P granule-like droplets in vitro using a single protein PGL-3. By combining in vitro reconstitution with measurements of intracellular concentrations, we show that competition between PGL-3 and MEX-5 for mRNA can regulate the formation of PGL-3 droplets. Using theory, we show that, in a MEX-5 gradient, this mRNA competition mechanism can drive a gradient of P granule assembly with similar spatial and temporal characteristics to P granule assembly in vivo. We conclude that gradients of polarity proteins can position RNP granules during development by using RNA competition to regulate local phase separation.

Left ventricular assist device-associated driveline infections as a specific form of complicated skin and soft tissue infection/acute bacterial skin and skin structure infection - issues and therapeutic options.

PURPOSE OF REVIEW: This review comments on the current guidelines for the treatment of wound infections under definition of acute bacterial skin and skin structure infections (ABSSSI). However, wound infections around a catheter, such as driveline infections of a left ventricular assist device (LVAD) are not specifically listed under this definition in any of the existing guidelines. RECENT FINDINGS: Definitions and classification of LVAD infections may vary across countries, and the existing guidelines and recommendations may not be equally interpreted among physicians, making it unclear if these infections can be considered as ABSSSI. Consequently, the use of certain antibiotics that are approved for ABSSSI may be considered as 'off-label' for LVAD infections, leading to rejection of reimbursement applications in some countries, affecting treatment strategies, and hence, patients' outcomes. However, we believe driveline exit site infections related to LVAD can be included within the ABSSSI definition. SUMMARY: We argue that driveline infections meet the criteria for ABSSSI which would enlarge the 'on-label' antibiotic armamentarium for treating these severe infections, thereby improving the patients' quality of life.

Norwegian population-based study of long-term effects, safety, and predictors of response of vagus nerve stimulation treatment in drug-resistant epilepsy: The NORPulse study.

OBJECTIVE: This study was undertaken to evaluate the efficacy of vagus nerve stimulation (VNS) over time, and to determine which patient groups derive the most benefit. METHODS: Long-term outcomes are reported in 436 epilepsy patients from a VNS quality registry (52.8% adults, 47.2% children), with a median follow-up of 75 months. Patients were stratified according to evolution of response into constant responders, fluctuating responders, and nonresponders. The effect was evaluated at 6, 12, 24, 36, and 60 months. Multivariate regression analysis was used to identify predictors of response. RESULTS: The cumulative probability of ≥50% seizure reduction was 60%; however, 15% of patients showed a fluctuating course. Of those becoming responders, 89.5% (230/257) did so within 2 years. A steady increase in effect was observed among constant responders, with 48.7% (19/39) of those becoming seizure-free and 29.3% (39/133) with ≥75% seizure reduction achieving these effects within 2-5 years. Some effect (25%-<50%) at 6 months was a positive predictor of becoming a responder (odds ratio [OR] = 10.18, p < .0001) and having ≥75% reduction at 2 years (OR = 3.34, p = .03). Patients without intellectual disability had ORs of 3.34 and 3.11 of having ≥75% reduction at 2 and 5 years, respectively, and an OR of 6.22 of being seizure-free at last observation. Patients with unchanged antiseizure medication over the observation period showed better responder rates at 2 (63.0% vs. 43.1%, p = .002) and 5 years (63.4% vs. 46.3%, p = .031) than patients whose antiseizure medication was modified. Responder rates were higher for posttraumatic (70.6%, p = .048) and poststroke epilepsies (75.0%, p = .05) than other etiologies (46.5%). SIGNIFICANCE: Our data indicate that the effect of VNS increases over time and that there are important clinical decision points at 6 and 24 months for evaluating and adjusting the treatment. There should be better selection of candidates, as certain patient groups and epilepsy etiologies respond more favorably.

Cotrimoxazole and clindamycin in skin and soft tissue infections.

PURPOSE OF REVIEW: The aim of this study was to present recent microbiological, experimental, clinical and tolerance data for cotrimoxazole and clindamycin in the specific field of skin and soft tissue infections (SSTIs). RECENT FINDINGS: Staphylococcus aureus and streptococci remain the leading cause of SSTIs. Cotrimoxazole is a good anti-Gram-positive agent with preserved activity against methicillin-susceptible and methicillin-resistant S. aureus (MRSA) and streptococci. Although clindamycin has good methicillin-susceptible S. aureus activity, a growing number of resistant MRSA and streptococci have been reported. Strong experimental data support the antitoxin activity of clindamycin, but clinical observations remain scarce. Several recent randomized trials involving cotrimoxazole and/or clindamycin demonstrate the efficacy and tolerance of both drugs. The oral formulation of both drugs may facilitate the implementation of early switch and early discharge protocols in clinical practice. SUMMARY: Recent publications demonstrate that cotrimoxazole and clindamycin remain reliable and realistic therapeutic approaches for SSTIs.

