Discovery of 3-((4-Benzylpyridin-2-yl)amino)benzamides as Potent GPR52 G Protein-Biased Agonists.

Orphan GPR52 is emerging as a promising neurotherapeutic target. Optimization of previously reported lead 4a employing an iterative drug design strategy led to the identification of a series of unique GPR52 agonists, such as 10a (PW0677), 15b (PW0729), and 24f (PW0866), with improved potency and efficacy. Intriguingly, compounds 10a and 24f showed greater bias for G protein/cAMP signaling and induced significantly less in vitro desensitization than parent compound 4a, indicating that reducing GPR52 ß-arrestin activity with biased agonism results in sustained GPR52 activation. Further exploration of compounds 15b and 24f indicated improved potency and efficacy, and excellent target selectivity, but limited brain exposure warranting further optimization. These balanced and biased GPR52 agonists provide important pharmacological tools to study GPR52 activation, signaling bias, and therapeutic potential for neuropsychiatric and neurological diseases.

Macromolecular Crowding by Polyethylene Glycol Reduces Protein Breathing.

Most efforts to understand macromolecular crowding focus on global (i.e., complete) unfolding, but smaller excursions, often called breathing, promote aggregation, which is associated with several diseases and the bane of pharmaceutical and commercial protein production. We used NMR to assess the effects of ethylene glycol (EG) and polyethylene glycols (PEGs) on the structure and stability of the B1 domain of protein G (GB1). Our data show that EG and PEGs stabilize GB1 differently. EG interacts with GB1 more strongly than PEGs, but neither affects the structure of the folded state. EG and 12000 g/mol PEG stabilize GB1 more than PEGs of intermediate size, but EG and smaller PEGs stabilize GB1 enthalpically while the largest PEG acts entropically. Our key finding is that PEGs turn local unfolding into global unfolding, and meta-analysis of published data supports this conclusion. These efforts provide knowledge that can be applied to improve biological drugs and commercial enzymes.

14-3-3γ mediates the long-term inhibition of peripheral kappa opioid receptor antinociceptive signaling by norbinaltorphimine.

Long-term inhibition of kappa opioid receptor (KOR) signaling in peripheral pain-sensing neurons is a potential obstacle for development of peripherally-restricted KOR agonists that produce analgesia. Such a long-term inhibitory mechanism is invoked from activation of c-Jun N-terminal kinase (JNK) that follows a single injection of the KOR antagonist norbinaltorphimine (norBNI). This effect requires protein synthesis of an unknown mediator in peripheral pain-sensing neurons. Using 2D difference gel electrophoresis with tandem mass spectrometry, we have identified that the scaffolding protein 14-3-3γ is upregulated in peripheral sensory neurons following activation of JNK with norBNI. Knockdown of 14-3-3γ by siRNA eliminates the long-term reduction in KOR-mediated cAMP signaling by norBNI in peripheral sensory neurons in culture. Similarly, knockdown of 14-3-3γ in the rat hind paw abolished the norBNI-mediated long-term reduction in peripheral KOR-mediated antinociception. Further, overexpression of 14-3-3γ in KOR expressing CHO cells prevented KOR-mediated inhibition of cAMP signaling. These long-term effects are selective for KOR as heterologous regulation of other receptor systems was not observed. These data suggest that 14-3-3γ is both necessary and sufficient for the long-term inhibition of KOR by norBNI in peripheral sensory neurons.

Age-related changes in peripheral nociceptor function.