Current management of necrotizing soft-tissue infections.

PURPOSE OF REVIEW: The aim of the article is to present recent epidemiological, microbiological, and clinical data for the surgical, antimicrobial, and adjunctive management of necrotizing soft-tissue infections (NSTI). RECENT FINDINGS: NSTI can be caused by a broad variety of organisms. Reports about NSTI caused by multidrug-resistant bacteria are increasing. Owing to the rareness of NSTI, general clinical awareness is low and prompt diagnosis is often delayed. New diagnostic instruments (scoring systems, MRI) have either a low accuracy or are time consuming and cannot guide clinicians reliable currently. The value of adjunctive measures (intravenous immunoglobulin, hyperbaric oxygen therapy) is uncertain as well. Morbidity and mortality in NSTI remain high, ranging from 20 up to over 30%. SUMMARY: Early radical surgical debridement and empirical broad-spectrum antimicrobial treatment remain the cornerstones of therapy in NSTI. Further clinical research is necessary to shorten diagnostic pathways and to optimize surgical, antimicrobial, and adjunctive treatment.

Current and future options for treating complicated skin and soft tissue infections: focus on fluoroquinolones and long-acting lipoglycopeptide antibiotics.

Bacterial skin and soft tissue infections are among the most common bacterial infections and constitute a major burden for patients and healthcare systems. Care is complicated by the variety of potential pathogens, some with resistance to previously effective antimicrobial agents, the wide spectrum of clinical presentations and the risk of progression to life-threatening forms. More-efficient care pathways are needed that can reduce hospital admissions and length of stay, while maintaining a high quality of care and adhering to antimicrobial stewardship principles. Several agents approved recently for treating acute bacterial skin and skin structure infections have characteristics that meet these requirements. We address the clinical and pharmacological characteristics of the fourth-generation fluoroquinolone delafloxacin, and the long-acting lipoglycopeptide agents dalbavancin and oritavancin.

Stage-specific combinations of opposing poly(A) modifying enzymes guide gene expression during early oogenesis.

RNA-modifying enzymes targeting mRNA poly(A) tails are universal regulators of post-transcriptional gene expression programs. Current data suggest that an RNA-binding protein (RBP) directed tug-of-war between tail shortening and re-elongating enzymes operates in the cytoplasm to repress or activate specific mRNA targets. While this concept is widely accepted, it was primarily described in the final meiotic stages of frog oogenesis and relies molecularly on a single class of RBPs, i.e. CPEBs, the deadenylase PARN and cytoplasmic poly(A) polymerase GLD-2. Using the spatial and temporal resolution of female gametogenesis in the nematode C. elegans, we determined the distinct roles of known deadenylases throughout germ cell development and discovered that the Ccr4-Not complex is the main antagonist to GLD-2-mediated mRNA regulation. We find that the Ccr4-Not/GLD-2 balance is critical for essentially all steps of oocyte production and reiteratively employed by various classes of RBPs. Interestingly, its two deadenylase subunits appear to affect mRNAs stage specifically: while a Caf1/GLD-2 antagonism regulates mRNA abundance during all stages of oocyte production, a Ccr4/GLD-2 antagonism regulates oogenesis in an mRNA abundance independent manner. Our combined data suggests that the Ccr4-Not complex represents the evolutionarily conserved molecular opponent to GLD-2 providing an antagonistic framework of gene-specific poly(A)-tail regulation.

MAPK signaling couples SCF-mediated degradation of translational regulators to oocyte meiotic progression.