Pain and pain management in the elderly population is a significant social and medical problem. Pain sensation is a complex phenomenon that typically involves activation of peripheral pain-sensing neurons (nociceptors) which send signals to the spinal cord and brain that are interpreted as pain, an unpleasant sensory experience. In this work, young (4-5 months) and aged (26-27 months) Fischer 344 x Brown Norway (F344xBN) rats were examined for nociceptor sensitivity to activation by thermal (cold and heat) and mechanical stimulation following treatment with inflammatory mediators and activators of transient receptor potential (TRP) channels. Unlike other senses that decrease in sensitivity with age, sensitivity of hindpaw nociceptors to thermal and mechanical stimulation was not different between young and aged F344xBN rats. Intraplantar injection of bradykinin (BK) produced greater thermal and mechanical allodynia in aged versus young rats, whereas only mechanical allodynia was greater in aged rats following injection of prostaglandin E2 (PGE2). Intraplantar injection of TRP channel activators, capsaicin (TRPV1), mustard oil (TRPA1) and menthol (TRPM8) each resulted in greater mechanical allodynia in aged versus young rats and capsaicin-induced heat allodynia was also greater in aged rats. A treatment-induced allodynia that was greater in young rats was never observed. The anti-allodynic effects of intraplantar injection of kappa and delta opioid receptor agonists, salvinorin-A and D-Pen2,D-Pen5]enkephalin (DPDPE), respectively, were greater in aged than young rats, whereas mu opioid receptor agonists, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) and morphine, were not effective in aged rats. Consistent with these observations, in primary cultures of peripheral sensory neurons, inhibition of cAMP signaling in response to delta and kappa receptor agonists was greater in cultures derived from aged rats. By contrast, mu receptor agonists did not inhibit cAMP signaling in aged rats. Thus, age-related changes in nociceptors generally favor increased pain signaling in aged versus young rats, suggesting that changes in nociceptor sensitivity may play a role in the increased incidence of pain in the elderly population. These results also suggest that development of peripherally-restricted kappa or delta opioid receptor agonists may provide safer and effective pain relief for the elderly.

Investigating the secondary care system burden of CRSwNP in sinus surgery patients with clinically relevant comorbidities using the HES database.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic condition that can adversely affect quality of life for patients. There is no cure for CRSwNP, and patients may require intermittent systemic corticosteroids (SCS) and surgery in addition to intranasal treatment throughout their lifetime. This places a significant burden on the NHS which can be compounded by comorbid conditions such as asthma or NSAID-exacerbated respiratory disease (NERD). Patients with comorbidities are likely to experience higher rates of surgery and more secondary care visits. The aim of this study was to evaluate revision rates and the associated burden for patients with CRSwNP undergoing surgery and compare this to sub-cohorts of patients with comorbidities. MATERIALS AND METHODS: This study has utilised the Hospital Episodes Statistics (HES) database across a ten-year time period (April 2010 to March 2020) to investigate the NHS resource use attributable to CRSwNP for all patients with the condition who have undergone sinus surgery, and to examine the burden of clinically relevant sub-groups. RESULTS: Our results showed that 101,054 patients underwent at least one sinus surgery in relation to their nasal polyps, with Kaplan Meier survival analysis estimating that the 10-year probability of revision is between 71-90% for comorbid patients, and 51% for non-comorbid patients. Patients with a relevant comorbid condition in addition to their CRSwNP were up to 4.7 times more likely to undergo at least one revision surgery during the ten-year analytical time window when compared to patients without a comorbidity. Further to this, comorbid patients had a higher tariff associated with their CRSwNP care across the analytical time window and were therefore likely to be more costly to the healthcare system. CONCLUSIONS: In conclusion, this study demonstrates that there is a high burden attached to CRSwNP-related sinus surgery and that comorbidities are a key driver of NHS resource use.

Long-term antagonism and allosteric regulation of mu opioid receptors by the novel ligand, methocinnamox.

Opioid overdose is a leading cause of death in the United States. The only treatment available currently is the competitive antagonist, naloxone (Narcan® ). Although naloxone is very effective and has saved many lives, as a competitive antagonist it has limitations. Due to the short half-life of naloxone, renarcotization can occur if the ingested opioid agonist remains in the body longer. Moreover, because antagonism by naloxone is surmountable, renarcotization can also occur in the presence of naloxone if a relatively larger dose of opioid agonist is taken. In such circumstances, a long-lasting, non-surmountable antagonist would offer an improvement in overdose treatment. Methocinnamox (MCAM) has been reported to have a long duration of antagonist action at mu opioid receptors in vivo. In HEK cells expressing the human mu opioid receptor, MCAM antagonism of mu agonist-inhibition of cAMP production was time-dependent, non-surmountable and non-reversible, consistent with (pseudo)-irreversible binding. In vivo, MCAM injected locally into the rat hindpaw antagonized mu agonist-mediated inhibition of thermal allodynia for up to 96 h. By contrast, antagonism by MCAM of delta or kappa agonists in HEK cells and in vivo was consistent with simple competitive antagonism. Surprisingly, MCAM also shifted the concentration-response curves of mu agonists in HEK cells in the absence of receptor reserve in a ligand-dependent manner. The shift in the [D-Ala2 ,N-MePhe4 ,Gly-ol5 ]-enkephalin (DAMGO) concentration-response curve by MCAM was insensitive to naloxone, suggesting that in addition to (pseudo)-irreversible orthosteric antagonism, MCAM acts allosterically to alter the affinity and/or intrinsic efficacy of mu agonists.

Treatment outcomes of patients with Atopic Dermatitis (AD) treated with dupilumab through the Early Access to Medicines Scheme (EAMS) in the UK.

BACKGROUND: Dupilumab, a monoclonal antibody against interleukin (IL)-4 receptor alpha that inhibits IL-4/IL-13 signalling is indicated in dermatology for the treatment of moderate-to-severe atopic dermatitis (AD) in adult and adolescent patients 12 years and older and severe AD in children 6-11 years, who are candidates for systemic therapy. Dupilumab received Early Access to Medicines Scheme (EAMS) approval for adults in March 2017. OBJECTIVES: The purpose of this study was to assess the efficacy outcomes of treatment with dupilumab in EAMS. METHODS: A retrospective analysis of adult patients enrolled in the dupilumab EAMS in the UK. Scores were assessed at baseline and follow up, including the Eczema Area and Severity Index (EASI), Investigator's Global Assessment Score (IGA) and Dermatology Life Quality Index (DLQI). RESULTS: Data were available for 57 adult patients treated with dupilumab for at least 12 weeks; 73.6% of patients had received prior treatment with 3 or 4 immunosuppressants. Baseline scores for the EASI and DLQI were 27.93 (standard deviation, SD 13.09) and 18.26 (SD 6.18) respectively. AD severity scores showed statistically significant improvement at week 16±4 weeks (p <0.001 for all). The mean change in EASI was 14.13 points with 66.7% and 36.7% achieving a 50% (EASI-50) and 75% (EASI-75) improvement in EASI, respectively at 16+/- 4 weeks. IGA scores improved by at least two categories for 75% patients. DLQI scores decreased by a mean of 9.0 points, with 80% patients demonstrating a MCID 4-point improvement. For 85% patients, clinicians rated the treatment response as being either 'better' (19%) or 'much better' (65%). CONCLUSIONS: Dupilumab is associated with a significant and clinically relevant improvements in AD as measured by patient- and physician-reported outcome measures. Importantly, the clinical efficacy, despite the refractory disease of this EAMS cohort, is comparable to that previously reported in clinical trials.

Household Rules regarding Cannabis Use and Tobacco Smoking in Denver Airbnb Venues.

Cannabis legalization threatens to undermine clean indoor air norms. We investigated the prevalence and nature of tobacco and cannabis use rules in Airbnb venues in Denver, Colorado, where recreational cannabis was legalized in 2014. The study used publicly available Inside Airbnb data for all Denver listings (N = 4,511) collected on 06/29/2019. We analyzed reported tobacco smoking and cannabis use house rules. Tobacco smoking with or without conditions was allowed in 9.7% of venues. Of all venues, 23.7% included details about cannabis use. Of these, 75.9% allowed cannabis use without or with conditions. Of the venues that allowed cannabis use, 30.5% also allowed tobacco smoking. Of the venues that did not allow cannabis use, 0.4% allowed tobacco smoking. Additional multilevel regression models revealed that venues in higher income neighborhoods were less likely to allow cannabis and tobacco use. A substantial number of Airbnb listings in Denver, Colorado permit cannabis use and venues permitting cannabis use may be more likely to also permit tobacco smoking. Findings support the idea that cannabis legalization threatens clean indoor air norms. Airbnb should consider including cannabis use in house rules in jurisdictions that have legalized cannabis to help guests identify spaces with clean air.

Supplementing neonatal Jersey calves with a blend of probiotic bacteria improves the pathophysiological response to an oral Salmonella enterica serotype Typhimurium challenge.