RNA-binding proteins (RBPs) are important regulators of gene expression programs, especially during gametogenesis. How the abundance of particular RBPs is restricted to defined stages of meiosis remains largely elusive. Here, we report a molecular pathway that subjects two nonrelated but broadly evolutionarily conserved translational regulators (CPB-3/CPEB and GLD-1/STAR) to proteosomal degradation in Caenorhabditis elegans germ cells at the transition from pachytene to diplotene of meiotic prophase. Both RBPs are recognized by the same ubiquitin ligase complex, containing the molecular scaffold Cullin-1 and the tumor suppressor SEL-10/FBXW7 as its substrate recognition subunit. Destabilization of either RBP through this Skp, Cullin, F-box-containing complex (SCF) ubiquitin ligase appears to loosen its negative control over established target mRNAs, and presumably depends on a prior phosphorylation of CPB-3 and GLD-1 by MAPK (MPK-1), whose activity increases in mid- to late pachytene to promote meiotic progression and oocyte differentiation. Thus, we propose that the orchestrated degradation of RBPs via MAPK-signaling cascades during germ cell development may act to synchronize meiotic with sexual differentiation gene expression changes.

[Prevention of Surgical Site Infections]. / Prävention postoperativer Wundinfektionen.

The burden of surgical site infections (SSIs) is increasing. The number of surgical procedures continues to rise, and surgical patients present increasingly complex comorbidities. Half of SSIs are deemed preventable using evidence-based strategies. It is recommended for patients to bathe or shower prior to surgery. Hair should be removed only with a clipper. Shaving is strongly discouraged at all times. Antimicrobial prophylaxis should be administered only when indicated, based on guidelines, and timed correctly in order to achieve a bactericidal concentration in the tissues when the incision is made. Prophylaxis must not be continued beyond surgery. For skin preparation in the operating room an alcohol-based agent plus chlorhexidine or octenidine is recommended. During surgery, glycemic control and goal-directed fluid therapy should be implemented. Normothermia should be targeted in all patients. The perioperative use of an increased fraction of inspired oxygen may reduce the risk of SSI. Using a surgical safety checklist during a team time-out immediately before surgery reduces the incidence of SSI.

Polyadenylation is the key aspect of GLD-2 function in C. elegans.

The role of many enzymes extends beyond their dedicated catalytic activity by fulfilling important cellular functions in a catalysis-independent fashion. In this aspect, little is known about 3'-end RNA-modifying enzymes that belong to the class of nucleotidyl transferases. Among these are noncanonical poly(A) polymerases, a group of evolutionarily conserved enzymes that are critical for gene expression regulation, by adding adenosines to the 3'-end of RNA targets. In this study, we investigate whether the functions of the cytoplasmic poly(A) polymerase (cytoPAP) GLD-2 in C. elegans germ cells exclusively depend on its catalytic activity. To this end, we analyzed a specific missense mutation affecting a conserved amino acid in the catalytic region of GLD-2 cytoPAP. Although this mutated protein is expressed to wild-type levels and incorporated into cytoPAP complexes, we found that it cannot elongate mRNA poly(A) tails efficiently or promote GLD-2 target mRNA abundance. Furthermore, germ cell defects in animals expressing this mutant protein strongly resemble those lacking the GLD-2 protein altogether, arguing that only the polyadenylation activity of GLD-2 is essential for gametogenesis. In summary, we propose that all known molecular and biological functions of GLD-2 depend on its enzymatic activity, demonstrating that polyadenylation is the key mechanism of GLD-2 functionality. Our findings highlight the enzymatic importance of noncanonical poly(A) polymerases and emphasize the pivotal role of poly(A) tail-centered cytoplasmic mRNA regulation in germ cell biology.

Essentials in the management of necrotizing soft-tissue infections.

AIMS: Necrotizing soft-tissue infections (NSTI) are rare but severe diseases with rapid progression. Rates of mortality and morbidity are high and early diagnosis, immediate surgical intervention and antibiotic treatment are essential to improve prognosis. Thus, our commentary emphasizes important information in the management of NSTI. METHODS: We describe the essentials in the management of necrotizing soft-tissue infections. RESULTS: Six essentials were identified: 1. Necrotizing soft-tissue infections (NSTI) are primarily diagnosed clinically; pain out of proportion, rapid progression of skin infection and systemic signs should alert clinicians. 2. Early diagnosis can be rather delayed by several factors such as absence of fever, significant cutaneous manifestations, elevation of inflammatory parameters, systemic signs, and non-specific imaging tests. 3. NSTI can occur both in the elderly or patients with underlying diseases after major trauma (usually polymicrobial Gram-negative and Gram-positive pathogens) but also in healthy patients after minor trauma (often monomicrobial; most common among Gram-positive organisms: group A Streptococcus). 4. Immediate and radical debridement (incl. re-debridement after 24 h) remains the cornerstone of surgical therapy. 5. Empirical broad-spectrum antimicrobial treatment has to be administered shortly after admission. After isolation of the causative bacteria therapy should be tailored. 6. The value of adjunctive measures (hyperbaric oxygen therapy, intravenous immunoglobulines) is uncertain and their routine use cannot be recommended. Further efforts should be undertaken to increase the awareness for and the adherence to the essentials in the management of necrotizing soft-tissue infections.

S2k guidelines for skin and soft tissue infections Excerpts from the S2k guidelines for "calculated initial parenteral treatment of bacterial infections in adults - update 2018".

These first German S2k guidelines for bacterial skin and soft tissue infections were developed as one chapter of the recommendations for "calculated initial parenteral treatment of bacterial infections" issued under the auspices of the Paul-Ehrlich Society, of which the main part is presented here. Well-calculated antibiotic therapies require precise diagnostic criteria. Erysipelas is defined as non-purulent infection considered to be caused by beta-hemolytic strepto-cocci. It is diagnosed clinically by its bright-red erythema and early fever or chills at disease onset. Penicillin is the treatment of choice. Limited soft tissue infection (cellulitis) is usually caused by Staphylococcus (S.) aureus, frequently originates from chronic wounds and presents with a more violaceous-red hue and only rarely with initial fever or chills. Treatment consists of first- or second--generation cephalosporins or flucloxacillin (IV). Severe cellulitis is a purulent, partially necrotic infection which extends through tissue boundaries to fascias and requires surgical management in addition to antibiotics. Moreover, it frequently fulfills the criteria for "complicated soft tissue infections", as previously defined by the Food and Drug Administration for use in clinical trials (they include comorbidities such as uncontrolled diabetes, peripheral artery disease, neutropenia). It requires antibiotics which besides S. aureus target anaerobic and/or gramnegative bacteria. The rare so-called necrotizing skin and soft tissue infections represent a distinct entity. They are characterized by rapid, life-threatening progression due to special bacterial toxins that cause ischemic necrosis and shock and need rapid and thorough debridement in addition to appropriate antibiotics. For cutaneous abscesses the first-line treatment is adequate drainage. Additional antibiotic therapy is required only under certain circumstances (e.g., involvement of the face, hands, or anogenital region, or if drainage is somehow complicated). The present guidelines also contain consensus-based recommendations for higher doses of antibiotics than those approved or usually given in clinical trials. The goal is to deliver rational antibiotic treatment that is both effective and well-tolerated and that exerts no unnecessary selection pressure in terms of multidrug resistance.

When to switch to an oral treatment and/or to discharge a patient with skin and soft tissue infections.

PURPOSE OF REVIEW: Skin and soft tissue infections prevalence is increasing and represent a frequent cause of hospital admission. New guidelines have become available in order to better define these infections and their response to antimicrobial treatment. Gram-positive bacteria, in particular Staphylococcus aureus, remain the most frequently isolated pathogens in skin and soft tissue infections. To treat complicated forms and infections caused by drug-resistant bacteria, hospital admission and administration of intravenous antibiotics are often required, impacting on healthcare costs and patients' morbidity. RECENT FINDINGS: New therapeutic options offer efficacy against drug-resistant Gram-positive bacteria as well as potential to favor early patients' discharge, including the possibility for intravenous to oral switch and infrequent drug administration because of prolonged drug half-life. Although data from real-world studies on new antimicrobials is awaited, clinicians need clear direction on how to optimize the treatment of skin and soft tissue infections in order to avoid prolonged hospitalizations and extra costs. Early assessment of patient's clinical conditions and response to treatment appear useful in order to facilitate patients' discharge. SUMMARY: We have reported the evidence for early intravenous to oral switch and early hospital discharge for patients with skin and soft tissue infections. New therapeutic options that represent promising tools in promoting an optimized management of these infections have also been reviewed.

Structural basis for the antagonistic roles of RNP-8 and GLD-3 in GLD-2 poly(A)-polymerase activity.