The objectives of the current study were to determine the effects of supplementing a blend of probiotic bacteria (Provida Calf, MB Nutritional Sciences, Lubbock, TX) on the pathophysiological response to an oral Salmonella enterica serotype Typhimurium challenge in neonatal Jersey calves. Twenty-four Jersey bull calves within 24 h of birth were acquired from a local calf ranch, blocked by total serum protein and initial body weight, and randomly assigned to 1 of 3 treatments (n = 8). Calves were assigned to either (1) Control (CON); base milk replacer, (2) Control + Salmonella Typhimurium (CON+ST); base milk replacer and challenged with Salmonella Typhimurium on d 7; or (3) Provida Calf probiotics + Salmonella Typhimurium (PRO+ST); same milk replacer supplemented with a proprietary blend of Lactobacillus casei and Enterococcus faecium strains and challenged with Salmonella Typhimurium on d 7. The PRO+ST calves were supplemented for the first 3 d with 2 × 1010 cfu/d and then with 2 × 109 cfu/d for the remainder of the study. The CON+ST and PRO+ST calves were each challenged with approximately 5 × 106 cfu of Salmonella Typhimurium (ATCC# 14028), which was a mild challenge that did not cause scours in the calves. Peripheral blood samples were collected on d 0, 7, 10, 14, and 21 and analyzed for hematology; serum was collected and analyzed for haptoglobin, glucose, and urea N. Rectal temperatures were collected daily from d 6 to 21, when all calves were killed, so that persistent colonization of Salmonella Typhimurium and histomorphology of both the duodenum and ileum could be determined. Serum haptoglobin and urea N concentrations were increased among CON+ST on d 10. In contrast, the peak rectal temperature on d 10 in PRO+ST calves was 40.4°C, which was greater than that for CON and CON-ST (38.9°C and 39.7°C, respectively). The neutrophil percentage in peripheral circulation in PRO+ST calves was 55.4%, which was greater than that for CON and CON+ST (34.8 and 41.8%, respectively). Seven of the 8 PRO+ST calves had elevated neutrophil percentages on d 10 compared with d 7, whereas 4 of the 8 CON+ST calves had reduced neutrophil percentages on d 10 compared with d 7. Villus height-to-crypt depth ratios in the duodenum were greater among CON and PRO+ST calves, being 1.38, 0.84, and 1.43 for CON, CON+ST, and PRO+ST, respectively. In the ileum, the PRO+ST calves had greater villus height-to-crypt depth ratios than both the CON and CON+ST calves (1.64, 1.53, and 2.43 for CON, CON+ST, and PRO+ST, respectively). These data indicate that supplementing neonatal calves with the blend of probiotic bacteria used in the current study can influence the pathophysiological response to a mild enteric Salmonella Typhimurium challenge.

Reported fire safety and first-aid amenities in Airbnb venues in 16 American cities.

Airbnb helps hosts rent all or part of their home to guests as an alternative to traditional hospitality settings. Airbnb venues are not uniformly regulated across the USA. This study quantified the reported prevalence of fire safety and first-aid amenities in Airbnb venues in the USA. The sample includes 120 691 venues in 16 US cities. Proportions of host-reported smoke and carbon monoxide (CO) detectors, fire extinguishers and first-aid kits were calculated. The proportion of venues that reportedly contained amenities are as follows: smoke detectors 80% (n=96 087), CO detectors 57.5% (n=69 346), fire extinguishers 42% (n=50 884) and first-aid kits 36% (n=43 497). Among this sample of Airbnb venues, safety deficiencies were noted. While most venues had smoke alarms, approximately 1/2 had CO alarms and less than 1/2 reported having a fire extinguishers or first-aid kits. Local and state governments or Airbnb must implement regulations compliant with current National Fire Protection Association fire safety standards.

Patterning and Reversible Actuation of Liquid Gallium Alloys by Preventing Adhesion on Rough Surfaces.

This work reports a simple approach to form, study, and utilize rough coatings that prevent the adhesion of gallium-based liquid metal alloys. Typically, liquids with large interfacial tension do not wet nonreactive surfaces, regardless of surface topography. However, these alloys form a surface oxide "skin" that adheres to many substrates, even those with low surface energy. This work reports a simple approach to render closed channels and surfaces, including soft materials, to be "oxide-phobic" via spray-coating (NeverWet, which is commercially available and inexpensive). Surface spectroscopic techniques and metrology tools elucidate the coatings to comprise silica nanoparticles grafted with silicones that exhibit dual length scales of roughness. Although prior work shows the importance of surface roughness in preventing adhesion, the present work confirms that both hydrophobic and hydrophilic rough surfaces prevent oxide adhesion. Furthermore, the coating enables reversible actuation through submillimeter closed channels to form a reconfigurable antenna in the gigahertz range without the need for corrosive acids or bases that remove the oxide. In addition, the coating enables open surface patterning of conductive traces of liquid metal. This shows it is possible to actuate liquid metals in air without leaving neither metal nor oxide residue on surfaces to enable reconfigurable electronics, microfluidics, and soft electrodes.

Poly(meta-phenylene oxides) for the design of a tunable, efficient, and reusable catalytic platform.

We present poly(meta-phenylene oxides) as versatile and tunable scaffolds for immobilized catalyst design. Their modular synthesis enables the rational incorporation of different side chain groups with positional control along the polymer backbone, providing an easy means to modulate polymer properties, and their corresponding catalytic activity. The coordinative convolution of these polymers with (NH4)2PdCl4 affords efficient, reusable catalysts for various organic transformations.

Radiation chemistry of solid acetone in the interstellar medium - a new dimension to an old problem.

A laboratory investigation of acetone, an interstellar and cometary molecule, has produced new results concerning its decomposition in a radiation environment. Mid-infrared spectroscopy has been used to follow amorphous acetone's destruction by ionizing radiation (1 MeV protons) at 20 K. Radiation products identified are the CH4, CO, and CO2 usually made in such experiments, along with ketene, allene, and the acetonyl radical, all identified here for the first time in irradiated solid acetone. Evidence for the reduction product 2-propanol was suggestive, but a firm identification could not be made either for it or for the C2 hydrocarbons (i.e., C2H6, C2H4, C2H2). The acetyl radical was not observed as a radiation product. Isotopically labeled reagents were used to demonstrate ketene formation and to emphasize that multiple approaches are needed for robust assignments of infrared spectral features of irradiated icy solids. Results from a supporting radiation experiment with isotopically labeled acetic acid are described. Comparisons are made to a previous study of acetone's stability in extraterrestrial radiation environments, and caution is urged in measuring and interpreting CO abundances in irradiated icy solids.

Pharmacological augmentation of nicotinamide phosphoribosyltransferase (NAMPT) protects against paclitaxel-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) arises from collateral damage to peripheral afferent sensory neurons by anticancer pharmacotherapy, leading to debilitating neuropathic pain. No effective treatment for CIPN exists, short of dose-reduction which worsens cancer prognosis. Here, we report that stimulation of nicotinamide phosphoribosyltransferase (NAMPT) produced robust neuroprotection in an aggressive CIPN model utilizing the frontline anticancer drug, paclitaxel (PTX). Daily treatment of rats with the first-in-class NAMPT stimulator, P7C3-A20, prevented behavioral and histologic indicators of peripheral neuropathy, stimulated tissue NAD recovery, improved general health, and abolished attrition produced by a near maximum-tolerated dose of PTX. Inhibition of NAMPT blocked P7C3-A20-mediated neuroprotection, whereas supplementation with the NAMPT substrate, nicotinamide, potentiated a subthreshold dose of P7C3-A20 to full efficacy. Importantly, P7C3-A20 blocked PTX-induced allodynia in tumored mice without reducing antitumoral efficacy. These findings identify enhancement of NAMPT activity as a promising new therapeutic strategy to protect against anticancer drug-induced peripheral neurotoxicity.

Infrared spectra and band strengths of amorphous and crystalline N2O.

Infrared transmission spectra from 4000 to 400 cm-1, and associated band strengths and absorption coefficients, are presented for the first time for both amorphous and crystalline N2O. Changes in the spectra as a function of ice thickness and ice temperature are shown. New measurements of density, refractive index, and specific refraction are reported for amorphous and crystalline N2O. Comparisons are made to published results, and the most-likely reason for some recent disagreements in the literature is discussed. As with CO2, its isoelectronic congener, the formation of amorphous N2O is found to require greater care than the formation of amorphous solids from more-polar molecules.

Infrared spectra and band strengths of CH3SH, an interstellar molecule.

Three solid phases of CH3SH (methanethiol or methyl mercaptan) have been prepared and their mid-infrared spectra recorded at 10-110 K, with an emphasis on the 17-100 K region. Refractive indices have been measured at two temperatures and used to estimate ice densities and infrared band strengths. Vapor pressures for the two crystalline phases of CH3SH at 110 K are estimated. The behavior of amorphous CH3SH on warming is presented and discussed in terms of Ostwald's step rule. Comparisons to CH3OH under similar conditions are made, and some inconsistencies and ambiguities in the CH3SH literature are examined and corrected.

Enhanced oral delivery of celecoxib via the development of a supersaturable amorphous formulation utilising mesoporous silica and co-loaded HPMCAS.