Cytoplasmic polyadenylation drives the translational activation of specific mRNAs in early metazoan development and is performed by distinct complexes that share the same catalytic poly(A)-polymerase subunit, GLD-2. The activity and specificity of GLD-2 depend on its binding partners. In Caenorhabditis elegans, GLD-2 promotes spermatogenesis when bound to GLD-3 and oogenesis when bound to RNP-8. GLD-3 and RNP-8 antagonize each other and compete for GLD-2 binding. Following up on our previous mechanistic studies of GLD-2-GLD-3, we report here the 2.5 Å resolution structure and biochemical characterization of a GLD-2-RNP-8 core complex. In the structure, RNP-8 embraces the poly(A)-polymerase, docking onto several conserved hydrophobic hotspots present on the GLD-2 surface. RNP-8 stabilizes GLD-2 and indirectly stimulates polyadenylation. RNP-8 has a different amino-acid sequence and structure as compared to GLD-3. Yet, it binds the same surfaces of GLD-2 by forming alternative interactions, rationalizing the remarkable versatility of GLD-2 complexes.

Attitudes of physicians from 10 European countries on adherence and how treatment modalities in ABSSSI affect adherence: results from a Delphi survey.

To explore the attitudes of European physicians on adherence and how treatment modalities impact adherence in complicated forms of soft skin and skin structure infections, now referred as acute bacterial skin and skin structures infections (ABSSSI). After literature review, a questionnaire was prepared. Topics focused on (1) the importance of adherence, (2) the importance of administration regimen on adherence, (3) the importance of drug selection on adherence, (4) the importance of complexity on choice of drug for treatment, (5) the role of adherence in drug resistance, and (6) the role of adherence in administration of long-acting antibiotics (ABs). The questionnaire was administered to 323 European infectious diseases specialists, of whom 74% responded. A modified Delphi method was used to obtain the highest consensus. Results varied by countries. We found a high degree of agreement of the importance of adherence in ABSSSI treatment. Experts agreed that complexity of patient's conditions, drug selection, drug resistance, the type of regimen, and the number of infusions impact adherence. Two items linking oral switching and adherence did not reach consensus. Adherence for ABSSSI therapies appears a crucial factor for therapeutic management and reduces the risk of AB resistance. Among new treatment opportunities, long-acting agents, with their characteristics, may represent an interesting options.

Correction to: Attitudes of physicians from 10 European countries on adherence and how treatment modalities in ABSSSI affect adherence: results from a Delphi survey.

In the originally published article, the name of the last author was not correct. The name is Paolo Antonio Grossi, which is correctly shown above.

Structural basis for the activation of the C. elegans noncanonical cytoplasmic poly(A)-polymerase GLD-2 by GLD-3.

The Caenorhabditis elegans germ-line development defective (GLD)-2-GLD-3 complex up-regulates the expression of genes required for meiotic progression. GLD-2-GLD-3 acts by extending the short poly(A) tail of germ-line-specific mRNAs, switching them from a dormant state into a translationally active state. GLD-2 is a cytoplasmic noncanonical poly(A) polymerase that lacks the RNA-binding domain typical of the canonical nuclear poly(A)-polymerase Pap1. The activity of C. elegans GLD-2 in vivo and in vitro depends on its association with the multi-K homology (KH) domain-containing protein, GLD-3, a homolog of Bicaudal-C. We have identified a minimal polyadenylation complex that includes the conserved nucleotidyl-transferase core of GLD-2 and the N-terminal domain of GLD-3, and determined its structure at 2.3-Å resolution. The structure shows that the N-terminal domain of GLD-3 does not fold into the predicted KH domain but wraps around the catalytic domain of GLD-2. The picture that emerges from the structural and biochemical data are that GLD-3 activates GLD-2 both indirectly by stabilizing the enzyme and directly by contributing positively charged residues near the RNA-binding cleft. The RNA-binding cleft of GLD-2 has distinct structural features compared with the poly(A)-polymerases Pap1 and Trf4. Consistently, GLD-2 has distinct biochemical properties: It displays unusual specificity in vitro for single-stranded RNAs with at least one adenosine at the 3' end. GLD-2 thus appears to have evolved specialized nucleotidyl-transferase properties that match the 3' end features of dormant cytoplasmic mRNAs.

The disordered P granule protein LAF-1 drives phase separation into droplets with tunable viscosity and dynamics.