Stabilization of amorphous formulations via mesoporous silica has gained considerable attention for oral delivery of poorly soluble drugs. The release of the drug from the silica is expected to generate supersaturation which is often associated with subsequent precipitation. The aim of the study was hence to develop a novel supersaturable amorphous formulation through the co-loading of a BCS class II drug Celecoxib (CXB) with a precipitation inhibitor hydroxypropyl methylcellulose acetate succinate (HPMCAS) onto the silica. The addition of HPMCAS did not hamper the adsorption but on the contrary promoted the complete solid state conversion of the drug as proved by DSC analysis. In an in vitro pH shift assay, the CXB-HPMCAS co-loaded silica achieved a 5-fold solubility increase over the crystalline CXB and over the CXB-loaded silica blended with HPMCAS which did not show any enhancement. The drug co-loaded silica was then suspended in an aqueous vehicle facilitating the dosing to animals. The CXB-HPMCAS co-loaded silica suspension achieved 15-fold solubility increase in vitro over the crystalline counterpart which translated in 1.35-fold Cmax increase in vivo after oral dosing in rats. This approach represents a novel formulation strategy to maximize in vivo exposure of poorly soluble drugs critical for discovery studies.

Estimating the impact of better management of glycaemic control in adults with Type 1 and Type 2 diabetes on the number of clinical complications and the associated financial benefit.

AIM: To estimate potential cost avoidance through modest and achievable improvements in glycaemic control in adults with Type 1 or Type 2 diabetes mellitus in the UK healthcare system. METHODS: The IMS Core Diabetes Model was used to examine the impact of improved glycaemic control (indicated by reduction in HbA1c level), in a representative cohort of adults with Type 1 or Type 2 diabetes. The cumulative incidence of microvascular and macrovascular complications was modelled across 5-year periods to a 25-year time horizon. Complication costs were applied to the data to estimate potential accrued cost avoidance. RESULTS: Significant cost avoidance of ~£340 m is apparent in the first 5 years, increasing to ~£5.5bn after 25 years of sustained improvement in control. The overwhelming majority of cost avoidance arises from reductions in microvascular complications. In people with Type 1 diabetes the greatest cost avoidance comes from a reduction in renal disease (74% of cost avoidance), while in people with Type 2 diabetes it is generated by a reduction in foot ulcers, amputations and neuropathy: 57% cost avoidance). Greater cost reduction is accrued more rapidly in people with higher starting HbA1c levels. CONCLUSION: Modest improvements in glycaemic control generate significant reductions in the incidence and, therefore, cost of microvascular complications in people with Type 1 or Type 2 diabetes. This study provides clear support for the premise that prioritized and sustained investment in early and better intervention can provide concrete financial benefits in both the short and longer term.

Mothers and offspring: The rabbit as a model system in the study of mammalian maternal behavior and sibling interactions.

UNLABELLED: This article is part of a Special Issue "Parental Care". Jay Rosenblatt effectively promoted research on rabbit maternal behavior through his interaction with colleagues in Mexico. Here we review the activities of pregnant and lactating rabbits (Oryctolagus cuniculus), their neuro-hormonal regulation, and the synchronization of behavior between mother and kits. Changing concentrations of estradiol, progesterone, and prolactin throughout gestation regulate nest-building (digging, straw-carrying, fur-pulling) and prime the mother's brain to respond to the newborn. Nursing is the only mother-young contact throughout lactation. It happens once/day, inside the nest, with ca. 24h periodicity, and lasts around 3min. Periodicity and duration of nursing depend on a threshold of suckling as procedures reducing the amount of nipple stimulation interfere with the temporal aspects of nursing, though not with the doe's maternal motivation. Synchronization between mother and kits, critical for nursing, relies on: a) the production of pheromonal cues which guide the young to the mother's nipples for suckling; b) an endogenous circadian rhythm of anticipatory activity in the young, present since birth. Milk intake entrains the kits' locomotor behavior, corticosterone secretion, and the activity of several brain structures. Sibling interactions within the huddle, largely determined by body mass at birth, are important for: a) maintaining body temperature; b) ensuring normal neuromotor and social development. Suckling maintains nursing behavior past the period of abundant milk production but abrupt and efficient weaning occurs in concurrently pregnant-lactating does by unknown factors. CONCLUSION: female rabbits have evolved a reproductive strategy largely dissociating maternal care from maternal presence, whose multifactorial regulation warrants future investigations.