P granules and other RNA/protein bodies are membrane-less organelles that may assemble by intracellular phase separation, similar to the condensation of water vapor into droplets. However, the molecular driving forces and the nature of the condensed phases remain poorly understood. Here, we show that the Caenorhabditis elegans protein LAF-1, a DDX3 RNA helicase found in P granules, phase separates into P granule-like droplets in vitro. We adapt a microrheology technique to precisely measure the viscoelasticity of micrometer-sized LAF-1 droplets, revealing purely viscous properties highly tunable by salt and RNA concentration. RNA decreases viscosity and increases molecular dynamics within the droplet. Single molecule FRET assays suggest that this RNA fluidization results from highly dynamic RNA-protein interactions that emerge close to the droplet phase boundary. We demonstrate than an N-terminal, arginine/glycine rich, intrinsically disordered protein (IDP) domain of LAF-1 is necessary and sufficient for both phase separation and RNA-protein interactions. In vivo, RNAi knockdown of LAF-1 results in the dissolution of P granules in the early embryo, with an apparent submicromolar phase boundary comparable to that measured in vitro. Together, these findings demonstrate that LAF-1 is important for promoting P granule assembly and provide insight into the mechanism by which IDP-driven molecular interactions give rise to liquid phase organelles with tunable properties.

GLD-4-mediated translational activation regulates the size of the proliferative germ cell pool in the adult C. elegans germ line.

To avoid organ dysfunction as a consequence of tissue diminution or tumorous growth, a tight balance between cell proliferation and differentiation is maintained in metazoans. However, cell-intrinsic gene expression mechanisms controlling adult tissue homeostasis remain poorly understood. By focusing on the adult Caenorhabditis elegans reproductive tissue, we show that translational activation of mRNAs is a fundamental mechanism to maintain tissue homeostasis. Our genetic experiments identified the Trf4/5-type cytoplasmic poly(A) polymerase (cytoPAP) GLD-4 and its enzymatic activator GLS-1 to perform a dual role in regulating the size of the proliferative zone. Consistent with a ubiquitous expression of GLD-4 cytoPAP in proliferative germ cells, its genetic activity is required to maintain a robust proliferative adult germ cell pool, presumably by regulating many mRNA targets encoding proliferation-promoting factors. Based on translational reporters and endogenous protein expression analyses, we found that gld-4 activity promotes GLP-1/Notch receptor expression, an essential factor of continued germ cell proliferation. RNA-protein interaction assays documented also a physical association of the GLD-4/GLS-1 cytoPAP complex with glp-1 mRNA, and ribosomal fractionation studies established that GLD-4 cytoPAP activity facilitates translational efficiency of glp-1 mRNA. Moreover, we found that in proliferative cells the differentiation-promoting factor, GLD-2 cytoPAP, is translationally repressed by the stem cell factor and PUF-type RNA-binding protein, FBF. This suggests that cytoPAP-mediated translational activation of proliferation-promoting factors, paired with PUF-mediated translational repression of differentiation factors, forms a translational control circuit that expands the proliferative germ cell pool. Our additional genetic experiments uncovered that the GLD-4/GLS-1 cytoPAP complex promotes also differentiation, forming a redundant translational circuit with GLD-2 cytoPAP and the translational repressor GLD-1 to restrict proliferation. Together with previous findings, our combined data reveals two interconnected translational activation/repression circuitries of broadly conserved RNA regulators that maintain the balance between adult germ cell proliferation and differentiation.

Two conserved regulatory cytoplasmic poly(A) polymerases, GLD-4 and GLD-2, regulate meiotic progression in C. elegans.

Translational regulation is heavily employed during developmental processes to control the timely accumulation of proteins independently of gene transcription. In particular, mRNA poly(A) tail metabolism in the cytoplasm is a key determinant for balancing an mRNA's translational output and its decay rate. Noncanonical poly(A) polymerases (PAPs), such as germline development defective-2 (GLD-2), can mediate poly(A) tail extension. Little is known about the regulation and functional complexity of cytoplasmic PAPs. Here we report the discovery of Caenorhabditis elegans GLD-4, a cytoplasmic PAP present in P granules that is orthologous to Trf4/5p from budding yeast. GLD-4 enzymatic activity is enhanced by its interaction with GLS-1, a protein associated with the RNA-binding protein GLD-3. GLD-4 is predominantly expressed in germ cells, and its activity is essential for early meiotic progression of male and female gametes in the absence of GLD-2. For commitment into female meiosis, both PAPs converge on at least one common target mRNA-i.e., gld-1 mRNA-and, as a consequence, counteract the repressive action of two PUF proteins and the putative deadenylase CCR-4. Together our findings suggest that two different cytoplasmic PAPs stabilize and translationally activate several meiotic mRNAs to provide a strong fail-safe mechanism for early meiotic progression.